TW202535408A - Ruxolitinib for treating hidradenitis suppurativa (hs) - Google Patents

Abstract

This disclosure relates to methods for treating patients with hidradenitis suppurativa (HS) by administering a ruxolitinib formulation one to two times per day. In some instances, the patient has mild, moderate, or severe HS. The present disclosure is also directed to methods for reducing skin pain and/or reducing itch in patients with HS by administering a ruxolitinib formulation one to two times per day.

Description

Ruxolitinib is used to treat hidradenitis suppurativa (HS).

This invention relates to a method for treating patients with hidradenitis suppurativa (HS) by administering a ruxolitinib formulation once or twice daily. This invention also relates to a method for reducing skin pain and/or itching in patients with HS by administering a ruxolitinib formulation once or twice daily.

Suppurative hidradenitis is a debilitating chronic inflammatory skin condition that affects hair follicles, leading to inflammation of the perifollicular lymphoid tissue cells. (Zouuboulis CC, Desai N, Emtestam L, et al., European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-644). It is characterized by persistent or recurrent painful inflammatory nodules and abscesses, as well as drainage channels called sinuses and fistulas, typically located in skin folds in the armpits, groin, buttocks, and perianal region. Saunte DML, Jemec GBE. Hidradenitis suppurativa: advances in diagnosis and treatment. JAMA 2017;318:2019-2032. Irreversible scarring can be identified in more severe cases. Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. Nat Rev Dis Primers 2020;6:18. Diagnosis of suppurative hidradenitis based on clinical assessment, and disease severity can be measured based on clinical presentation including nodular phenotypes in rubellad areas of the body. The disease course ranges from mild (recurrent formation of single or multiple isolated abscesses, without sinuses or scarring) to severe (deep, pulsatile abscesses, draining sinuses, and severe interconnected sinuses or scarring). (Frew JW. Therapeutic biomarkers in hidradenitis suppurativa: one step closer to the clinic. Br J Dermatol 2021;185:696-697.) Patients with hidradenitis suppurativa experience a severe impact on their quality of life, leading to psychological problems (such as anxiety and depression) and poor body image. Kurek A, Johanne Peters EM, Sabat R, Sterry W, Schneider-Burrus S. Depression is a frequent co-morbidity in patients with acne inversa. J Dtsch Derm Ges 2013;11:743-750; Schneider-Burrus S, Jost A, Peters EMJ, Witte-Haendel E, Sterry W, Sabat R. Association of hidradenitis suppurativa with body image. JAMA Dermatol 2018;154:447-451.

The estimated prevalence of hidradenitis suppurativa (HS) varies depending on the population and reporting method. It is reported that the highest prevalence (approximately 4%) is observed in the 20-40 age group, with onset typically around age 20 and a gradual decline after age 50. (Jemec GBE, Kimball AB. Hidradenitis suppurativa: epidemiology and scope of the problem. J Am Acad Dermatol 2015;73(Supplement 1):S4-S7). It is reported that the incidence of HS in women is up to three times higher than in men. (Canoui-Poitrine F, Le Thuaut A, Revuz JE et al., Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. J Invest Dermatol 2013;133:1506-1511.)

The etiology of HS is multifactorial, including genetic and environmental factors, lifestyle (e.g., smoking), hormonal status, and other comorbidities (metabolic syndrome, cardiovascular disease, inflammatory bowel disease), etc. (Zouuboulis CC, Tzellos T, Kyrgidis A et al., Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br J Dermatol 2017;177:1401-1409.)

Current treatment guidelines recommend tailoring HS treatment to the individual's subjective impact and the objective severity of the disease. (Zouuboulis CC, Desai N, Emtestam L, et al., European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-644). The initial management goal for HS patients is to reduce lesion development and minimize disease progression. Treatment includes topical antiseptics, antibiotics (clindamycin, rifampin, tetracyclines) as first-line therapy, followed by intralesional steroid injections (triamcinolone), acitretin, hormone therapy (Estrace, Prefest), biologics (adalimumab, infliximab), and surgery in more advanced cases. Currently, adalimumab ( ^Humira® ) is the only FDA-approved treatment for moderate to severe HS in patients aged 12 years and older. It is a fully human monoclonal antibody against TNF-α administered subcutaneously. Adalimumab has demonstrated adequate HiSCR response rates in all phase 3 trials (42% and 59% respectively, compared to 26% and 28% for placebo). Frew JW, Jiang CS, Singh N et al., Clinical response rates, placebo response rates, and significantly associated covariates are dependent on choice of outcome measure in hidradenitis suppurativa: a post hoc analysis of PIONEER 1 and 2 individual patient data. J Am Acad Dermatol 2020;82:1150-1157. Currently, there are no FDA-approved therapies for patients with mild HS. Treatment for patients with mild HS remains an unmet medical need, aimed at managing disease progression to moderate to severe symptoms. This invention addresses this need, as well as other needs.

In particular, this invention provides methods for treating human patients suffering from hidradenitis suppurativa (HS), methods comprising administering ruxolitinib or a medically acceptable salt thereof.

This invention also addresses a method for reducing skin pain in human patients with HS, which involves administering ruxolitinib or a medically acceptable salt thereof.

The present invention further addresses a method for reducing itching in human patients with HS, comprising administering ruxolitinib or a medically acceptable salt thereof.

The present invention further provides a topical formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

This invention also provides the use of topical formulations containing ruxotinib or a pharmaceutically acceptable salt thereof for the manufacture of medicaments for use by any of the methods described herein.

Details of one or more embodiments of the present invention are set forth in the following embodiments. Other features, objectives and advantages of the present invention will be apparent from the embodiments, the drawings and the scope of the claims.

This application claims priority to U.S. Provisional Application No. 63/604,937, filed December 1, 2023; U.S. Provisional Application No. 63/617,826, filed January 5, 2024; U.S. Provisional Application No. 63/551,210, filed February 8, 2024; and U.S. Provisional Application No. 63/643,875, filed May 7, 2024, the contents of which are incorporated herein by reference in their entirety.

Definition

As used in this article, "affected skin area" refers to the skin area of a patient with hidradenitis suppurativa (HS).

As used in this article, "ruxotinib phosphate" means ruxotinib phosphate, in which ruxotinib and phosphate are in a 1:1 ratio.

In some embodiments, "cream" means a semi-solid emulsion form intended for application to the skin.

When the method mentions administration on "day 2", "week 4", "week 8", "week 12", "within 36 hours" or "within 12 hours", this refers to the time period after the first dose of localized preparation, during which there is no interruption in administration.

The definitions and illustrations of various HS lesions are provided in Table 1 to help identify different morphologies.

Table 1 : Definition of suppurative hidradenitis lesions HS lesions Definition Schematic diagram abscess There are tender, fluctuating (compressible), palpable lesions, accompanied by erythema. Inflammatory nodules Solid, spherical, palpable lesions >1 cm; tender and/or erythematous. Note: Non-inflammatory nodules are defined as non-tender, non-erythematous nodules. Channel (non-drainage) Pressure on the surrounding structure will not cause the contents to drain. Channel (drainage) a It may be a linear channel leading to the skin surface; drainage occurs when the skin is at rest or when the surrounding structure is under pressure.

As used herein, "clinical response to suppurative hidradenitis" or "HiSCR" is defined as a decrease of at least 50% in the number of anaplastic nodules (AN) relative to baseline, with no increase in the number of abscesses or draining fistulas. As used herein, "AN number" refers to the total number of abscesses and inflammatory nodules. As used herein, "modified clinical response to suppurative hidradenitis" or "mHiSCR" is defined as a decrease of at least 50% in the number of inflammatory nodules relative to baseline, with no increase in the number of abscesses or draining fistulas. As discussed above, "inflammatory nodules" refers to non-tender, non-erythematous nodules.

As used in this article, the International Hidradenitis Suppurativa Severity Score System (IHS4) is a comprehensive, dynamic, and validated tool for assessing the severity of HS. (Zouuboulis CC, Tzellos T, Kyrgidis A et al., Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br J Dermatol 2017;177:1401-1409.) It uses a weighted scale, employing the number of inflammatory nodules, abscesses, and drainage channels (fungi or sinuses) with corresponding weighting factors of 1, 2, and 4 (e.g., an IHS4 score equals the number of inflammatory nodules [multiplied by 1] plus the number of abscesses [multiplied by 2] plus the number of drainage channels [multiplied by 4]). In the following text, "ISH4-55" refers to a total ISH4 score that is ≥55% lower than baseline. In some implementations, the ISH4-55 score is measured at a single time point, such as at week 16. The ISH4-55 score represents a milder group of patients with moderate to severe HS.

As used in this article, "outbreak incidence" is a measure of outbreaks, which are an important component of treatment and whose incidence is associated with a decline in patients' quality of life (Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. Nat Rev Dis Primers 2020;6:18.). An outbreak is defined as an increase of at least 25% in the number of anterior descending arteries (ANs) relative to baseline, with an AN increase of at least 2.

As used in this article, the "Hurley classification" is a static assessment, and the Hurley stages of suppurative hidradenitis are provided in Table 2 .

Table 2 : Helich's disease stages of suppurative hidradenitis Hurley's disease describe I It can form abscesses, single or multiple, without sinuses or scarring/scarring. II One or more widely separated recurrent abscesses, with sinus formation and scarring/scarring. III There are multiple interconnected sinuses and abscesses spanning the entire area, indicating diffuse or near-diffuse invasion.

As used in this article, the total surface area (BSA) percentage can be roughly estimated using the Palm Method as a guide, with the closest estimate being 0.1%. The palm plus five fingers (fingers together and thumb folded to the side (handprint)) is considered 1% BSA, and the thumb is considered 0.1% BSA.

As used herein, the NRS for skin pain and itching recorded in the electronic diary is a daily measurement (24-hour recall) of the most severe skin pain and itching intensity associated with HS, reported by the patient. As used herein, "itching NRS" and "skin pain NRS" are defined by the following patient assessments:

Skin pain NRS: The severity of pain in the HS is assessed by selecting a number from 0 (no pain) to 10 (most severe pain imaginable) to best describe the most severe pain in the past 24 hours.

NRS for itching: The severity of itching in the HS is assessed by selecting a number from 0 (no itching) to 10 (the most severe itching imaginable) to best describe the most severe itching experienced in the past 24 hours.

As used in this article, "Hidradenitis Suppurativa Quality of Life" or "HiSQOL" is a health-related quality of life tool for HS that includes 17 items, has a 7-day recall period (Kirby JS, Thorlacius L, Villumsen B et al., The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development and validation of a measure for clinical trials. Br J Dermatol 2020;183:340-348), and can be used to assess the impact of HS symptoms and HS problems on quality of life.

As used in this paper, the Dermatology Life Quality Index (DLQI) is a 10-question, validated questionnaire that measures the impact of skin problems on participants over the past 7 days (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) — a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-216). Participants will answer the questionnaire using the following options: (1) very, (2) a lot, (3) a little, or (4) none at all. The questionnaire is analyzed under the following 6 headings:

Symptoms and sensations (Questions 1 and 2)

Daily activities (Questions 3 and 4)

Leisure (Questions 5 and 6)

Work and school (Question 7)

Personal relationships (Questions 8 and 9)

Treatment (Question 10)

As used in this study, “Patient Overall Impression Change” or “PGIC” is a self-reported measure that reflects a patient’s belief in the efficacy of treatment. PGIC is a 7-point scale that describes participants’ assessment of overall improvement and will be collected during on-site visits, as outlined in SoA (Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manipulative Physiol Ther 2004;27:26-35). Patients will answer as follows: “Since the start of treatment in this study, your HS has improved: (1) significantly, (2) much, (3) slightly, (4) unchanged, (5) slightly worsened, (6) severely worsened, (7) very severely worsened.”

As used in this paper, the "Work Productivity and Activity Impairment-Hidradenitis Suppurativa" (WPAI-HS) questionnaire is used to measure impairment in paid and unpaid work. It measures absences, sham attendance, and impairment in unpaid activity over the past 7 days due to hidradenitis suppurativa and other health problems. The least clinically significant difference is defined as half the standard deviation of the baseline score for the overall population. Absences, sham attendance, and overall work impairment will be assessed only for the patients used (Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 1993;4:353-365).

As used in this paper, "EQ-5D-5L" is a questionnaire used to measure health outcomes (Herdman M, Gudex C, Lloyd A et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-1736). EQ-5D-5L provides data for economic modeling and analysis, including developing health utility or quality-adjusted life years. EQ-5D-5L consists of two parts: the EQ-5D descriptive system and the EQ VAS. The descriptive system includes five dimensions: activity level, self-care, common activities, pain/discomfort, and anxiety/depression. Each dimension has five levels: no problem, minor problem, moderate problem, severe problem, and extreme problem. The EQ VAS records participants’ self-rated health status on a vertical visual analog scale (0 to 100), with endpoints labeled as “the best health condition you can imagine” and “the worst health condition you can imagine”.

As used in this article, "BID" refers to twice a day.

As used in this article, "QD" refers to once a day.

As used in this article, "statistically significant" means a p-value < 0.05 (e.g., < 0.001, and such as < 0.0001).

As used herein, the phrase "pharmaceutically acceptable" means compounds, substances, compositions, and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in contact with human and animal tissues. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other recognized pharmacopoeia for use in animals, and more specifically for use in humans.

This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic groups (such as amines); alkali metal salts or organic salts of acidic groups (such as carboxylic acids); and analogues thereof. Pharmaceutically acceptable salts of this invention include, for example, known nontoxic salts of parent compounds formed from nontoxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using known chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both. Non-aqueous media are generally preferred, such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN). A list of suitable salts can be found in Remington's Pharmaceutical Sciences , 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science , 66, 2 (1977), both of which are incorporated herein by reference in their entirety. In some embodiments, pharmaceutically acceptable salts are phosphates, sulfates, or maleate.

As used herein, in a given context, the term "emulsifier component" refers to a substance or mixture of substances that holds elements or particles in a suspension within a fluid medium. In some embodiments, the emulsifier component allows the oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component refers to one or more nonionic surfactants.

As used in this article, the term "occlusive agent component" refers to a hydrophobic agent or mixture of hydrophobic agents that forms an occlusive film on the skin, thereby reducing transepidermal water loss (TEWL) by preventing water from evaporating from the stratum corneum.

As used herein, the term "hardening agent component" refers to a substance or mixture of substances that increases the viscosity and/or consistency of a cream or improves the rheology of a cream.

As used in this article, the term "moisturizing component" refers to a drug that softens or soothes the skin or soothes the inner surface of the skin that is irritated.

As used herein, the term "stabilizing component" refers to a substance or mixture of substances that improves the stability of a cream and/or the compatibility of its components. In some embodiments, the stabilizer component prevents emulsion aggregation and stabilizes droplets in an oil-in-water emulsion.

As used herein, the term "solvent component" refers to a liquid substance or mixture of liquid substances capable of dissolving ruxotinib (or its salts) or other substances in a cream. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which ruxotinib or its pharmaceutically acceptable salts have reasonable solubility. For example, the solubility of ruxotinib (free base) or its phosphate (1:1 salt) is reported in Table 3. In some embodiments, the solvent is a substance or mixture thereof in which ruxotinib or its pharmaceutically acceptable salts (whichever is used) have a solubility of at least about 10 mg/mL or higher, at least about 15 mg/mL or higher, or at least about 20 mg/mL or higher.

As used in this article, the phrase "antimicrobial preservative component" refers to a substance or mixture of substances that inhibits the growth of microorganisms in a cream.

As used in this article, the phrase "chelating agent component" refers to a compound or mixture of compounds that can bind strongly to metal ions.

As used in this article, "% by weight of emulsion" means that the concentration percentage of the components in the emulsion is expressed as weight/weight. For example, 1% w/w of component A = [(mass of component A) / (total mass of emulsion)] × 100.

As used herein, ruxolitinib or its pharmaceutically acceptable salts as "% w/w of emulsion as free base" means % w/w based on the weight of ruxolitinib in the total emulsion. For example, ruxolitinib phosphate as "1.5% w/w of free base" means that for 100 grams of total formulation, there are 1.98 grams of ruxolitinib phosphate in the emulsion (which is equivalent to 1.5 grams of free base, ruxolitinib).

As used herein, ruxolitinib or its pharmaceutically acceptable salts, expressed as "% w/w of the formulation in terms of free base," means % w/w based on the weight of ruxolitinib in the total formulation. For example, ruxolitinib phosphate, expressed as "1.5% w/w of free base," means that for every 100 grams of total formulation, there are 0.66 grams of ruxolitinib phosphate present in the formulation (which is equivalent to 1.5 grams of free base, ruxolitinib).

As used in this article, the term "component" can mean a substance or a mixture of substances.

As used herein, the term "fatty acid" refers to a saturated or unsaturated aliphatic acid. In some embodiments, fatty acids are in the form of mixtures of different fatty acids. In some embodiments, fatty acids have an average of about eight to about thirty carbons. In some embodiments, fatty acids have an average of about 12 to 20, 14 to 20, or 16 to 18 carbons. Suitable fatty acids include, but are not limited to: cetearic acid, stearic acid, lauric acid, myristic acid, sinapic acid, palmitic acid, palm oleic acid, capric acid, octanoic acid, oleic acid, linoleic acid, hypolinoleic acid, hydroxystearic acid, 12-hydroxystearic acid, cetearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, docosanoic acid, isodocosahexadecanoic acid, and eicosatraenoic acid, or mixtures thereof.

As used herein, the term "fatty alcohol" refers to saturated or unsaturated aliphatic alcohols. In some embodiments, fatty alcohols are in the form of mixtures of different fatty alcohols. In some embodiments, fatty alcohols have an average of about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons. Suitable fatty alcohols include (but are not limited to) stearyl alcohol, lauryl alcohol, palmitol, cetyl alcohol, decanol, octanol, oleyl alcohol, linolenic acid alcohol, eicosapentaenoic acid alcohol, docosanol, isodocosanol, shark oil alcohol, liver alcohol, and linolenic acid alcohol, or mixtures thereof.

As used herein, the term "polyalkylene glycol," used alone or in combination with other terms, refers to a polymer containing an oxyalkylene monomer unit, or a copolymer of different oxyalkylene monomer units, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene" refers to a group of the formula -O-alkyl-. In some embodiments, the polyalkylene glycol is polyethylene glycol.

As used herein, the term "dehydrated sorbitol fatty acid ester" includes products derived from dehydrated sorbitol or sorbitol and fatty acids, and, where appropriate, poly(ethylene glycol) units, including dehydrated sorbitol esters and polyethoxylated dehydrated sorbitol esters. In some embodiments, the dehydrated sorbitol fatty acid ester is a polyethoxylated dehydrated sorbitol ester.

As used herein, the term "sorbitol ester" refers to a compound or mixture of compounds derived from the esterification of sorbitol with at least one fatty acid. Suitable fatty acids for deriving sorbitol esters include (but are not limited to) those described herein. Suitable sorbitol esters include (but are not limited to) the Span ^™ series (available from Uniqema), which includes Span 20 (sorbitol monolaurate), 40 (sorbitol monopalmitate), 60 (sorbitol monostearate), 65 (sorbitol tristearate), 80 (sorbitol monooleate), and 85 (sorbitol trioleate). Other suitable dehydrated sorbitol esters include those listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, which are incorporated herein by reference in their entirety.

As used herein, the term "polyethoxylated dehydrated sorbitol ester" refers to a compound or mixture thereof derived from the ethoxylation of a dehydrated sorbitol ester. The polyoxyethylene moiety of the compound may be located between the fatty acid ester and the dehydrated sorbitol moiety. As used herein, the term "dehydrated sorbitol ester" refers to a compound or mixture thereof derived from the esterification of sorbitol and at least one fatty acid. Fatty acids suitable for deriving polyethoxylated dehydrated sorbitol esters include (but are not limited to) the fatty acids described herein. In some embodiments, the polyoxyethylene moiety of the compound or mixture has about 2 to about 200 ethylene oxide units. In some embodiments, the polyoxyethylene moiety of the compound or mixture has about 2 to about 100 ethylene oxide units. In some embodiments, the polyoxyethylene moiety of the compound or mixture has about 4 to about 80 ethylene oxide units. In some embodiments, the polyethylene oxide portion of the compound or mixture has about 4 to about 40 polyethylene oxide units. In some embodiments, the polyethylene oxide portion of the compound or mixture has about 4 to about 20 polyethylene oxide units. Suitable polyethoxylated dehydrated sorbitan esters include (but are not limited to) the Tween™ series (purchased from Uniqema), which includes Tween 20 (POE(20) dehydrated sorbitan monolaurate), 21 (POE(4) dehydrated sorbitan monolaurate), 40 (POE(20) dehydrated sorbitan monopalmitate), 60 (POE(20) dehydrated sorbitan monostearate), 60K (POE(20) dehydrated sorbitan monostearate), 61 (POE(4) dehydrated sorbitan monostearate), 65 (POE(20) dehydrated sorbitan tristearate), 80 (POE(20) dehydrated sorbitan monooleate), 80K (POE(20) dehydrated sorbitan monooleate), 81 (POE(5) dehydrated sorbitan monooleate) and 85 (POE(20) dehydrated sorbitan trioleate). As used herein, the abbreviation "POE" refers to polyethylene oxide. The number following POE indicates the number of repeating ethylene oxide units in the compound. Other suitable polyethoxylated dehydrated sorbitan esters include the polyethoxylated dehydrated sorbitan fatty acid esters listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, which is incorporated herein by reference in its entirety. In some embodiments, the polyethoxylated dehydrated sorbitan ester is a polysorbate. In some embodiments, the polyethoxylated dehydrated sorbitan ester is polysorbate 20.

As used herein, the term "glycerol fatty acid ester" refers to a monoglyceride, diglyceride, or triglyceride of a fatty acid. Glycerol fatty acid esters may, where applicable, be substituted with a sulfonic acid group or a pharmaceutically acceptable salt. Suitable fatty acids for deriving glycerol esters of fatty acids include, but are not limited to, those described herein. In some embodiments, the glycerol fatty acid ester is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glycerol fatty acid ester is glyceryl stearate.

As used herein, the term "triglyceride" refers to a triglyceride of fatty acids. In some embodiments, the triglyceride is a medium-chain triglyceride.

As used herein, the term "alkanediol" refers to a group of the formula -O-alkyl-, wherein the alkyl group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkanediol is propylene glycol (1,2-propanediol).

As used herein, the term "polyethylene glycol" refers to a polymer containing an ethylene glycol monomer of the formula -O- _CH2 - _CH2- . Suitable polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a low number of alkyl groups (e.g., methyl). Polyethylene glycol derivatives having esterifiable carboxyl groups are also suitable. The polyethylene glycols suitable for use in this invention may be polymers having any chain length or molecular weight, and may include branching. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include (but are not limited to) polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number after the dash in the name refers to the average molecular weight of the polymer.

As used herein, the term "contact" means bringing together the indicated portion in an in vivo or in vivo system. For example, "contacting" JAK with the compound of the invention includes administering the compound of the application to an individual or patient with JAK, such as a human, and, for example, introducing the compound of the invention into a sample containing cells or a purified preparation containing JAK.

As used in this article, "contains" is equivalent to "includes".

As used herein, the interchangeable terms "subject/individual" or "patient" refer to a human being. In some implementations, the "subject/individual" or "patient" requires the treatment.

In some embodiments, compounds described herein, or their pharmaceutically acceptable salts or pharmaceutical formulations thereof, or their topical formulations, are administered in therapeutically effective amounts. As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or pharmaceutical preparation that elicits a biological or pharmaceutical response sought by an investigator, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

As used herein, the term “treating” or “treatment” means one or more of the following: (1) suppressing disease; for example, suppressing the disease, symptoms, or condition of an individual experiencing or manifesting the pathology or symptom of the disease (i.e., halting further development of the pathology and/or symptom); or (2) improving disease; for example, improving the disease, symptoms, or condition of an individual experiencing or manifesting the pathology or symptom (i.e., reversing the pathology and/or symptom), such as reducing the severity of the disease. In some embodiments, treatment means suppressing or improving disease. In some embodiments, treatment is for the prevention of disease.

In some embodiments, the components exist within a precisely specified range (e.g., the term "about" does not exist). In some embodiments, "about" means 10% of the value added or subtracted.

Treatment methods

This invention provides, in particular, a method for treating suppurative hidradenitis (HS) in human patients of need, comprising topically administering ruxolitinib or a medically acceptable salt thereof to the affected skin area of the patient. This invention also relates to a method for reducing skin pain and/or itching in patients with HS, comprising topically administering ruxolitinib or a medically acceptable salt thereof to the affected skin area of the patient. In some embodiments, ruxolitinib or its salt is administered as a topically prepared ruxolitinib formulation once or twice daily. Ruxolitinib is a JAK1/JAK2 inhibitor selective for JAK1 and JAK2 relative to JAK3.

In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinib phosphate.

In some implementations, ruxolitinib or a pharmaceutically acceptable salt thereof is administered as a topical formulation.

In some embodiments, the topical formulation is administered as a topical formulation comprising about 0.1% to about 3% of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base.

In some embodiments, the topical formulation is administered as a topical formulation comprising about 0.5% to about 2% of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base.

In some embodiments, the topical formulation is administered as a topical formulation comprising about 0.5% to about 1.5% of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base.

In some embodiments, the topical formulation is administered as a topical formulation comprising about 0.75% to about 1.5% of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base.

In some embodiments, the topical formulation is administered as a topical formulation containing about 0.5% ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the topical formulation is administered as a topical formulation containing about 0.75% ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the topical formulation is administered as a topical formulation containing about 1% ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base. In some embodiments, the topical formulation is administered as a topical formulation containing about 1.5% ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base.

In some embodiments, the composition is administered twice daily (BID). In other embodiments, the composition is administered once daily (QD).

In some implementations, the investment lasted for 16 weeks.

In some implementations, daily injections continued for 16 weeks.

In some implementations, ruxolitinib or a pharmaceutically acceptable salt thereof is administered in combination with another treatment.

In some embodiments, administration includes administration of ruxolitinib or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

In some implementations, the patients were 18 years of age or older.

In some cases, the patient was diagnosed with HS for at least 3 months. In some cases, the patient had Helix stage I or II HS. In some cases, the patient had no drainage pathway. In some cases, the patient had a total abscess and inflammatory nodule count (AN count) of less than 10. In some specific cases, the patient had Helix stage I or II HS without drainage pathway. In some cases, the patient had Helix stage I or II HS with an AN count of less than 10. In some cases, the patient had Helix stage I or II HS without drainage pathway and an AN count of less than 10. In some embodiments, the following are diagnostic criteria for HS (Heary stage I or II): (a) a total AN number of 3 to ≤10 at screening and baseline visits, with no drainage pathway; and (b) AN number at screening and baseline visits: AN of 3 should affect at least one distinct anatomical region and AN >3 to ≤10 should affect at least two distinct anatomical regions.

In some implementations, the patient's baseline skin pain or itching NRS score was ≥ 1.

In some implementations, the efficacy of the treatment methods disclosed herein can be determined based on the change in the patient's AN number relative to the baseline. The "number of abscesses and inflammatory nodules" (AN number) is calculated by the change in the AN number relative to the baseline, and AN50, AN75, AN90, and AN100 are defined as a decrease in the AN number relative to the baseline of at least 50%, 75%, 90%, and 100%, respectively.

In some embodiments, the present invention relates to a method for treating patients with suppurative hidradenitis (HS) comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a relative baseline reduction in total analgesia (AN) numbers after administration for at least 2, 4, 8, 12, or 16 weeks. In some embodiments, the patient achieves a relative baseline reduction in total AN numbers after administration for at least 2 weeks. In some embodiments, the patient achieves a relative baseline reduction in total AN numbers after administration for at least 4 weeks. In some embodiments, the patient achieves a relative baseline reduction in total AN numbers after administration for at least 8 weeks. In some embodiments, the patient achieves a relative baseline reduction in total AN numbers after administration for at least 12 weeks. In some implementations, patients achieved a relative baseline reduction in total analgesia after at least 16 weeks of administration.

In some embodiments, the present invention relates to a method for treating patients with suppurative hidradenitis (HS), the method comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a reduction in total analgesia (AN) numbers relative to baseline after at least 16 weeks of administration. In some embodiments, the patient achieves a reduction in total AN numbers relative to baseline of at least 1 after at least 16 weeks of administration. In some embodiments, the patient achieves a reduction in total AN numbers relative to baseline of at least 2 after at least 16 weeks of administration. In some embodiments, the patient achieves a reduction in total AN numbers relative to baseline of at least 3 after at least 16 weeks of administration.

In some embodiments, the efficacy of the treatment methods disclosed herein can be determined based on the patient achieving an AN50 at week 16. An AN50 responder is defined as a participant achieving an AN50% or greater reduction from baseline. In some embodiments, the invention pertains to a method for treating patients with suppurative hidradenitis (HS) comprising administering a therapeutically effective dose of ruxolitinib or a pharmaceutically acceptable saline thereof to the patient, wherein the patient achieves an AN50 at least 16 weeks prior.

In some embodiments, the efficacy of the treatment methods disclosed herein can be determined based on the patient achieving AN75 at week 16. AN75 responders are defined as participants achieving an AN number that is >= 75% lower than baseline. In some embodiments, the invention pertains to a method for treating patients with suppurative hidradenitis (HS) comprising administering a therapeutically effective dose of ruxolitinib or a pharmaceutically acceptable saline thereof to the patient, wherein the patient achieves AN75 at least before week 16.

In some embodiments, the efficacy of the treatment methods disclosed herein can be determined based on the patient achieving an AN90 at week 16. An AN90 responder is defined as a participant achieving an AN number that is >= 90% lower than the baseline. In some embodiments, the invention pertains to a method for treating patients with suppurative hidradenitis (HS) involving the administration of a therapeutically effective dose of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves an AN90 at least by week 16.

In some embodiments, the efficacy of the treatment methods disclosed herein can be determined based on the patient achieving an AN100 at week 16. An AN100 responder is defined as a participant achieving an AN number that is >= 100% lower than the baseline. In some embodiments, the invention pertains to a method for treating patients with suppurative hidradenitis (HS) comprising administering a therapeutically effective dose of ruxolitinib or a pharmaceutically acceptable saline thereof to the patient, wherein the patient achieves an AN100 at least before week 16.

In some embodiments, the present invention relates to a method for treating hidradenitis suppurativa (HS) in human patients of need, the method comprising: twice daily topical administration of a topical preparation containing 1.5% (w/w) ruxolitinib or a pharmaceutically acceptable salt thereof, based on free base, to the affected skin area of a patient, wherein the patient has no drainage pathways, wherein the patient is ≥18 years of age at baseline, and wherein the abscess and/or inflammatory nodules of the patient are reduced relative to baseline after at least one of 2, 4, 8, 12 or 16 weeks of administration.

In some embodiments, abscesses decreased relative to baseline after at least one of 2, 4, 8, 12, or 16 weeks of administration. In some embodiments, abscesses decreased relative to baseline after at least 12 or 16 weeks of administration. In some embodiments, inflammatory nodules decreased relative to baseline after at least one of 2, 4, 8, 12, or 16 weeks of administration. In some embodiments, inflammatory nodules decreased relative to baseline after at least 12 or 16 weeks of administration. In some embodiments, both abscesses and inflammatory nodules decreased relative to baseline after at least one of 2, 4, 8, 12, or 16 weeks of administration. In some implementations, the relative baseline of abscesses and inflammatory nodules decreased after at least 12 or 16 weeks.

In some practices, the efficacy of the treatments described herein can be determined based on changes in patient-reported NRS scores relative to baseline. In some practices, ruxolitinib or its pharmaceutically acceptable salts and/or the methods of use described herein resulted in relative improvements in patient response to the NRS. In some practices, ruxolitinib or its pharmaceutically acceptable salts and/or the methods of use described herein resulted in relative improvements in patient response to the NRS of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. The NRS is a daily patient-reported measurement of pain intensity (24-hour recall). Patients will be asked to rate the severity of their pain caused by HS by selecting a number from 0 (no pain) to 10 (most severe pain imaginable) that best describes their pain level over the past 24 hours. In a non-limiting example, a handheld device (electronic diary) may be provided to the patient to record the pain severity. The patient may be instructed to complete the electronic diary each night.

In some embodiments, the present invention relates to a method for treating HS in patients, the method comprising administering to the patient a therapeutically effective amount of ruxotinib or a pharmaceutically acceptable salt thereof, wherein the patient achieves a relative reduction in the NRS score for skin pain. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 1 point in the NRS score for skin pain. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 2 points in the NRS score for skin pain. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 3 points in the NRS score for skin pain. In some embodiments, the patient achieves a relative improvement (reduction) of 4 points in the NRS score for skin pain.

In some embodiments, the invention pertains to a method for treating patients with hepatitis B (HS) comprising administering to the patient a therapeutically effective dose of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a change in skin pain NRS score relative to baseline at each baseline follow-up. In some embodiments, the baseline follow-up ranges from 2 to 16 weeks. In some embodiments, the baseline follow-up is 2 weeks. In some embodiments, the baseline follow-up is 4 weeks. In some embodiments, the baseline follow-up is 8 weeks. In some embodiments, the baseline follow-up is 12 weeks. In some embodiments, the baseline follow-up is 12 weeks.

In some embodiments, the invention relates to a method for treating patients with HS, comprising administering to the patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the patient achieves a change in skin pain NRS score relative to baseline at week 16. In some embodiments, the patient achieves a reduction in skin pain NRS score relative to baseline at week 16. In some embodiments, the patient achieves a skin pain NRS score improvement (reduction) ≥ 1 point relative to baseline at week 16. In some embodiments, the patient achieves a skin pain NRS score improvement (reduction) ≥ 2 points relative to baseline at week 16. In some embodiments, the patient achieves a skin pain NRS score improvement (reduction) ≥ 3 points relative to baseline at week 16. In some implementations, patients achieved a relative improvement (reduction) of ≥ 4 points in the NRS score for skin pain at week 16.

In some practices, the efficacy of the treatment methods disclosed herein can be determined based on the Numerical Rating Scale for Itching (NRS). In some practices, efficacy can be demonstrated by achieving a predetermined proportion of patients with an NRS improvement of at least 2 or 4 points (e.g., at week 16). In some practices, efficacy can be demonstrated by observing the time to achieve a 2:2 or 2:4 improvement in the NRS relative to baseline. In some practices, ruxolitinib or its pharmaceutically acceptable saline and/or the method of use described herein induce a relative improvement in the patient's NRS response to pruritus. In some practices, ruxolitinib or its pharmaceutically acceptable salts and/or the methods of use described herein resulted in a relative baseline improvement in patient response to the pruritus NRS of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. The pruritus NRS is a daily patient-reported measurement of pruritus intensity (24-hour recall). Patients will be asked to assess the severity of pruritus caused by their HS by selecting a number from 0 (no pruritus) to 10 (most conceivable pruritus) that best describes the severity of their pruritus over the past 24 hours. In a non-limiting example, a handheld device (electronic diary) may be provided to the patient to record the severity of pruritus. Patients can be instructed to complete an electronic diary each night.

In some embodiments, the present invention relates to a method for treating HS in patients, the method comprising administering to the patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a relative reduction in the pruritus NRS score compared to baseline. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 1 point in the pruritus NRS score. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 2 points in the pruritus NRS score. In some embodiments, the patient achieves a relative improvement (reduction) of ≥ 3 points in the pruritus NRS score. In some embodiments, the patient achieves a relative improvement (reduction) of 4 points in the pruritus NRS score.

In some embodiments, the invention relates to a method for treating patients with HS, comprising administering to the patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a change in pruritus NRS score relative to baseline at each baseline follow-up. In some embodiments, the baseline follow-up ranges from 2 to 16 weeks. In some embodiments, the baseline follow-up is 2 weeks. In some embodiments, the baseline follow-up is 4 weeks. In some embodiments, the baseline follow-up is 8 weeks. In some embodiments, the baseline follow-up is 12 weeks. In some embodiments, the baseline follow-up is 16 weeks.

In some embodiments, the present invention relates to a method for treating patients with HS, the method comprising administering to the patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a change in pruritus NRS score relative to baseline at week 16. In some embodiments, the patient achieves a reduction in pruritus NRS score relative to baseline at week 16. In some embodiments, the patient achieves a ≥ 1 point improvement (reduction) in pruritus NRS score relative to baseline at week 16. In some embodiments, the patient achieves a ≥ 2 point improvement (reduction) in pruritus NRS score relative to baseline at week 16. In some embodiments, the patient achieves a ≥ 3 point improvement (reduction) in pruritus NRS score relative to baseline at week 16. In some implementations, patients achieved a relative improvement (reduction) of ≥ 4 points in their NRS score for itching at week 16.

In some embodiments, the efficacy of the treatment methods disclosed herein can be assessed based on the Histomachic Rupture Response (HiSCR). In some embodiments, achieving HiSCR is defined as a reduction of at least 50% in the number of inflammatory nodules (ANs) relative to baseline, with no increase in the number of abscesses or draining fistulas. In some embodiments, the efficacy of the treatment methods disclosed herein can be assessed based on a modified Histomachic Rupture Response, or "mHiSCR". mHiSCR is defined as a reduction of at least 50% in the number of inflammatory nodules relative to baseline, with no increase in the number of abscesses or draining fistulas. As used herein, "inflammatory nodules" refers to non-tender, non-erythematous nodules.

In some embodiments, the present invention relates to a method for treating patients with HS, the method comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the patient achieves HiSCR. In some embodiments, the patient achieves HiSCR at week 2. In some embodiments, the patient achieves HiSCR at week 4. In some embodiments, the patient achieves HiSCR at week 8. In some embodiments, the patient achieves HiSCR at week 12. In some embodiments, the patient achieves HiSCR at week 16.

In some embodiments, the present invention relates to a method for treating patients with HS, the method comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the patient achieves mHiSCR. In some embodiments, the patient achieves mHiSCR at week 2. In some embodiments, the patient achieves mHiSCR at week 4. In some embodiments, the patient achieves mHiSCR at week 8. In some embodiments, the patient achieves mHiSCR at week 12. In some embodiments, the patient achieves mHiSCR at week 16.

In some embodiments, the efficacy of the treatment methods described herein can be determined based on the Hidradenitis Suppurativa International Score System (IHS4). In some embodiments, the IHS4 score is calculated by multiplying the number of inflammatory nodules (by 1) by the number of abscesses (by 2) by the number of drainage channels (by 4).

In some embodiments, the present invention relates to a method for treating HS in patients, the method comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the patient achieves a reduction in IHS4 score, demonstrating treatment of HS. In some embodiments, the patient achieves an IHS4 reduction at least 2 weeks prior. In some embodiments, the patient achieves an IHS4 reduction at least 4 weeks prior. In some embodiments, the patient achieves an IHS4 reduction at least 8 weeks prior. In some embodiments, the patient achieves an IHS4 reduction at least 12 weeks prior. In some embodiments, the patient achieves an IHS4 reduction at least 16 weeks prior. In some implementations, patients achieved a reduction in their IHS4 score at least by week 2, 4, 8, 12, 20, 24, 28, or 32. In some implementations, patients achieved a reduction in their IHS4 score at least by week 20. In some implementations, patients achieved a reduction in their IHS4 score at least by week 24. In some implementations, patients achieved a reduction in their IHS4 score at least by week 28. In some implementations, patients achieved a reduction in their IHS4 score at least by week 32.

In some embodiments, the efficacy of the treatment methods disclosed herein can be determined based on the International Score System for Suppurative Hidradenitis Sinus (ISH4-55), which defines a reduction of ≥55% (ISH4-55) in the total ISH4 score relative to baseline. In some embodiments, the ISH4-55 score is in the range of approximately 55% to approximately 85% of the total ISH4 score relative to baseline. In some embodiments, the ISH4-55 score is approximately 40%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, or approximately 85% of the total ISH4 score relative to baseline. In some embodiments, the ISH4-55 score is approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, or approximately 85% of the total ISH4 score relative to baseline. In some implementations, the ISH4-55 score represents a reduction of approximately 55% in the total ISH4 score relative to the baseline.

In some embodiments, the present invention pertains to a method for treating HS in patients, comprising administering to a patient a therapeutically effective amount of ruxolitinib or a pharmaceutically acceptable saline thereof, wherein the patient achieves a total IHS4 score reduction of ≥55% relative to baseline, demonstrating the effectiveness of HS treatment. In some embodiments, the patient achieves an IHS4-55 reduction at least 2 weeks prior. In some embodiments, the patient achieves an IHS4-55 reduction at least 4 weeks prior. In some embodiments, the patient achieves an IHS4-55 reduction at least 8 weeks prior. In some embodiments, the patient achieves an IHS4-55 reduction at least 12 weeks prior. In some embodiments, the patient achieves an IHS4-55 reduction at least 16 weeks prior. In some implementations, patients achieved a reduction in their IHS 4-55 score at least by week 2, 4, 8, 12, 20, 24, 28, or 32. In some implementations, patients achieved a reduction in their IHS 4-55 score at least by week 20. In some implementations, patients achieved a reduction in their IHS 4-55 score at least by week 24. In some implementations, patients achieved a reduction in their IHS 4-55 score at least by week 28. In some implementations, patients achieved a reduction in their IHS 4-55 score at least by week 32.

Ruxotinib

Ruxotinib is a potent JAK1/JAK2 inhibitor, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (INCB018424; ruxotinib; the active ingredient in JAKAFI®) and its pharmaceutically acceptable salts have been previously described in U.S. Patent No. 7,598,257, which is incorporated herein by reference in its entirety. Ruxotinib phosphate has been previously described in U.S. Patent Publication No. 2008/0312259, which is incorporated herein by reference in its entirety. Ruxotinib

Ruxotinib is a small-molecule JAK inhibitor specific to JAK1 and JAK2, which play important roles in signal transduction following the binding of intercytokines and growth factors to their receptors. Increased production of intercytokines and growth factors is associated with several chronic inflammatory symptoms, including Alzheimer's disease (AD), vitiligo, and other autoimmune skin diseases. In cell-based analyses relating to the pathogenesis of inflammatory skin diseases, such as IL-2-stimulated STAT phosphorylation and IL-2-induced T cell proliferation, ruxotinib demonstrated excellent potency ( _IC50 values of 10 to 40 nM). Ruxotinib also strongly inhibits STAT protein phosphorylation and the production of pro-inflammatory factors induced by intercytokines such as IL-23 and IFN-γ.

Ruxotinib cream has demonstrated efficacy in Alzheimer's disease (AD) and vitiligo. Ruxotinib cream has shown statistically significant and clinically meaningful efficacy in adults and adolescents with mild to moderate AD and 3% to 20% of diseased basal sarcoplasmic scalp (BSA) (excluding scalp) in two pivotal phase 3 studies (INCB 18424-303 and INCB 18424-304). In both AD phase 3 studies, more than 50% (53.8% and 51.3%) of participants who applied 1.5% ruxotinib cream for 8 weeks (≥12 years) achieved IGA-TS (i.e., an IGA score of 0 or 1, representing a relative improvement of ≥2 points from baseline) compared to 15.1% and 7.9% of participants who applied the mordant cream, respectively. In both studies, participants applying ruxolitinib cream also showed substantial improvement in pruritus (a 4-point reduction in the pruritus NRS score) compared to those applying the mordant (50.7% and 52.2% for ruxolitinib cream, compared to 16.3% and 15.4% for the mordant, respectively). Furthermore, the 1.5% ruxolitinib cream administered by BID was safe and well-tolerated in adolescent and adult participants with Alzheimer's disease (AD). 1.5% ruxolitinib cream is approved in the United States under the name Opzelura™ for the short-term, non-continuous chronic treatment of mild to moderate AD in non-immune-impaired patients aged 12 years and older whose disease is not adequately controlled by topical prescription therapy or when such therapy is not recommended.

1.5% ruxolitinib cream has been shown to be effective in treating vitiligo. Studies INCB 18424-306 and INCB 18424-307 were identically designed randomized, vitamin C, phase 3 studies in adolescents and adults with vitiligo (≥12 years old, approximately 10% of whom were adolescents). Participants received 24 weeks of blinded treatment followed by an additional 28 weeks of BID treatment with 1.5% ruxolitinib cream. Both studies met their primary endpoints (p < 0.0001), demonstrating a significantly greater number of participants treated with 1.5% ruxolitinib cream BID showing a ≥ 75% improvement in facial vitiligo area score relative to baseline at week 24 compared to participants treated with a mediator. In addition, 1.5% ruxolitinib cream is safe and well-tolerated in adolescents and adults with vitiligo.

Cream formulation

In some embodiments, the cream formulation is an oil-in-water emulsion. In some embodiments, the cream is a dissolved cream. In some embodiments, the cream has a pH of about 2.7 to about 3.9, about 2.7 to about 3.6, or about 2.8 to about 3.6. In the case of pH, "about" means ±0.3 (e.g., ±0.2 or such as ±0.1).

In some embodiments, the cream comprises an oil-in-water emulsion containing 1.5% (w/w) of ruxotinib phosphate, based on free base.

In some embodiments, the cream is an oil-in-water emulsion as described in US 2015/0250790, which is incorporated herein by reference in its entirety. Specifically, Examples 3-6 of US 2015/0250790 (and specifically Tables 3-5 and the accompanying text) are incorporated herein by reference.

In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about 10% to about 24% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about 18% to about 24% by weight of the emulsion.

In some embodiments, the oil component comprises one or more substances independently selected from paraffin, fatty alcohol, mineral oil, triglycerides and polysiloxane oil.

In some embodiments, the oil component comprises one or more substances independently selected from: white wax, whale wax alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides and dimethyl polysiloxane.

In some embodiments, the oil component includes a occlusive agent component.

In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.

In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.

In some embodiments, the occlusive component comprises one or more substances selected from: fatty acids (e.g., lanolinic acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbons and waxes (e.g., paraffin), polyols (e.g., propylene glycol), polysiloxanes (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).

In some embodiments, the occlusive component comprises one or more substances selected from: lanolin fatty alcohol, lanolin alcohol, paraffin, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

In some embodiments, the occlusive agent component contains paraffin.

In some embodiments, the occlusive agent component includes white wax.

In some embodiments, the oil component includes a hardener component.

In some embodiments, the hardener component is present in an amount of about 2% to about 8% by weight of the emulsion.

In some embodiments, the hardener component is present in an amount of about 3% to about 6% by weight of the emulsion.

In some embodiments, the hardener component is present in an amount of about 4% to about 7% by weight of the emulsion.

In some embodiments, the hardener component contains one or more substances independently selected from fatty alcohols.

In some embodiments, the hardener component contains one or more substances independently selected from _C12-20 fatty alcohols.

In some embodiments, the hardener component contains one or more substances independently selected from _C16-18 fatty alcohols.

In some embodiments, the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

In some embodiments, the oil component includes emollient components.

In some embodiments, the moisturizing agent component is present in an amount of about 5% to about 15% by weight of the emulsion.

In some embodiments, the emollient component is present in an amount of about 7% to about 13% by weight of the emulsion.

In some embodiments, the emollient component comprises one or more substances independently selected from mineral oils and triglycerides.

In some embodiments, the emollient component comprises one or more substances independently selected from light mineral oils and medium-chain triglycerides.

In some embodiments, the emollient component comprises one or more substances independently selected from: light mineral oil, medium-chain triglycerides and dimethyl polysiloxane.

In some embodiments, water is present in an amount of about 35% to about 65% by weight of the emulsion.

In some embodiments, water is present in an amount of about 40% to about 60% of the emulsion weight.

In some embodiments, water is present in an amount of about 45% to about 55% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the emulsion.

In some embodiments, the emulsion includes an emulsifier component and a hardener component, wherein the combined amount of the emulsifier component and the hardener component accounts for at least about 8% of the weight of the emulsion.

In some embodiments, the emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and dehydrated sorbitol fatty acid esters.

In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

In some embodiments, the emulsion further includes stabilizer components.

In some embodiments, the stabilizer component is present in an amount of about 0.05% to about 5% by weight of the emulsion.

In some embodiments, the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the emulsion.

In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the emulsion.

In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.

In some embodiments, the stabilizer component includes senna.

In some embodiments, the emulsion further includes a solvent component.

In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the emulsion.

In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the emulsion.

In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the emulsion.

In some embodiments, the solvent component comprises one or more substances independently selected from alkyldiols and polyalkyldiols.

In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

In some embodiments, the emulsion comprises:

Water constitutes approximately 35% to 65% of the emulsion's weight;

Oil components comprising approximately 10% to 40% of the emulsion weight;

Emulsifier components comprising approximately 1% to approximately 9% by weight of the emulsion;

Solvent components comprising approximately 10% to 35% of the emulsion weight;

A stabilizer component comprising approximately 0.05% to approximately 5% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 35% to 65% of the emulsion's weight;

Oil components comprising approximately 10% to 24% of the emulsion weight;

Emulsifier components comprising approximately 1% to approximately 9% by weight of the emulsion;

Solvent components comprising approximately 10% to 35% of the emulsion weight;

A stabilizer component comprising approximately 0.05% to approximately 5% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 40% to 60% of the emulsion's weight;

Oil components comprising approximately 15% to 30% of the emulsion weight;

Emulsifier components comprising approximately 2% to approximately 6% of the emulsion weight;

Solvent components comprising approximately 15% to 30% of the emulsion weight;

A stabilizer component comprising approximately 0.1% to approximately 2% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 40% to 60% of the emulsion's weight;

Oil components comprising approximately 15% to 30% of the emulsion weight;

Emulsifier components comprising approximately 2% to approximately 6% of the emulsion weight;

Solvent components comprising approximately 15% to 24% of the emulsion weight;

A stabilizer component comprising approximately 0.1% to approximately 2% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 45% to 55% of the emulsion's weight;

Oil components comprising approximately 15% to 24% of the emulsion weight;

Emulsifier components comprising approximately 3% to 5% of the emulsion weight;

Solvent components comprising approximately 20% to 25% of the emulsion weight;

A stabilizer component comprising approximately 0.3% to approximately 0.5% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 45% to 55% of the emulsion's weight;

Oil components comprising approximately 15% to 24% of the emulsion weight;

Emulsifier components comprising approximately 4% to 7% of the emulsion weight;

Solvent components comprising approximately 20% to 25% of the emulsion weight;

A stabilizer component comprising approximately 0.3% to approximately 0.5% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some implementations:

The oil component comprises one or more substances independently selected from the following: paraffin, fatty alcohol, mineral oil, triglycerides and dimethylsiloxane;

The emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and dehydrated sorbitol fatty acid esters;

The solvent component comprises one or more substances independently selected from alkyldiols and polyalkyldiols; and

The stabilizer component comprises one or more substances independently selected from polysaccharides.

In some implementations:

The oil component comprises one or more substances independently selected from the following: white wax, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides and dimethyl polysiloxane;

The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;

The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and

The stabilizer component includes three-grain glue.

In some embodiments, the emulsion comprises:

Water constitutes approximately 35% to 65% of the emulsion's weight;

The occlusive agent component comprises approximately 2% to 15% of the emulsion weight;

The hardener component comprises approximately 2% to 8% of the emulsion weight;

The emulsion contains emollients comprising approximately 5% to 15% of its weight.

Emulsifier components comprising approximately 1% to approximately 9% by weight of the emulsion;

A stabilizer component comprising approximately 0.05% to approximately 5% by weight of the emulsion;

Solvent components comprising approximately 10% to approximately 35% of the emulsion weight; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 40% to 60% of the emulsion's weight;

The occlusive agent component comprises approximately 5% to 10% of the emulsion weight;

The hardener component comprises approximately 2% to 8% of the emulsion weight;

The emulsion contains emollients comprising approximately 7% to 12% of its weight.

Emulsifier components comprising approximately 2% to approximately 6% of the emulsion weight;

A stabilizer comprising approximately 0.1% to approximately 2% of the emulsion weight;

Solvent components comprising approximately 15% to 30% of the emulsion weight; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 45% to 55% of the emulsion's weight;

The occlusive agent component comprises approximately 5% to 10% of the emulsion weight;

The hardener component comprises approximately 3% to 6% of the emulsion weight;

The emulsion contains emollients comprising approximately 7% to 13% of its weight.

Emulsifier components comprising approximately 3% to 5% of the emulsion weight;

A stabilizer component comprising approximately 0.3% to approximately 0.5% of the emulsion weight;

Solvent components comprising approximately 20% to 25% of the emulsion weight; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 45% to 55% of the emulsion's weight;

The occlusive agent component comprises approximately 5% to 10% of the emulsion weight;

The hardener component comprises approximately 4% to 7% of the emulsion weight;

The emulsion contains emollients comprising approximately 7% to 13% of its weight.

Emulsifier components comprising approximately 4% to 7% of the emulsion weight;

A stabilizer component comprising approximately 0.3% to approximately 0.5% of the emulsion weight;

Solvent components comprising approximately 20% to 25% of the emulsion weight; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, the emulsion comprises:

Water constitutes approximately 45% to 55% of the emulsion's weight;

The occlusive agent comprises approximately 7% of the emulsion by weight;

The hardener component comprises approximately 4.5% to 5% of the emulsion weight;

The emulsion contains approximately 10% emulsion by weight of moisturizing agent.

Emulsifier component comprising approximately 4% to approximately 4.5% of the emulsion weight;

A stabilizer component comprising approximately 0.4% of the emulsion weight;

Solvent component comprising approximately 22% by weight of the emulsion; and

Ruxotinib or its pharmaceutically acceptable salt, comprising 1.5% of the emulsion weight on a free base basis.

In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in the form of ruxolitinib phosphate.

In some embodiments, the emulsion contains 1.5% ruxotinib or a pharmaceutically acceptable salt thereof by weight of the emulsion.

In some embodiments, the emulsion contains 1.5% ruxotinib phosphate by weight of the emulsion.

In some embodiments, the combined amount of the hardener and emulsifier components is at least about 8% of the emulsion weight.

In some implementations:

The occlusive agent contains paraffin;

The hardener component contains one or more substances independently selected from one or more fatty alcohols;

The moisturizing ingredients contain one or more substances independently selected from mineral oils and triglycerides;

The emulsifier component comprises one or more substances independently selected from glycerol fatty acid esters and dehydrated sorbitol fatty acid esters;

The stabilizer component comprises one or more substances independently selected from polysaccharides; and

The solvent component contains one or more substances independently selected from alkyldiols and polyalkyldiols.

In some implementations:

The occlusive agent contains white wax;

The hardener component contains one or more substances independently selected from cetyl alcohol and stearyl alcohol;

The emollient components comprise one or more substances independently selected from: light mineral oil, medium-chain triglycerides and dimethyl polysiloxane;

The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;

The stabilizer component includes three-grain glue; and

The solvent component contains one or more substances independently selected from propylene glycol and polyethylene glycol.

In some embodiments, the emulsion further includes antimicrobial preservative components.

In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the emulsion.

In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the emulsion.

In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from p-hydroxybenzoic acid ester and phenoxyethanol.

In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and phenoxyethanol.

In some embodiments, the emulsion further includes chelating agents.

In some embodiments, the chelating agent component includes sodium edetate.

Ruxotinib can be prepared as described in U.S. Patent 7,598,257 and U.S. Patent Publication No. 2009/0181959, the entire contents of which are incorporated herein by reference. 1:1 ruxotinib phosphate can be prepared as described in U.S. Patent Publication No. 2008/0312259, the entire contents of which are incorporated herein by reference.

As will be understood, some components of the creams (lotions) described herein may have multiple functions. For example, a given substance may act as both an emulsifier and a stabilizer. In some such cases, the function of a given component may be considered singular, even if its properties allow for multiple functionalities. In some embodiments, the components of the formulation contain different substances or mixtures of substances.

It should be further understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination.

combination therapy

The methods described herein may further include administering one or more additional treatments. One or more additional treatments may be administered to the patient simultaneously or sequentially, or they may be administered in a single preparation or combined into a single preparation.

In some embodiments, the additional treatment is a vitamin D3 analogue (e.g., calcipotriol or mascaracalcidol). In some embodiments, the additional treatment is calcipotriol. In some embodiments, the additional treatment is mascaracalcidol. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof and a vitamin D3 analogue, calcipotriol or mascaracalcidol, are administered in a single formulation. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof and calcipotriol are administered in a single formulation. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof and mascaracalcidol are administered in a single formulation. In some embodiments, the combination therapy includes an anhydrous topical skin formulation comprising (a) ruxotinib or a pharmaceutically acceptable salt thereof, and (b) a vitamin D3 analogue, namely calcipotriol or mascaracalciferol. In some embodiments, the formulation is an anhydrous cream, anhydrous foam, anhydrous ointment, anhydrous lotion, or anhydrous gel. In some embodiments, the formulation is an anhydrous cream. In some embodiments, the formulation is an anhydrous ointment. In some embodiments, the combination therapy includes ruxotinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analogue is calcipotriol. In some embodiments, the combination therapy includes ruxolitinib or a pharmaceutically acceptable salt thereof, and the vitamin D3 analogue is mashacalciferol. In some embodiments, the combination therapy includes ruxolitinib or a pharmaceutically acceptable salt thereof at a concentration of about 0.5% to about 3.0%, about 0.5% to about 2.0%, or about 0.5% to about 1.5% w/w, based on the free base. In some embodiments, the combination therapy comprises approximately 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.05%, 1.15% by weight of the formulation, based on free base. %, approximately 1.2%, approximately 1.25%, approximately 1.3%, approximately 1.35%, approximately 1.4%, approximately 1.45%, approximately 1.5%, approximately 1.55%, approximately 1.6%, approximately 1.65%, approximately 1.7%, approximately 1.75%, approximately 1.8%, approximately 1.85%, approximately 1.9%, approximately 1.95%, approximately 2.0%, approximately 2.5%, or approximately 3.0% of ruxolitinib or its pharmaceutically acceptable salt. In some embodiments, the combination therapy comprises approximately 0.0005% w/w to approximately 0.05%, approximately 0.0005% to approximately 0.01%, or approximately 0.0005% w/w of a vitamin D3 analogue. In some embodiments, the combination therapy comprises approximately 1.5% w/w ruxolitinib or a pharmaceutically acceptable salt thereof and approximately 0.005% w/w a vitamin D3 analogue. In some embodiments, the combination therapy further comprises a solvent component and an oil component. In some embodiments, the combination therapy further comprises an antioxidant component.

In some embodiments, the additional treatment is a steroid. In some embodiments, the additional treatment is a corticosteroid. In some embodiments, the steroid is such as pimecrolimus, tacrolimus, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, or flumetholone.

In some embodiments, the additional treatment is a topical calcineurin inhibitor. In some embodiments, the topical calcineurin inhibitor is tacrolimus ointment or pimecrolimus cream.

In some embodiments, the additional treatment is an antibiotic. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, erythromycin, metronidazole, rifampin, moxifloxacin, dapsone, or combinations thereof. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim-sulfamethoxazole, or a combination of erythromycin and metronidazole. In some embodiments, the antibiotic is a combination of rifampin, moxifloxacin, and metronidazole. In some implementations, the antibiotic is a combination of moxifloxacin and rifampin.

In some embodiments, the additional treatment is a retinoid. In some embodiments, the retinoid is adapalene, etretinate, acitretin, or isotretinoin.

In some embodiments, the additional treatment is an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate or cyclosporine A. In some embodiments, the immunosuppressant is mycophenolate mofetil or sodium mycophenolate.

Set

This application also includes pharmaceutical kits applicable to, for example, the treatment and/or prevention of hidradenitis suppurativa (HS), comprising containers containing one or more pharmaceutical compositions comprising a therapeutically effective amount of ruxotinib or a pharmaceutically acceptable salt thereof, as described herein. If desired, such kits may further include one or more of various known pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit may also include instructions in the form of inserts or labels indicating the amount of components to be administered, administration guidelines, and/or guidelines for mixing components. Examples

This invention will be described in more detail with the help of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily identify the various non-critical parameters that can be changed or modified to produce substantially the same results.

Example 1 : Preparation of ruxotinib (INCB018424) Phosphate-in-oil cream formulation

First, to determine the solubility of ruxotinib (free base) or its 1:1 phosphate, approximately 5 mL of potential solvent was added to approximately 50 mg of API or its salt at room temperature. The mixture was suspended on a wheel and rotated. If the mixture became a clear solution, more solids were added. The suspension was then suspended for more than 24 hours. The sample was filtered through a 0.2 μm filter. The liquid fraction was collected and diluted with 50/50 water/methanol/water. The concentration of the diluted sample was analyzed by HPLC. When the free base or salt is poorly soluble, the results are only approximate. Their findings are presented in Table 3 .

surface 3 Potential solvents Solubility of phosphate (mg/mL) Solubility of free alkali (mg/mL) water 2.7 2.0 pH 4, citrate buffer, 0.1 M 1.5 1.1 pH 6, citrate buffer, 0.1 M 0.2 0.15 Ethanol 7.3 5.5 Isopropanol 0.6 0.45 Benzyl alcohol 3 2.3 Propylene glycol twenty four 18.2 PEG 200 twenty three 17.4 PEG 300 14 10.6 Glycerin 11 8.3 Diethylene glycol monoethyl ether 10 7.6 Triethanolamine 51 38.6 Water/PEG 200 (50/50) twenty three 17.4 Water/Glycerin (50/50) twenty one 15.9 Water/Glycerin/Triethanolamine (40/40/20) 18 13.6 Isopropyl myristate <0.1 0.08 Isosorbide dimethyl ether 0.4 0.3 Mineral oil <0.1 0.08 Oil alcohol 0.1 0.08 Dimethicone <0.2 0.15 _C12-15 alcohol benzoate <0.2 0.15 Caprylic/Capric Triglyceride <0.2 0.15

Oil-in-water cream formulations were prepared for 1:1 ruxolitinib phosphate at 0.5%, 1.0%, and 1.5% (free base equivalent) by weight of the formulation. 15-gram tubes of the formulations are provided in Table 2 below. All three formulations were identical except for adjustments to the amount of purified water based on the amount of active ingredient. All excipients used in the formulations were pharmacopoeia grade (i.e., USP/NF or BP) or approved for use in topical products.

The quantitative formulations of the cream formulations, representing 400 kg batches at 0.5%, 1.0%, and 1.5%, are also provided in Tables 3, 4, and 5, respectively.

The oil-in-water emulsion formulation is synthesized in 3.5 kg or 400 kg batches according to the following procedure (when produced in 3.5 kg batches, the amounts in Tables 4-6 are adjusted proportionally as appropriate). Minor variations related to scaling up may occur in some batches, such as the size of the mixing container and mixer. Generally, an overhead mixer with high-shear and low-shear mixing blades is suitable for this process.

program

1. The p-hydroxybenzoate phase was prepared by mixing methyl p-hydroxybenzoate and propyl p-hydroxybenzoate with a portion of propylene glycol ( see Table 3-6 for percentages).

2. Next, the three-skin glue phase was prepared by mixing three-skin glue with propylene glycol ( see Table 3-6 for percentages).

3. Next, an oil phase is prepared by mixing light mineral oil, glyceryl stearate, polysorbate 20, white wax, cetyl alcohol, stearyl alcohol, dimethyl polysiloxane, and medium-chain triglycerides. This phase is heated to 70-80°C to melt and form a homogeneous mixture.

4. Next, an aqueous phase is prepared by mixing purified water, polyethylene glycol, and disodium EDTA. The phase is then heated to 70-80°C.

5. Combine the aqueous phase of step 4, the p-hydroxybenzoate phase of step 1, and Example 2 (phosphate of API) to form a mixture.

6. Next, add the three-particle glue phase from step 2 to the mixture from step 5.

7. Subsequently, the oil phase from step 3 is combined with the mixture from step 6 under high-shear mixing to form an emulsion.

8. Next, add phenoxyethanol to the emulsion from step 7. Continue mixing, and then cool the product under low-shear mixing.

surface 4 formula Function Percentage of the total (% w/w) gram / Tube Mutually Components p-Hydroxylbenzoate Propylene glycol USP Solvent 10.00 1.5 Methyl p-hydroxybenzoate NF Antimicrobial preservatives 0.10 0.015 propyl p-hydroxybenzoate NF Antimicrobial preservatives 0.05 0.0075 Three Immortals Glue Propylene glycol USP Solvent 5.00 0.75 Three Immortals Glue NF Suspending agents, stabilizers, and thickeners 0.40 0.06 Oil Light mineral oil (NF) Moisturizers, solvents 4.00 0.6 Glyceryl stearate SE Emulsifiers 3.00 0.45 Polysorbate 20 NF Emulsifiers/Stabilizers 1.25 0.1875 White wax USP Occlusive agents 7.00 1.05 Whale Wax Alcohol NF Hardener, consistency improver 3.00 0.45 Stearyl NF Hardener 1.75 0.2625 Dimethicone 360 NF Skin care products 1.00 0.15 Medium-chain triglycerides (NF) Moisturizers, solvents 5.00 0.75 Water-based/Active Agent Purified Water USP Solvent 50.24 - 48.92 7.536 - 7.338 Sodium edetate USP Chelating agents 0.05 0.0075 Polyethylene glycol USP Solvent 7.00 1.05 Example 2 * Activator 0.66 - 1.98 0.099 - 0.297 Ultimately Phenoxyethanol BP Antimicrobial preservatives 0.50 0.075 Total 100.00% 15

surface 5 Element Kilogram percentage (w/w) Ruxotinib phosphate 2.64 (phosphate) / 2.0 (free alkali) 0.66 (phosphate) / 0.5 (free alkali) Propylene glycol USP 40.0 10.00 Methyl p-hydroxybenzoate NF 0.4 0.10 propyl p-hydroxybenzoate NF 0.2 0.05 Propylene glycol USP 20.0 5.00 Three Immortals Glue NF 1.6 0.40 Light mineral oil (NF) 16.0 4.00 Glyceryl stearate SE 12.0 3.00 Polysorbate 20 NF 5.0 1.25 White wax USP 28.0 7.00 Whale Wax Alcohol NF 12.0 3.00 Stearyl NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00 Medium-chain triglycerides (NF) 20.0 5.00 Purified Water USP (Approximate Value) 201 50.25 Sodium edetate USP 0.2 0.05 Polyethylene glycol USP 28.0 7.00 Phenoxyethanol BP 2.0 0.5 Total (approximate value) 400.0 100

surface 6 Element Kilogram percentage (w/w) Ruxotinib phosphate 5.28 (phosphate) / 4.0 (free alkali) 1.32 (phosphate) / 1.00 (free alkali) Propylene glycol USP 40.0 10.00 Methyl p-hydroxybenzoate NF 0.4 0.10 propyl p-hydroxybenzoate NF 0.2 0.05 Propylene glycol USP 20.0 5.00 Three Immortals Glue NF 1.6 0.40 Light mineral oil (NF) 16.0 4.00 Glyceryl stearate SE 12.0 3.00 Polysorbate 20 NF 5.0 1.25 White wax USP 28.0 7.00 Whale Wax Alcohol NF 12.0 3.00 Stearyl NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00 Medium-chain triglycerides (NF) 20.0 5.00 Purified Water USP (Approximate Value) 198.5 49.6 Sodium edetate USP 0.2 0.05 Polyethylene glycol USP 28.0 7.00 Phenoxyethanol BP 2.0 0.5 Total (approximate value) 400.0 100

surface 7 Element Kilogram percentage (w/w) Ruxotinib phosphate 7.92 (phosphate) / 6.0 (free alkali) 1.98 (phosphate) / 1.5 (free alkali) Propylene glycol USP 40.0 10.00 Methyl p-hydroxybenzoate NF 0.4 0.10 propyl p-hydroxybenzoate NF 0.2 0.05 Propylene glycol USP 20.0 5.00 Three Immortals Glue NF 1.6 0.40 Light mineral oil (NF) 16.0 4.00 Glyceryl stearate SE 12.0 3.00 Polysorbate 20 NF 5.0 1.25 White wax USP 28.0 7.00 Whale Wax Alcohol NF 12.0 3.00 Stearyl NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00 Medium-chain triglycerides (NF) 20.0 5.00 Purified Water USP (Approximate Value) 195.5 48.9 Sodium edetate USP 0.2 0.05 Polyethylene glycol USP 28.0 7.00 Phenoxyethanol BP 2.0 0.5 Total (approximate value) 400.0 100

Larger, thicker batches (e.g., 140 kg) can be obtained by gradually adding ruxolitinib phosphate to the aqueous phase and then combining it with other phases. Similarly, thicker batches can be obtained by slower cooling (e.g., using room temperature water instead of cold water in the outer casing of the reactor).

Table 8 shows the formulations of 0.75% and 1.5% ruxolitinib cream; the 1.5% ruxolitinib cream formulation in Table 6 is the formulation used in Example 2.

surface 8 Components 0.75% Cream 1.5% Cream wt% g/60 g Tube wt% g/60 g Tube Ruxotinib phosphate 0.99 (0.751)) 0.594 1.98 (1.50b) 1.188 Propylene glycol 15.0 9.00 15.0 9.00 Methyl p-hydroxybenzoate 0.10 0.06 0.10 0.06 propyl p-hydroxybenzoate 0.05 0.03 0.05 0.03 Three Immortals Glue 0.40 0.24 0.40 0.24 Light mineral oil 4.00 2.40 4.00 2.40 Glyceryl stearate SE 3.00 1.80 3.00 1.80 Polysorbate 20 1.25 0.75 1.25 0.75 White wax 7.00 4.20 7.00 4.20 Whale wax alcohol 3.00 1.80 3.00 1.80 Stearyl alcohol 1.75 1.05 1.75 1.05 Dimethicone 360 1.00 0.60 1.00 0.60 Medium-chain triglycerides 5.00 3.00 5.00 3.00 purified water 49.91 29.95 48.92 29.36 Sodium edetate 0.05 0.03 0.05 0.03 Polyethylene glycol 200 7.00 4.20 7.00 4.20 Phenoxyethanol 0.50 0.30 0.50 0.30 Total 100% 60 g 100% 60 g

Stability tests were conducted on each batch at 25°C, and the products remained stable for up to 24 months, with pH values consistent with the aforementioned pH range (see Tables 7, 9, 11, 12, 13, 15, 17, and 19 of U.S. Patent Publication No. 2015/0250790, which is incorporated herein by reference in its entirety). The viscosity of the cream formulation (e.g., containing 0.75% or 1.5% ruxotinib phosphate based on free base) was ≥17,000 cP at release and ≥10,000 cP during shelf life.

Example 2 : Using ruxolitinib to treat hidradenitis suppurativa (HS) Of II Periodic study

This (INCB 18424-221) is a phase 2 randomized, double-blind, mediator-controlled (DBVC) study with a DBVC period of 16 weeks, followed by a 16-week open-label extension (OLE) period.

Participants will undergo screening for up to 28 days prior to the first application of 1.5% ruxolitinib cream or carboxylate cream. Key inclusion criteria for participants include a diagnosis of HS (Herlich stage I or II) at least 3 months prior to the screening visit, a total anterior descending artery (AN) number of 3 to ≤ 10 at screening and baseline, and the absence of drainage pathways. An AN number of 3 may affect at least one distinct anatomical region; however, an AN number > 3 to ≤ 10 will definitely affect at least two distinct anatomical regions.

Approximately 60 eligible participants aged ≥ 18 years were randomly assigned 1:1 to either 1.5% ruxolitinib cream or carboxylate cream. Participants were stratified based on baseline AN numbers (≥ 3 to 4 or ≥ 5 to 10). By week 16, participants applied either 1.5% ruxolitinib cream or carboxylate cream (both BID) to all diseased areas identified at baseline.

At week 16, participants who meet the criteria (compliance with the protocol and no safety issues) will enter the 16-week OLE period. Participants randomly assigned to the media BID during the DBVC period will cross-use the 1.5% ruxolitinib cream BID, and participants randomly assigned to the 1.5% ruxolitinib cream BID at baseline will continue to use the 1.5% ruxolitinib cream BID on an open-label basis until week 32. At week 16, researchers will assess the HS treatment area to evaluate the disease and determine whether continued treatment is necessary during OLE (AN number ≥ 1 and/or skin pain NRS ≥ 1) or whether participants can re-enter the observation/no-treatment cycle (AN number = 0 and skin pain NRS = 0). During OLE, participants will only treat symptomatic lesions (e.g., existing lesions, pain, and/or itching), including new lesions, totaling no more than 20% of BSA.

Researchers and participants will be unaware of treatment allocation during the DBVC period until all participants complete the study or discontinue the study and complete the safety follow-up period.

During the DBVC and OLE phases, participants treated with HS lesion rescue drugs and/or procedures were considered unresponsive to treatment and the study was discontinued.

Tables 9A and 9B summarize the event schedule.

Table 9A : Activity Schedule. Visiting day (scope) Screening Baseline (Day 1) Treatment (Carrier Control Period) Treatment (open label expansion) a Unplanned visits Follow-up visit Day -28 to -1 Week 2 (± 3 days) Week 4 (± 3 days) Week 8 (± 3 days) Week 12 (± 3 days) Week 16a ± 3 days / ET1 Week 20 (± 3 days) Week 24 (± 3 days) Week 28 (± 3 days) Week 32 (± 3 days/ET2) 30 days (+7 days) after the last application Voting Procedure Informed Consent Form X Inclusion/Exclusion Criteria X X Population statistics data, medical history X Previous/concomitant medications X X X X X X X X X X X X X Contact IRT X X X X X X X X X X X Random allocation X Distribution Electronic Diary X Distribute reminder cards X X X X X X X X X X Electronic Diary Verification X X X X X X X X X X Application of research drugs in outpatient clinics X Weighing/Distributing Study Drugs X X X X X X X X X Collect/weigh research drugs and review research drug diaries X X X X X X X X X Evaluation of investigational drug compliance X X X X X X X X X X Safety assessment AE Assessment X X X X X X X X X X X X X physical examination X ^b X ^c Xb Xc vital signs X X X X X X X X X X X X X Height and weight X Efficacy evaluation BSA% X ^d X X X X X X X X X X X Number of lesions and assessment X X X X X X X X X X X X X total Hurley disease period X X X X X X Patient Report Results NRS (Near-Schönlein Skin Pain) Complete it every night until the last application of the research drug. NRS (Nutritional Rhinitis) Complete it every night until the last application of the research drug. Analgesic uses (excluding opiates) Complete it every night until the last application of the research drug. PGIC X X X X X X X X X X

Table 9B : Event Schedule (Continued) Visiting day (scope) Screening Baseline (Day 1) Treatment (Carrier Control Period) Treatment (open label expansion) a Unplanned visits Follow-up visit Day -28 to -1 Week 2 (± 3 days) Week 4 (± 3 days) Week 8 (± 3 days) Week 12 (± 3 days) Week 16a ± 3 days / ET1 Week 20 (± 3 days) Week 24 (± 3 days) Week 28 (± 3 days) Week 32 (± 3 days/ET2) 30 days (+7 days) after the last application Patient Report Results ( Continued ) HiSQoL X X X X X X X DLQI X X X X X X X WPAI-HS X X X X X X X EQ-5D-5L X X X X X X X Laboratory evaluation Chemical evaluation X X ^e X X Xf X Hematological assessment X X ^e X X Xf X hsCRP X X X X FSHg X Serum pregnancy test h X X Urine pregnancy test X X X X X X X X X HIV/Hepatitis Serology X Transformation assessment Serum biomarkers X X X X Photography (on a selected area) X X X X Drug exposure assessment Blood PK Sampling X Saliva PK Sampling X X X X

At each study visit, the "HS lesion count" will be assessed and used to calculate the following efficacy parameters: AN number, HiSCR, IHS4, ISH4-55, and outbreak rate. The lesion count and assessment will be recorded in the lesion count worksheet, which includes assessment of anatomical regions, including (but not limited to) the left and right axillae; or the left and right inguinal folds or the submammary region.

The number of abscesses and inflammatory nodules (AN number) will be recorded at all visits. The AN results will be used to calculate the change in AN number relative to the baseline, and AN50, AN75, AN90, and AN100, which are defined as a decrease in AN number relative to the baseline of at least 50%, 75%, 90%, and 100%, respectively.

The "HiSCR" or "Hidradenitis Suppurativa Clinical Response" was initially developed based on a phase 2 trial of adalimumab and validated based on meaningful changes in pain scores and DLQI (Kimball AB, Sobell JM, Zouboulis CC et al., HiSCR (Hidradenitis Suppurativa Clinical Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with hidradenitis suppurativa from the placebo-controlled portion of a phase 2 adalimumab study. J Eur Acad Dermatol Venereol 2016;30:989-994; Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. Nat Rev Dis Primers 2020;6:18). Participants with drainage fistulas (channels) will be excluded from the study. If a randomly assigned participant develops a drainage channel during the study period, that participant will be discontinued from the study.

The Herley classification was originally designed to select appropriate treatment for a specific body location (Zouboulis CC, Tzellos T, Kyrgidis A et al., Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br J Dermatol 2017;177:1401-1409): Stage I is medical therapy, Stage II is local surgery, and Stage III is extensive surgical resection (see Table 2). Participants diagnosed with HS (Herley Stage I or II) according to the inclusion criteria will be included in the study.

Baseline skin pain NRS and pruritus NRS are determined before the first dose of medication as follows: The average pruritus NRS score of the baseline visit will be collected (data from at least 4 of the 7 days).

Participants are eligible to be included in the study only if they meet all of the following criteria:

(1) Be able to understand and be willing to sign a written ICF for the study.

(2) Male or female participants must be 18 years of age or older.

(3) Screening should be conducted at least 3 months prior to the visit, based on clinical history and physical examination to diagnose HS.

(4) The following criteria are used to diagnose HS (Heary Stage I or II): (a) a total AN number of 3 to ≤10 at screening and baseline visits, with no drainage pathway. and (b) AN number at screening and baseline visits: an AN of 3 should affect at least one distinct anatomical region and an AN >3 to ≤10 should affect at least two distinct anatomical regions. Note: Anatomical regions include (but are not limited to) the left and right axillae; or the left and right inguinal folds or the submammary region.

(5) Baseline skin pain or itching NRS score ≥ 1. Baseline skin pain or itching NRS is defined as the average of the skin pain or itching NRS scores over the 7 days prior to day 1 (data from at least 4 days of the 7 days prior to day 1 is required).

(6) Agree not to use local or systemic antibiotics to treat HS during the study period.

(7) Agreed not to use diluted beach soap or topical disinfectants containing chlorhexidine gluconate or benzoyl peroxide on areas affected by HS lesions during the study period.

(8) Willing to avoid pregnancy or childbirth according to the following criteria: (a) Male participants of fertility potential must agree to take appropriate precautions to avoid childbirth from the time of selection until 90 days (one spermatogenesis cycle) after the last application of ruxolitinib cream, and must refrain from donating sperm during this period. Permissible methods of contraception should be communicated to participants and their understanding confirmed. (b) Female participants of WOCBP must have a negative serum pregnancy test at the time of selection and before the first application on Day 1, and must agree to take appropriate precautions to avoid pregnancy from the time of selection until 30 days (one menstrual cycle) after the last application of the study ruxolitinib cream, and must refrain from donating oocytes during this period. The permitted method of contraception should be communicated to the participants and their understanding should be confirmed. (c) Female participants who are considered to be without fertility potential are eligible.

Participants are excluded from the study if they meet any of the following criteria:

(1) There is a drainage channel during screening or baseline visits.

(2) Total HS morbidity BSA (excluding scalp) > 20%.

(3) Participants with comorbidities and other medical conditions: (a) Other active, persistent inflammatory skin diseases that may confound the assessment of HS, in addition to HS. (b) Any other coexisting skin condition (e.g., generalized erythroderma, such as Netherton's syndrome), pigmentation, or extensive scarring that the investigator believes may interfere with the assessment of HS AN or endanger the safety of the participant. (c) Active tuberculosis; or current latent tuberculosis and/or a history of latent tuberculosis, unless adequately treated. (d) Immune impairment (e.g., lymphoma, acquired immunodeficiency syndrome, or Wiskott-Aldrich syndrome). (e) Chronic or acute infections requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoal drugs, or antifungals within 2 weeks prior to the baseline. (f) Active acute bacterial, fungal, or viral skin infections (e.g., herpes simplex, herpes zoster, chickenpox, clinically infectious adenoiditis, or pustules) within 2 weeks prior to the baseline. (g) Unstable asthma or COPD requiring systemic treatment (such as intravenous steroids) or hospitalization or emergency room treatment within 3 months from the baseline; or stable asthma or COPD requiring more than 720 µg (BID, 2 sprays, 180 µg each time) or more than 440 µg (BID, 2 sprays, 110 µg each time) or other equivalent inhaled corticosteroids daily.

(4) Any serious illness or medical, physical or mental condition that, in the investigator’s view, would interfere with full participation in the study, including administration of the investigational drug and participation in required study visits, pose a significant risk to the participant, or interfere with the interpretation of the study data. For example: (a) clinically significant or uncontrolled cardiovascular disease, including unstable angina, acute myocardial infarction or stroke, New York Heart Association class III or IV congestive heart failure and arrhythmias requiring treatment or persistent uncontrolled hypertension (blood pressure > 150/90 mmHg) within 6 months from day 1 of administration of the investigational drug, unless approved by the medical monitor/trial commissioner. (b) Any malignant disease or history of malignancy within 5 years prior to baseline, except for non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin that has been adequately treated or removed, or cervical carcinoma in situ. (c) History of severe anemia, severe thrombocytopenia, or severe neutropenia.

(5) Any of the following clinical laboratory test results at screening: (a) Decreased blood cell count at screening, defined as: hemoglobin < 100 g/L (i.e., 10 g/dL); ANC < 1.5 × ^10⁹ /L (i.e., 1500/µL); and/or platelet count < 1 × ^10¹¹ /L (i.e., 100,000/µL). (b) Liver function tests: AST or ALT ≥ 2.5 × ULN; and/or total bilirubin > 1.5 × ULN, unless Gilbert's syndrome is present. (c) Estimated GFR < 30 mL/min/1.73 ^m² (using the Chronic Kidney Disease Epidemiological Cooperative Equation). (d) Positive HIV antibody serological test result at screening. (e) History of acute or chronic active HBV or HCV infection or current acute or chronic active HBV or HCV infection. Participants who have recovered or have been successfully treated and show no signs of active HBV or HCV infection, as well as participants who are immune due to hepatitis B vaccination, are eligible for enrollment. Participants who are positive for hepatitis B surface antigen are eligible if they are negative for HBV-DNA; participants who are positive for anti-HCV antibodies are eligible if they are negative for HCV-RNA. (f) Any other clinically significant laboratory results that, in the investigator's view, pose a significant risk to the participant.

(6) History of failure to treat HS or any other inflammatory condition with any systemic or local JAK or TYK2 inhibitor (e.g., abrocitinib, baricitinib, brepocitinib, deucravacitinib, filgotinib, lestaurtinib, pacritinib, ruxotinib, tofacitinib, upadacitinib) (assessed by the investigator through study participant interviews).

(7) Use any of the following treatments during the washout period prior to baseline visits: (a) for systemic immunosuppression or immunomodulatory biologics (e.g., adalimumab, anakinra, bermekimab, bimekizumab, brodalumab, certolizumab, dupilumab, etanercept, golimumab). (a) For any local or systemic JAK or TYK2 inhibitor (e.g., abrutinib, guselkumab, infliximab, iscalimab, ixekizumab, risankizumab, rituximab, secukinumab, vilobelimab, ustekinumab, etc.), 12 weeks or 5 half-lives (if known), whichever is longer. (b) For any local or systemic JAK or TYK2 inhibitor (e.g., abrutinib, baricitinib, brepotinib, deuterocelexitinib, filogrinib, lintatinib, paritinib, ruxotetinib, tofacitinib, uropatinib, etc.), 4 weeks. (c) 4 weeks - systemic corticosteroids or adrenocorticotropic hormone analogs, cyclosporine, methotrexate, azathioprine, or other systemic immunosuppressants or immunomodulators (e.g., mycophenolate mofetil or tacrolimus). (d) 2 weeks or 5 half-lives (whichever is longer) - potent systemic CYP3A4 inhibitors. (e) 2 weeks - systemic antibiotics and live attenuated vaccine immunization, sedative antihistamines, unless a long-term stable regimen is adopted (non-sedative antihistamines are permitted). (f) Several weeks - topical treatment of HS (e.g., topical disinfectants, topical antibiotics, topical corticosteroids, topical calcineurin inhibitors, other topical medications). (g) 2 weeks - any type of opium treatment.

(8) Currently receiving treatment, or receiving treatment with another investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the baseline visit, or currently enrolled in another investigational drug regimen.

(9) Participants who are known to be allergic to or have a reaction to any component of the study cream.

(10) Those with a history of alcohol or drug addiction within the year prior to screening, or currently drinking alcohol or using drugs, will be considered by the researchers to have a history of alcohol or drug addiction that would interfere with the participants’ ability to adhere to the drug administration schedule and the research evaluation.

(11) Participants who are pregnant or breastfeeding, or participants who are considering becoming pregnant during the study participation period.

(12) Participants with insufficient venous access in non-lesion areas or lesion areas that have not received treatment with the study drug in the past 7 days.

(13) Participants who are sent to mental health institutions in accordance with orders issued by judicial or administrative authorities.

(14) Participants who, in the researcher’s view, are unable or unlikely to comply with the drug administration schedule and study evaluation.

(15) The employees of the commissioner or researcher or their family members.

Apply 1.5% ruxolitinib cream or matching mediator cream as a thin film, twice daily, at least 1 hour before bedtime in the morning and at least 8 hours apart.

At the baseline visit, the IRT system will use an estimated percentage of BSA (≤ 20%) (excluding the scalp) affected by the HS (total AN number 3 to ≤ 10) to calculate the number of study drug tubes to be allocated. Participants will apply a thin film of study drug to each nodule and the area around the nodule (approximately 1 cm) in front of on-site staff at the baseline/Day 1 visit. Treatment of all areas identified at baseline should continue until the end of the DBVC period (week 16) unless the participant meets the criteria for discontinuing the study drug. If new analgesics (ANs) are identified and treatment is initiated, the investigational drug should be applied to these ANs (maximum total lesion area ≤ 20% BSA) in addition to the areas treated at baseline, after consultation with the investigator. The percentage of BSA to be treated should be recalculated and increased. This new estimate will be entered into the IRT system to calculate the number of investigational drug tubes to be allocated. If a participant develops additional treatment areas exceeding 20% BSA outside the areas identified at baseline visits, study treatment should be discontinued and an ET assessment should be completed.

At week 16, when the OLE period begins, researchers will assess participants to determine whether they require continued treatment due to an AN number ≥ 1 and/or the presence of pain (skin pain NRS ≥ 1), or whether they can begin the observation/no-treatment period due to an AN number = 0 and no pain [skin pain NRS = 0].

At week 16, the IRT system will allocate a predetermined number of tubes based on the total BSA assessment of the patients to be treated.

During OLE study visits, participants will treat all identified HS lesions (total affected area not exceeding 20% of BSA). If all HS signs and symptoms resolve during study visits, participants will contact the investigator to confirm that the study drug should be discontinued 3 days after the HS lesions (AN number = 0) disappear. If this 3-day window falls within the study visit period, and the investigator assesses AN number = 0 and skin pain NRS = 0, then treatment should be discontinued at the study visit.

Multiple treatment/no-treatment cycles may be used as needed, and the start/stop dates of treatment should be recorded in the electronic diary. If a participant discontinues treatment during the OLE period, treatment may be restarted in consultation with the investigator if the participant's AN count is ≥ 1 and/or if they experience pain (skin pain NRS score ≥ 1). During the OLE period, additional treatment areas may be approved by telephone, but the investigator may request the participant to return for unplanned visits at their discretion.

At any time during the OLE period, if a participant develops more than 20% BSA in new untreated areas outside of the areas identified at the last visit, the participant should discontinue the study treatment and complete the ET assessment. The amount of study drug used for each application will be determined by weighing the tube before and after the participant applies the study drug to the affected area. All study cream tubes (including caps) will be weighed before dispensing. All returned study cream tubes (including caps) will also be weighed. Table 10 presents the study treatment information.

Table 10 : Research and Treatment Information. Research on treatment 1 Research on treatment 2 Treatment Name: Ruxotinib Mediator Mechanism of action: JAK 1/2 inhibitor Not applicable Dosage preparation: Cream Cream Treatment intensity: 1.5% Not applicable Instructions for medication administration: DBVC phase: Apply a thin film to the affected area identified at baseline at least 1 hour before bedtime and in the morning, with an interval of approximately 8 hours between applications, for 16 weeks. OLE phase: Apply a thin film to the affected area as needed only at least 1 hour before bedtime and in the morning, with an interval of approximately 8 hours between applications, for 16 weeks. Packaging and labeling: Ruxotinib or cautery cream will be provided in 60 g tubes. Each tube will be labeled as required by national regulations. Storage: 15℃-30℃ (59℉-86℉) Treatment status in participating countries : Research

A preliminary analysis will be conducted based on the intention-to-treat (ITT) population. Tables 11 and 12 provide an overview of the primary and important/key secondary objectives and endpoints , as well as exploratory parameters.

Table 11 : Key Objectives and End Points Target Finish line main To determine the efficacy of 1.5% ruxolitinib cream BID in participants with HS. Changes in the number of abscesses and inflammatory nodules (ANs) relative to baseline at week 16.

Table 12 presents the key research design elements. Other research details are presented after the table.

Table 12 : Key Research Design Elements Study period Phase 2 Clinical indications Treatment of patients with suppurative hidradenitis group Males or females aged ≥ 18 years who have been diagnosed with HS (Heyer I and II) for at least 3 months; with a total AN number of 3 to ≤ 10. An AN number of 3 may affect at least one different anatomical region; however, an AN number > 3 to ≤ 10 will definitely affect at least two different anatomical regions. Number of participants Approximately 60 participants were randomly assigned 1:1 to one of two treatment groups (1.5% ruxolitinib cream BID or mordant cream BID). Research Design This was a randomly assigned 16-week DBVC study, followed by a 16-week OLE. Participants who completed the 16-week DBVC period received active treatment, followed by a 30-day post-treatment safety follow-up. The estimated duration of the study involved. The estimated total duration of participation was approximately 40 weeks, including up to 4 weeks of screening, up to 32 weeks of treatment, and 30 days of safety follow-up. Data Security Monitoring Committee / Data Monitoring Committee without Coordinating Principal Investigator Uncertain

Table 13 presents the objectives and endpoints. Target Finish line main To determine the efficacy of 1.5% ruxolitinib cream BID in participants with HS. Changes in the AN number relative to the baseline at week 16. secondary Further evaluation of the efficacy of 1.5% ruxolitinib cream BID in participants with HS. • Percentage of participants achieving AN50, AN75, AN90, and AN100 (AN numbers representing at least 50%, 75%, 90%, and 100% reduction from baseline, respectively) at week 16. • Change in skin pain NRS score relative to baseline at week 16. • Change in itching NRS score relative to baseline at week 16. • Percentage of participants achieving HiSCR at week 16. Note: HiSCR is defined as a reduction in AN number of at least 50% relative to baseline, without an increase in the number of abscesses or draining fistulas. • Change in International Hidradenitis Severity Scale (IHS4) score relative to baseline at week 16. Note: The IHS4 score is calculated by adding the number of inflammatory nodules (multiplied by 1), the number of abscesses (multiplied by 2), and the number of drainage channels (multiplied by 4). To evaluate the safety and tolerability of 1.5% ruxolitinib cream BID in participants with HS. The type, frequency, and severity of acute exacerbations (AEs), as well as changes in vital signs, hematological and serological parameters.

Approximately 60 participants were randomly assigned 1:1 to either a 1.5% ruxolitinib cream BID or a mediator BID. The sample size was not calculated based on statistical power, but rather to demonstrate preliminary findings of clinical response. It is anticipated that the sample size of approximately 60 participants will allow for the generation of sufficient data to assess whether ruxolitinib cream warrants further investigation in the HS. Furthermore, it is believed that this sample size is sufficient to provide adequate data for an initial assessment of the safety profile.

The primary efficacy analysis used the Multi-Mean Reaction Matrix (MMRM) to compare the mean change in AN number relative to baseline between 1.5% ruxolitinib cream and carton cream. The MMRM included fixed effect, stratification factors (AN number ≥ 3 to 4 or AN number ≥ 5 to 10 at baseline), visits, and visits based on treatment interactions. The variance-covariance matrix of intra-participant errors in the MMRM was modeled as unstructured.

The primary opposition hypothesis (superiority of the 1.5% active ruxolitinib cream BID group compared to the mediator) will be tested at a two-sided α = 0.1 level using the least-squares mean estimate of the change in the AN number relative to the baseline at week 16 in the MMRM described above. Subgroup analysis will be performed based on baseline characteristics.

Descriptive statistics based on the ITT population will be used to summarize all secondary and exploratory power variables. For categorical measurements, summary statistics will include sample size, frequency, and percentage. For continuous measurements, summary statistics will include sample size, mean, median, standard deviation, standard error of the mean, minimum, and maximum. Where applicable, summary statistics for continuous measurements will be provided for baseline, actual measurements at each visit, and change from baseline at each visit, and percentage change. Skin pain NRS scores at each visit will be determined by averaging the skin pain NRS scores of the seven daily visits prior to the corresponding visit date. If four or more daily scores are missing (out of seven), the skin pain NRS score at the visit will be set to missing. The itching NRS score at each visit will be determined using a similar method.

Example 3 : Example 2 : Using ruxolitinib to treat hidradenitis suppurativa (HS) Of II Results of blinded testing in a periodic study

The clinical trial described in Example 2 (a phase 2, randomized, double-blind, mediator-controlled (DBVC) study, with a 16-week DBVC period followed by a 16-week open-label extension (OLE) period) was conducted, and blinded data were obtained from all enrollees after week 32. Preliminary blinded data are presented below.

Tables 14 , 15 , and 16 summarize the demographic data and baseline characteristics of the study participants, their baseline disease characteristics, and the participant distribution during the DBVC period. Specifically, Table 14 presents an overview of the demographic data and baseline characteristics of the intended treatment population. Table 15 presents an overview of the baseline disease characteristics of the intended treatment population. Table 16 presents an overview of the participant distribution during the DBVC period for the intended treatment population. Table 14 Variables Total (N=69) Age (in years) n 69 average value 31.7 STD 9.76 Minimum value 18 Median 29.0 Maximum value 59 18 to 29 (ages) -n (%) 36 (52.2) 30 to 49 (ages) -n (%) 29 (42.0) 50 to 65 (ages) -n (%) 4 (5.8) > 65 (ages) - n (%) 0 ( 0.0) Gender - n(%) male 7 (10.1) female 62 (89.9) Ethnic Group - n(%) Hispanic or Latino 8 (11.6) Non-Hispanic or Latino 61 (88.4) Unreported 0 ( 0.0) unknown 0 ( 0.0) other 0 ( 0.0) Race - n (%) Caucasian 31 (44.9) Black/African American 29 (42.0) Asians 2 (2.9) Native Americans/Alaska Natives 0 ( 0.0) Native Hawaiians/Pacific Islanders 0 ( 0.0) Unreported 0 ( 0.0) unknown 1 (1.4) other 6 (8.7) Baseline height (cm) n 69 average value 166.50 STD 6.379 Minimum value 150.0 Median 167.00 Maximum value 182.9 Baseline body weight (kg) n 69 average value 96.61 STD 23.283 Minimum value 51.7 Median 93.00 Maximum value 170.1 Baseline body mass index (kg/ ^m² ) n 69 average value 34.90 STD 8.374 Minimum value 19.2 Median 19.2 Maximum value 62.4 Table 15 Variables Total (N=69) Duration of illness (in months) n 69 average value 88.1 STD 83.08 Minimum value 4.6 Median 52.5 Maximum value 457.5 Previous surgical treatment for HS - n (%) yes 15 (21.7) no 54 (78.3) Previously received treatment for HS -n (%) yes 52 (75.4) no 17 (24.6) HS Family History - n (%) yes 18 (26.1) no 51 (73.9) Select comorbidities - n (%) Atopic dermatitis 4 (5.8) psoriasis 2 (2.9) Acne 11 (15.9) High blood pressure 10 (14.5) diabetes 3 (4.3) Chronic kidney disease 0 ( 0.0) malignant disease 0 ( 0.0) Other autoimmune diseases 1 (1.4) Anxiety 17 (24.6) Depression 16 (23.2) obesity 14 (20.3) Inflammatory bowel disease 0 ( 0.0) Number of anatomical regions with HS n 69 average value 2.8 STD 0.99 Minimum value 1.0 Median 3.0 Maximum value 6.0 Number of days until the current HS outbreak/event begins n 69 average value 360.8 STD 704.16 Minimum value 18.0 Median 58.0 Maximum value 3691.0 Number of HS outbreaks since diagnosis n 69 average value 51.1 STD 85.06 Minimum value 1.0 Median 20.0 Maximum value 500.0 Hurley stage-n (%) Phase I 35 (50.7) Phase II 34 (49.3) Phase III 0 ( 0.0) AN number category - n (%) ≥ 3 to 4 27 (39.1) ≥ 5 to 10 42 (60.9) AN number n 69 average value 5.4 STD 1.81 Minimum value 3.0 Median 5.0 Maximum value 9.0 Number of abscesses n 69 average value 0.7 STD 1.28 Minimum value 0.0 Median 0.0 Maximum value 5.0 Number of inflammatory nodules n 69 average value 4.8 STD 2.05 Minimum value 0.0 Median 5.0 Maximum value 9.0 Number of non-drainage channels n 69 average value 0.3 STD 0.94 Minimum value 0.0 Median 0.0 Maximum value 6.0 Number of diversion channels n 69 average value 0.0 STD 0.00 Minimum value 0.0 Median 0.0 Maximum value 0.0 NRS score for skin pain n 68 average value 4.3 STD 2.36 Minimum value 0.0 Median 3.8 Maximum value 9.2 NRS rating for itching n 68 average value 4.1 STD 2.67 Minimum value 0.0 Median 3.4 Maximum value 10.0 Violation of the total BSA n 69 average value 2.0 STD 1.49 Minimum value 0.2 Median 2.0 Maximum value 7.5 Table 16 Variables Total (N=69) Number of participants receiving treatment (%) 69 (100.0) Number of participants receiving continuous treatment (%) 8 (11.6) Number of participants who completed treatment (%) 50 (72.5) Number of participants who discontinued treatment (%) 11 (15.9) The main reason for discontinuing treatment Adverse events 2 (2.9) die 0 ( 0.0) Lack of efficacy 0 ( 0.0) lost to follow-up 5 (7.2) Non-compliance with investigational drugs 0 ( 0.0) pregnant 0 ( 0.0) Plan Deviation 1 (1.4) Physician Decision 0 ( 0.0) Trial commissioner terminates study 0 ( 0.0) Individual Exit 1 (1.4) other 2 (2.9) Number of participants who withdrew from the study (%) 11 (15.9) The main reason for stopping the research Adverse events 2 (2.9) die 0 ( 0.0) Lack of efficacy 0 ( 0.0) lost to follow-up 5 (7.2) Physician Decision 0 ( 0.0) Plan Deviation 1 (1.4) Trial commissioner terminates study 0 ( 0.0) Individual Exit 1 (1.4) other 2 (2.9)

Table 17 presents an overview and analysis of the participants (intendency group) who achieved HiSCR during the study period. Table 17 Achieving HiSCR : Total Yes, n (%) Week 2 67 15(22.4) Week 4 66 27 (40.9) Week 8 63 38 (60.3) Week 12 58 35 (60.3) Week 16 53 33(62.3) Early termination of DBVC 6 0 (0.0) Follow DBVC 4 3 (75.0) Week 20 42 30(71.4) Week 24 29 24(82.8) Week 28 twenty two 17(77.3) Week 32 15 14 (93.3) Early termination of OLE 5 3 (60.0) Follow-up visit to OLE 3 3 (100.0)

Abbreviation: HiSCR = Clinical response to suppurative hidradenitis

HiSCR responders were defined as participants who, relative to baseline, achieved a reduction of AN number >= 50% and did not experience an increase in the number of abscesses or draining fistulas. As shown in Table 17 , the number of HiSCR responders increased from week 2 to week 16.

Table 18 presents an overview and analysis of the number of ANs during the study period. Table 18 AN number: n Average (STD) Median Baseline 69 5.45 (1.811) 5.00 Week 2 67 4.45 (2.382) 5.00 Changes relative to baseline in week 2 67 -1.03 (2.153) -1.00 Percentage change of AN number relative to baseline in week 2 67 -17.42 (42.817) -16.67 Week 4 66 3.59 (2.320) 3.00 Changes relative to baseline in week 4 66 -1.92 (2.248) -2.00 Percentage change of AN number relative to baseline in week 4 66 -34.52 (38.014) -29.17 Week 8 63 2.71 (2.296) 2.00 Changes relative to the baseline at week 8 63 -2.79 (2.641) -3.00 Percentage change of AN number relative to baseline in week 8 63 -47.58 (44.838) -57.14 Week 12 58 2.48 (2.458) 2.00 Change relative to baseline at week 12 58 -3.05 (2.481) -3.00 Percentage change of AN number relative to baseline at week 12 58 -56.01 (41.250) -66.67 Week 16 53 2.45 (2.099) 2.00 Change relative to baseline at week 16 53 -3.02 (2.349) -3.00 Percentage change of AN number relative to baseline at week 16 53 -54.17 (38.811) -60.00 Early termination of DBVC 6 6.33 (4.885) 5.00 Changes relative to baseline when DBVC is terminated early 6 0.83 (3.764) 0.00 Percentage change of AN number relative to baseline when DBVC is terminated early 6 12.50 (47.067) 0.00 Follow DBVC 4 2.75 (1.500) 3.00 Changes relative to baseline during DBVC visits 4 -4.00 (2.944) -4.50 Percentage change of AN number relative to baseline during DBVC follow-up 4 -52.78 (38.087) -63.89 Week 20 42 2.07 (1.827) 2.00 Change relative to baseline at week 20 42 -3.43 (2.097) -3.00 Percentage change of AN number relative to baseline at week 20 42 -62.55 (34.330) -66.67 Week 24 29 1.72 (1.791) 1.00 Change relative to baseline at week 24 29 -3.69 (2.156) -4.00 Percentage change of AN number relative to baseline at week 24 29 -67.34 (31.150) -75.00 Week 28 twenty two 1.91 (1.900) 2.00 Change relative to baseline at week 28 twenty two -3.41 (2.085) -4.00 Percentage change of AN number relative to baseline at week 28 twenty two -64.07 (30.218) -66.67 Week 32 15 1.00 (0.845) 1.00 Change relative to baseline at week 32 15 -4.20 (1.859) -4.00 Percentage change of AN number relative to baseline at week 32 15 -79.22 (18.095) -80.00 Early termination of OLE 5 2.60 (1.949) 2.00 Changes relative to the baseline when OLE is terminated early 5 -4.00 (2.646) -3.00 Percentage change of AN number relative to baseline when OLE is terminated early 5 -57.79 (30.872) -60.00 Follow-up visit to OLE 3 1.33 (1.155) 2.00 Changes relative to baseline during OLE visits 3 -4.67 (1.528) -5.00 Percentage change of AN number relative to baseline during OLE follow-up 3 -77.14 (20.603) -71.43

Abbreviations: AN = abscess and inflammatory nodules; STD = standard deviation.

From Table 18 , the AN number decreases from the baseline to week 16.

Table 19 presents an overview and analysis of participants who achieved AN50 during the study period. Table 19 Number of participants reaching AN50 (%) : Total Yes, n (%) Week 2 67 16 (23.9) Week 4 66 27 (40.9) Week 8 63 39(61.9) Week 12 58 38 (65.5) Week 16 53 35 (66.0) DBVC terminated early 6 0 (0.0) Follow DBVC 4 3 (75.0) Week 20 42 32(76.2) Week 24 29 25 (86.2) Week 28 twenty two 18(81.8) Week 32 15 14 (93.3) OLE terminated early 5 3 (60.0) Follow-up visit to OLE 3 3 (100.0)

Abbreviation: AN = abscess and inflammatory nodules.

AN50 respondents are defined as participants whose AN number decreases by ≥50% relative to the baseline. From Table 19 , the number of AN50 respondents increases from the baseline to week 16.

Table 20 presents an overview and analysis of participants who achieved AN75 during the study period. Table 20 Number of participants who achieved AN75 (%) : Total Yes, n (%) Week 2 67 4 (6.0) Week 4 66 16(24.2) Week 8 63 20(31.7) Week 12 58 23(39.7) Week 16 53 20(37.7) DBVC terminated early 6 0 (0.0) Follow DBVC 4 2 (50.0) Week 20 42 18(42.9) Week 24 29 15 (51.7) Week 28 twenty two 9(40.9) Week 32 15 11(73.3) OLE terminated early 5 1 (20.0) Follow-up visit to OLE 3 1(33.3)

Abbreviation: AN = abscess and inflammatory nodules.

AN75 responders are defined as participants whose AN number decreases by ≥75% relative to the baseline. From Table 20 , the number of AN75 responders increases from the baseline to week 16.

Table 21 presents an overview and analysis of participants who achieved AN90 during the study period. Table 21 Number of participants who achieved AN90 (%) : Total Yes, n (%) Week 2 67 3(4.5) Week 4 66 5(7.6) Week 8 63 10 (15.9) Week 12 58 13(22.4) Week 16 53 10 (18.9) DBVC terminated early 6 0 (0.0) Follow DBVC 4 0 (0.0) Week 20 42 11(26.2) Week 24 29 5(17.2) Week 28 twenty two 4(18.2) Week 32 15 4(26.7) OLE terminated early 5 1 (20.0) Follow-up visit to OLE 3 1(33.3)

Abbreviation: AN = abscess and inflammatory nodules.

AN90 responders are defined as participants whose AN number decreases by ≥90% relative to the baseline. From Table 21 , the number of AN90 responders increases from the baseline to week 16.

Table 22 presents an overview and analysis of participants who achieved AN100 during the study period. Table 22 Number of participants who achieved AN100 (%) : Total Yes, n (%) Week 2 67 3(4.5) Week 4 66 5(7.6) Week 8 63 10 (15.9) Week 12 58 13(22.4) Week 16 53 10 (18.9) DBVC terminated early 6 0 (0.0) Follow DBVC 4 0 (0.0) Week 20 42 11(26.2) Week 24 29 5(17.2) Week 28 twenty two 4(18.2) Week 32 15 4(26.7) OLE terminated early 5 1 (20.0) Follow-up visit to OLE 3 1(33.3)

Abbreviation: AN = abscess and inflammatory nodules.

AN100 responders are defined as participants whose AN number decreases by 100% relative to the baseline. From Table 22 , the number of AN100 responders increases from the baseline to week 16.

Table 23 presents an overview and analysis of the NRS scores for skin pain during visits during the study period. Table 23 NRS score for skin pain during visit : n Average (STD) Median Baseline 68 4.33 (2.362) 3.79 Week 2 53 3.18 (2.459) 2.83 Changes relative to baseline in week 2 52 -0.93 (1.908) -0.80 Week 4 54 2.55 (2.181) 2.15 Changes relative to baseline in week 4 53 -1.38 (2.088) -1.29 Week 8 49 2.21 (2.088) 2.00 Changes relative to the baseline in week 8 48 -1.95 (2.318) -1.82 Week 12 52 2.16 (2.379) 1.75 Changes relative to the baseline at week 12 51 -1.97 (2.883) -1.58 Week 16 43 1.91 (2.512) 1.00 Change relative to baseline at week 16 42 -2.35 (2.973) -2.29 DBVC terminated early 3 5.72 (0.948) 6.00 Changes relative to baseline when DBVC is terminated early 3 -1.33 (1.024) -1.36 Week 20 34 1.96 (2.601) 1.08 Change relative to baseline at week 20 33 -2.22 (2.990) -2.49 Week 24 twenty three 1.88 (2.143) 1.75 Change relative to baseline at week 24 twenty three -2.39 (2.519) -2.02 Week 28 13 1.83 (1.709) 1.75 Change relative to baseline at week 28 13 -2.19 (2.814) -1.11 Week 32 7 0.55 (0.712) 0.00 Change relative to baseline at week 32 7 -2.68 (2.915) -2.33 Early termination of OLE 2 5.70 (4.101) 5.70 Changes relative to the baseline when OLE is terminated early 2 2.60 (5.940) 2.60 Follow-up visit to OLE 1 0.00 (NA) 0.00 Changes relative to baseline during OLE visits 1 -7.86 (NA) -7.86

Abbreviations: NRS = Numerical Rating Scale; STD = Standard Deviation.

From Table 23 , the NRS score for skin pain decreased from baseline to week 16.

Table 24 presents an overview and analysis of the NRS scores for itching during patient visits during the study period. Table 24 NRS score for skin pain during visit : n Average (STD) Median Baseline 68 4.06 (2.674) 3.43 Week 2 53 3.16 (2.568) 2.60 Changes relative to baseline in week 2 52 -0.72 (1.628) -0.66 Week 4 54 2.61 (2.293) 2.18 Changes relative to baseline in week 4 53 -1.10 (2.169) -0.90 Week 8 49 2.01 (2.144) 1.50 Changes relative to the baseline at week 8 48 -1.88 (2.305) -1.40 Week 12 52 2.14 (2.300) 1.55 Change relative to baseline at week 12 51 -1.84 (2.877) -1.40 Week 16 43 1.93 (2.392) 1.00 Change relative to baseline at week 16 42 -2.13 (3.005) -1.56 DBVC terminated early 3 4.34 (1.645) 4.86 Changes relative to baseline when DBVC is terminated early 3 -2.61 (2.401) -1.57 Week 20 33 2.18 (2.453) 1.40 Change relative to baseline at week 20 32 -1.72 (2.782) -1.49 Week 24 twenty three 1.73 (2.477) 1.00 Change relative to baseline at week 24 twenty three -2.48 (2.846) -2.14 Week 28 13 1.74 (2.102) 1.25 Change relative to baseline at week 28 13 -2.16 (2.800) -1.50 Week 32 7 0.76 (0.990) 0.00 Change relative to baseline at week 32 7 -2.08 (2.530) -1.40 Early termination of OLE 2 5.10 (4.101) 5.10 Changes relative to the baseline when OLE is terminated early 2 4.40 (3.111) 4.40 Follow-up visit to OLE 1 0.00 (NA) 0.00 Changes relative to baseline during OLE visits 1 -6.00 (NA) -6.00

Abbreviations: NRS = Numerical Rating Scale; STD = Standard Deviation.

From Table 24 , the NRS score for pruritus decreased from baseline to week 16. Example 4 : Example 2 : Non-blinded results of a phase II study of ruxolitinib in the treatment of hidradenitis suppurativa (HS).

The clinical trial in Example 2 (a phase 2, randomized, double-blind, mediator-controlled (DBVC) study, with a 16-week DBVC period followed by a 16-week open-label extension (OLE) period) was conducted. Blinded data were available from full enrollment to week 32 (Example 3), and now, unblinded data are available after the completion of the DBVC period. The unblinded data are presented below.

As shown in Table 25 , the primary endpoint (i.e., determining the efficacy of 1.5% ruxolitinib cream BID in participants with HS) was reached based on the change in AN number relative to the baseline at week 16. Table 25 presents an overview and analysis of AN numbers during the study period . Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) AN number: n Average (STD) Median n Average (STD) Median Baseline 35 5.34 (1.814) 5.00 34 5.56 (1.829) 5.50 Week 2 35 4.63 (2.462) 4.00 32 4.31 (2.278) 5.00 Changes relative to baseline in week 2 -0.71 (2.283) -1.00 -1.31 (1.991) -1.00 Percentage change of AN number relative to baseline in week 2 -11.00 (47.964) -12.50 -22.89 (35.750) -15.48 Week 4 35 3.57 (1.899) 3.00 31 3.71 (2.710) 3.00 Changes relative to baseline in week 4 -1.77 (2.129) -2.00 -2.00 (2.338) -2.00 Percentage change of AN number relative to baseline in week 4 -30.65 (35.396) -25.00 -37.27 (40.081) -42.86 Week 8 34 3.03 (2.736) 2.00 29 2.31 (1.561) 2.00 Changes relative to the baseline at week 8 -2.32 (3.002) -3.00 -3.38 (2.007) -3.00 Percentage change of AN number relative to baseline in week 8 -39.17 (54.408) -55.00 -58.12 (26.614) -57.14 Week 12 34 2.79 (2.761) 2.00 26 2.15 (2.053) 1.50 Changes relative to the baseline at week 12 -2.56 (2.584) -3.00 -3.73 (2.426) -3.50 Percentage change of AN number relative to baseline at week 12 -50.25 (45.909) -66.67 -62.12 (35.402) -73.21 Week 16 32 2.91 (2.053) 3.00 twenty four 1.83 (1.857) 1.00 Change relative to baseline at week 16 -2.38 (2.196) -2.00 -4.04 (2.156) -4.00 Percentage change of AN number relative to baseline at week 16 -44.17 (40.093) -50.00 -68.69 (28.684) -75.00 Week 20 29 2.45 (1.804) 2.00 twenty two 2.14 (2.054) 2.00 Change relative to baseline at week 20 -2.69 (2.089) -3.00 -3.59 (2.364) -4.00 Percentage change of AN number relative to baseline at week 20 -51.68 (34.390) -60.00 -61.85 (43.233) -69.05 Week 24 twenty one 1.67 (1.983) 1.00 16 1.19 (1.223) 1.00 Change relative to baseline at week 24 -3.38 (2.376) -3.00 -4.50 (1.713) -4.00 Percentage change of AN number relative to baseline at week 24 -65.95 (35.525) -66.67 -80.23 (18.904) -83.33 Week 28 18 1.89 (2.111) 2.00 12 1.92 (1.676) 1.50 Change relative to baseline at week 28 -3.28 (2.321) -3.00 -4.08 (2.353) -4.00 Percentage change of AN number relative to baseline at week 28 -63.61 (32.986) -66.67 -66.29 (29.122) -73.33 Week 32 16 1.31 (1.302) 1.00 8 1.50 (1.069) 1.00 Change relative to baseline at week 32 -4.19 (2.105) -4.50 -4.25 (1.389) -4.00 Percentage change of AN number relative to baseline at week 32 -74.48 (25.499) -79.17 -74.21 (14.232) -77.50

Abbreviations: AN = abscess and inflammatory nodule; STD = standard deviation.

Figure 1 shows the mean and standard error of the AN number from the baseline to week 32 during the treatment period.

Table 26 below presents an overview and analysis of participants (intended-to-treat group) who achieved AN50 during the study period. AN50 responders were defined as participants whose AN number decreased by ≥50% from baseline. Table 26 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) Number of participants reaching AN50 (%) : Total Yes, n (%) Total Yes, n (%) Week 2 35 6(17.1) 32 9(28.1) Week 4 35 12(34.3) 31 14(45.2) Week 8 34 21(61.8) 29 18(62.1) Week 12 34 22(64.7) 26 16(61.5) Week 16 32 18 (56.3) twenty four 19(79.2) Week 20 29 19(65.5) twenty two 17(77.3) Week 24 twenty one 18 (85.7) 16 15 (93.8) Week 28 18 14 (77.8) 12 10 (83.3) Week 32 16 14 (87.5) 8 7 (87.5)

Figure 2 plots the number of participants at each visit relative to the AN50 response rate (%). From Table 26 and Figure 2 , the number of AN50 responders increased from baseline to week 16 with 1.5% ruxolitinib BID.

Table 27 below presents an overview and analysis of participants (intended-to-treat group) who achieved AN75 during the study period. AN75 responders were defined as participants whose AN number decreased by ≥75% from baseline. Table 27 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) Number of participants who achieved AN75 (%) : Total Yes, n (%) Total Yes, n (%) Week 2 35 1(2.9) 32 3(9.4) Week 4 35 7 (20.0) 31 8(25.8) Week 8 34 10 (29.4) 29 10 (34.5) Week 12 34 11(32.4) 26 13 (50.0) Week 16 32 8 (25.0) twenty four 13(54.2) Week 20 29 9 (31.0) twenty two 10 (45.5) Week 24 twenty one 10 (47.6) 16 12 (75.0) Week 28 18 6(33.3) 12 6 (50.0) Week 32 16 9(56.3) 8 6 (75.0)

Figure 3 shows the number of participants at each visit relative to the AN75 response rate (%). From Table 27 and Figure 3 , the number of AN75 responders increased from baseline to week 16 with 1.5% ruxolitinib BID.

Table 28 below presents an overview and analysis of the participants (intendency group) who achieved HiSCR during the study period. Table 28 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) Achieving HiSCR : n Yes, n (%) n Yes, n (%) Week 2 35 6(17.1) 32 9(28.1) Week 4 35 12(34.3) 31 14(45.2) Week 8 34 20 (58.8) 29 18(62.1) Week 12 34 19 (55.9) 26 16(61.5) Week 16 32 16 (50.0) twenty four 19(79.2) Week 20 29 17 (58.6) twenty two 17(77.3) Week 24 twenty one 17 (81.0) 16 15 (93.8) Week 28 18 13(72.2) 12 9 (75.0) Week 32 16 14 (87.5) 8 7 (87.5)

Abbreviation: HiSCR = Clinical response to suppurative hidradenitis

Figure 4 is a bar graph illustrating the patients who achieved HiSCR from week 2 to week 32 during the treatment period. From the bar graphs in Table 28 and Figure 4 , the treatment group with 1.5% ruxolitinib BID shows a significant proportion of HiSCR responses at week 16.

Table 29 below presents an overview and analysis of participants (intent-to-treat population) who achieved the modified HiSCR (modified Hidradenitis Suppurativa Clinical Response; mHiSCR) during the study period. As used herein, "modified Hidradenitis Suppurativa Clinical Response" or "mHiSCR" is defined as a reduction of at least 50% in the number of inflammatory nodules relative to baseline, with no increase in the number of abscesses or draining fistulas. Furthermore, "inflammatory nodules" refers to non-tender, non-erythematous nodules. All participants received a BID of 1.5% ruxolitinib cream after week 16. Table 29 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) Achieving HiSCR : n Yes, n (%) n Yes, n (%) Week 2 34 6(17.6) 31 8(25.8) Week 4 34 13(38.2) 30 14 (46.7) Week 8 33 19(57.6) 28 18(64.3) Week 12 33 18 (54.5) 26 17(65.4) Week 16 31 15 (48.4) twenty four 18 (75.0) Early termination of DBVC 2 0 (0.0) 5 0 (0.0) Follow DBVC 2 1 (50.0) 3 1(33.3) Week 20 28 16 (57.1) twenty two 17(77.3) Week 24 20 16 (80.0) 16 14 (87.5) Week 28 17 12 (70.6) 12 8(66.7) Week 32 15 12 (80.0) 8 7 (87.5) Early termination of OLE 3 1(33.3) 2 2 (100.0) Follow-up visit to OLE 10 8 (80.0) 6 3 (50.0)

From Table 29 , the treatment group with 1.5% ruxolitinib BID showed a significant proportion of mHiSCR responses at week 16.

Table 30 below presents an overview and analysis of the NRS scores for skin pain during visits during the study period. Table 30 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) NRS score for skin pain during visit : n Average (STD) Median n Average (STD) Median Baseline 34 4.24 (2.369) 4.01 34 4.42 (2.386) 3.69 Week 2 30 3.04 (2.224) 3.00 twenty three 3.36 (2.777) 2.67 Changes relative to baseline in week 2 -1.21 (1.763) -0.83 -0.57 (2.059) -0.80 Week 4 30 2.46 (2.069) 2.17 twenty four 2.67 (2.354) 2.08 Changes relative to baseline in week 4 -1.69 (2.210) -1.29 -1.00 (1.909) -1.77 Week 8 25 2.33 (2.177) 1.50 twenty four 2.09 (2.029) 2.00 Changes relative to the baseline at week 8 -2.08 (2.596) -1.71 -1.82 (2.051) -1.96 Week 12 31 2.32 (2.210) 2.00 twenty three 2.27 (2.764) 1.67 Changes relative to the baseline at week 12 -2.06 (2.634) -1.21 -1.51 (3.302) -1.67 Week 16 twenty three 1.83 (2.092) 2.00 twenty three 2.05 (2.784) 1.00 Change relative to baseline at week 16 -2.61 (2.458) -2.08 -1.85 (3.289) -2.00 Week 20 twenty three 2.17 (2.159) 2.00 20 2.27 (2.962) 1.20 Change relative to baseline at week 20 -2.26 (2.545) -2.50 -1.74 (3.310) -2.19 Week 24 17 1.50 (1.439) 1.14 14 1.37 (2.571) 0.00 Change relative to baseline at week 24 -2.15 (2.403) -2.02 -2.66 (2.135) -2.50 Week 28 13 1.59 (1.694) 1.33 9 0.82 (1.101) 0.25 Change relative to baseline at week 28 -2.38 (2.721) -1.81 -2.54 (2.207) -1.75 Week 32 10 1.75 (2.536) 0.50 4 0.52 (0.790) 0.20 Change relative to baseline at week 32 -2.20 (3.503) -2.38 -2.23 (3.048) -1.20

Abbreviations: NRS = Numerical Rating Scale; STD = Standard Deviation

Figure 5 shows the mean and standard error of the NRS for skin pain from baseline to the follow-up at week 32 during the treatment period.

Table 31 below presents an overview and analysis of the NRS scores for itching during visits during the study period. Table 31 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) NRS score for skin pain during visit : n Average (STD) Median n Average (STD) Median Baseline 34 4.14 (2.798) 3.76 34 3.98 (2.585) 3.00 Week 2 30 3.28 (2.427) 3.10 twenty three 3.01 (2.789) 2.14 Changes relative to baseline in week 2 -1.07 (1.644) -0.86 -0.29 (1.534) -0.57 Week 4 30 2.51 (1.990) 2.20 twenty four 2.74 (2.663) 2.07 Changes relative to baseline in week 4 -1.56 (2.331) -1.07 -0.53 (1.847) -0.65 Week 8 25 2.20 (2.187) 1.50 twenty four 1.80 (2.125) 1.34 Changes relative to the baseline in week 8 -2.04 (2.845) -1.87 -1.72 (1.646) -1.22 Week 12 31 2.10 (2.011) 2.00 twenty three 2.19 (2.658) 1.25 Change relative to baseline at week 12 -2.25 (2.757) -1.69 -1.23 (2.933) -0.97 Week 16 twenty three 1.73 (1.762) 1.00 twenty three 2.14 (2.792) 1.00 Change relative to baseline at week 16 -2.75 (2.884) -1.89 -1.42 (2.906) -1.20 Week 20 twenty two 2.42 (2.159) 2.20 20 2.05 (2.696) 1.14 Change relative to baseline at week 20 -2.02 (2.471) -1.61 -1.59 (2.789) -1.39 Week 24 17 1.32 (1.924) 1.00 14 1.58 (2.600) 0.71 Change relative to baseline at week 24 -2.56 (2.789) -2.14 -2.12 (2.121) -1.93 Week 28 13 1.50 (2.144) 0.43 9 0.69 (0.944) 0.17 Change relative to baseline at week 28 -3.12 (2.984) -2.29 -1.90 (2.162) -1.20 Week 32 10 1.66 (1.944) 1.00 4 0.38 (0.750) 0.00 Change relative to baseline at week 32 -2.51 (3.474) -1.91 -2.26 (2.995) -1.77

Abbreviations: NRS = Numerical Rating Scale; STD = Standard Deviation

Figure 6 shows the mean and standard error of the NRS for itching from baseline to the visit at week 32 during the treatment period.

Table 32 below presents an overview and analysis of the International Hidradenitis Severity Rating System (IHS4) during the study period. Table 32 Mediator BID (N=35) 1.5% ruxolitinib BID (N=34) IHS 4 score during the visit : n Average (STD) Median n Average (STD) Median Baseline 35 6.06 (2.388) 6.00 34 6.18 (2.393) 6.00 Week 2 35 5.34 (3.171) 5.00 32 4.91 (2.644) 5.00 Changes relative to baseline in week 2 -0.71 (2.383) -1.00 -1.38 (2.575) -1.00 Percentage change relative to baseline in week 2 -11.52 (43.131) -10.00 -19.96 (39.969) -13.39 Week 4 35 4.11 (2.336) 4.00 31 4.90 (4.915) 4.00 Changes relative to baseline in week 4 -1.94 (2.461) -2.00 -1.48 (5.131) -2.00 Percentage change relative to baseline at week 4 -28.57 (41.894) -20.00 -18.85 (112.445) -42.86 Week 8 34 3.50 (3.107) 2.50 29 2.79 (2.177) 2.00 Changes relative to the baseline in week 8 -2.59 (3.192) -3.00 -3.59 (2.922) -3.00 Percentage change relative to baseline at week 8 -38.08 (56.080) -52.27 -54.10 (39.285) -57.14 Week 12 34 3.21 (3.073) 2.00 26 2.38 (2.299) 1.50 Changes relative to the baseline at week 12 -2.88 (2.858) -3.00 -4.12 (3.115) -4.00 Percentage change relative to baseline at week 12 -49.72 (44.041) -66.67 -61.38 (37.171) -75.71 Week 16 32 3.28 (2.359) 3.00 twenty four 2.00 (2.147) 1.00 Change relative to baseline at week 16 -2.66 (2.535) -3.00 -4.46 (2.587) -4.00 Percentage change relative to baseline at week 16 -42.81 (42.393) -45.00 -69.59 (27.654) -75.00 Week 20 29 2.97 (2.353) 2.00 twenty two 2.36 (2.610) 2.00 Change relative to baseline at week 20 -2.83 (2.465) -3.00 -4.00 (2.878) -4.00 Percentage change relative to baseline at week 20 -49.06 (35.948) -50.00 -63.48 (42.644) -69.05 Week 24 twenty one 2.05 (2.578) 1.00 16 1.38 (1.668) 1.00 Change relative to baseline at week 24 -3.86 (2.726) -3.00 -4.88 (1.893) -4.50 Percentage change relative to baseline at week 24 -67.03 (32.700) -75.00 -80.83 (19.842) -83.33 Week 28 18 2.28 (2.608) 2.00 12 2.42 (2.392) 2.00 Change relative to baseline at week 28 -3.89 (2.654) -4.00 -4.33 (2.605) -4.00 Percentage change relative to baseline at week 28 -64.55 (32.312) -66.67 -64.79 (29.168) -66.67 Week 32 16 1.63 (1.746) 1.00 8 1.63 (1.408) 1.00 Change relative to baseline at week 32 -5.00 (2.221) -5.00 -4.50 (1.195) -4.00 Percentage change relative to baseline at week 32 -76.54 (24.509) -81.67 -75.03 (13.878) -80.00

Figure 7 graphically illustrates the mean and standard error of the IHS4 score during treatment. The IHS4 is a weighted scale that uses the number of inflammatory nodules, abscesses, and drainage channels (fungi or sinuses) with corresponding weighting factors of 1, 2, and 4 (Example: IHS4 score equals the number of inflammatory nodules [multiplied by 1] plus the number of abscesses [multiplied by 2] plus the number of drainage channels [multiplied by 4]). As shown in Table 31 and Figure 7 , with 1.5% ruxolitinib BID, the IHS4 score decreased from baseline to week 16, demonstrating the effectiveness of HS treatment.

The number of adverse events was similar between the ruxolitinib cream and the mordant group. Only one patient receiving ruxolitinib cream experienced pain at the application site.

Example 5 : Using ruxolitinib to treat hidradenitis suppurativa (HS) Of III Periodic study

This is a phase 3, double-blind, randomized, mediator-controlled (DBVC) study in participants aged at least 12 years with a confirmed diagnosis of hepatitis B (HS). The study will consist of a 16-week DBVC period followed by a 36-week open-label extension (OLE) period. The primary objective of this study is to evaluate the efficacy and safety of 1.5% ruxolitinib cream (BID) in participants with mild to moderate HS (Herlich stage I or II) and without drainage pathways.

Participants underwent screening for up to 28 days prior to the first application of 1.5% ruxolitinib cream or carboxylate cream for field treatment. Field treatment was defined as the application of the cream to the entire anatomical region containing abscesses and/or inflammatory nodules. Key inclusion criteria for participants included a diagnosis of HS (Heyer I or II) for at least 6 months, a total AN number ≥4 at screening or baseline, involvement of at least 2 distinct anatomical regions, and no drainage pathways.

Approximately 400 eligible participants aged at least 12 years were randomly assigned 1:1 to either 1.5% ruxolitinib cream or carboxylate cream. Participants were stratified based on baseline geographic region (North America and Europe) and prior HS therapy (previous HS therapy vs. no prior HS therapy). Participants with prior HS therapy comprised approximately 60% of the study population.

Participants will begin regional treatment on day 1 of the DBVC period, treating all diseased anatomical areas identified from baseline to week 16, even if HS has completely disappeared. If new body sites develop AN after day 1, participants should contact the investigator, and as long as the total diseased area remains ≤ 20% BSA, the new body sites will be treated in addition to those identified and treated since baseline. Participants should be instructed to use no more than one 60-gram tube per week. If BSA exceeds 20%, the participant will be withdrawn from the study. Planned study visits during the DBVC period will be conducted in week 2 after baseline, and then every 4 weeks thereafter (i.e., weeks 4, 8, 12, and 16).

During the DBVC period, participants who exhibit referral channels will be deemed ineligible and will be removed from the study.

At week 16, participants who meet the criteria (i.e., comply with the protocol and have no safety concerns) will enter the 16-week OLE period. Planned study visits will be conducted at weeks 20, 28, 36, 44, and 52, and planned telephone interviews will be conducted at weeks 24, 32, 40, and 48. Participants randomly assigned to the mediator cream BID during the DBVC period will cross-use the 1.5% ruxolitinib cream BID, and participants randomly assigned to the 1.5% ruxolitinib cream BID at baseline will continue using the 1.5% ruxolitinib cream BID on an open-label basis until week 52. Starting at the week 16 follow-up, researchers will assess the HS treatment area to evaluate the disease and determine whether continued treatment is needed during the OLE period (i.e., AN number ≥ 1), or whether the participant can re-enter an observation/no-treatment cycle (i.e., AN number = 0). During the OLE period, participants will only receive regional treatment on body sites with active lesions (e.g., AN lesions), with total BSA treatment not exceeding 20% (the actual BSA percentage will be entered for IRT cream allocation). If new ANs develop on new body sites during the OLE period, the participant should contact the researcher, and these body sites will be treated as long as the total affected area remains ≤20% BSA. By week 52 of the study, the BSA percentage entered into the IRT at previous visits will be used for IRT cream dispensing. Participants should be instructed to use no more than one 60-gram tube per week. Any participant whose total treated area exceeds 20% of BSA should discontinue study treatment.

Participants who developed drainage pathways or received HS lesion rescue drugs and/or procedures during the DBVC and OLE phases were considered unresponsive to treatment and the study was discontinued.

Participants who develop drainage pathways will be withdrawn from the study. Starting from week 20 to week 52 of OLE, if a participant's HS disease worsens (defined as an increase in AN number of 2.5 times or more relative to baseline) but drainage pathways do not develop, they will be eligible for one rescue treatment. Such participants will be considered non-responsive. Participants may withdraw from the study at any time for any reason; in this case, they will be able to use alternative knowledge therapy to treat their HS. This information will be extracted from the EDC.

Researchers and participants will be unaware of their treatment allocation during the DBVC period until after the last visit of the last participant in the study.

Safety follow-up should be conducted 30 days (+7-day follow-up window) after the 52-week/EOT2 or ET visit (or 30 days after the last application of the study cream if the 52-week/EOT2 or ET visit was not performed). If a participant is in the OLE period and has been in the observation/no-treatment period with AN number = 0 for at least 30 days prior to the 52-week/EOT2 visit, the 52-week/EOT2 visit will also be included in the safety follow-up.

The study begins when the first participant signs up for the ICF. Individuals are expected to participate for approximately 60 weeks, including a 28-day screening period, 16 weeks of treatment during the DBVC period, 36 weeks of treatment during the OLE period, and a 30-day follow-up period following the final application of the study treatment.

Study completion is defined as the date of the last visit of the last participant in the study. A participant is considered to have completed the study if they have completed all study visits, including safety follow-ups.

A preliminary analysis will be conducted based on the intention-to-treat (ITT) population. The endpoints, i.e., the primary, key secondary, and minor goals and an overview of the endpoints, are provided in Table 33 .

surface 33 Target The finish line main Determining the efficacy of 1.5% ruxolitinib cream BID in participants with HS At week 16, the HiSCR75 binary response status (defined as a ≥75% decrease in total AN count relative to baseline without an increase in the number of abscesses or drainage channels relative to baseline). Key secondary Evaluate the efficacy of 1.5% ruxolitinib cream (BID) in participants with hepatitis B. • At week 16, a binary response state characterized by ≥1 HS outbreak (defined as a ≥25% increase in total AN count relative to baseline, with at least a 2-fold increase in AN). • At week 16, a binary response state characterized by IHS 4-55 (defined as a ≥55% decrease in the weighted average of AN and drainage channels [calculated as the number of inflammatory nodules multiplied by 1, the number of abscesses multiplied by 2, and the number of drainage channels multiplied by 4] relative to baseline). secondary Further evaluation of the efficacy of 1.5% ruxolitinib cream BID in participants with HS • Bivariate response status of HiSCR 50/90/100 (defined as a decrease in total AN count ≥50%/90%/100% relative to baseline without an increase in the number of abscesses or drainage channels relative to baseline) at each planned follow-up visit after baseline. • Bivariate response status of ≥1 HS outbreak during the OLE period. • Changes in IHS4 scores relative to baseline at each planned follow-up visit after baseline. • Participant classification results in each IHS4 disease category at each follow-up visit (described as follows: total score 0-3 indicates mild, 4-10 indicates moderate, and 11 or higher indicates severe disease). • Changes in total AN count relative to baseline and percentage change at each planned follow-up visit after baseline. • Bivariate response status of participants with a baseline skin pain NRS score ≥3 (defined as a skin pain NRS score ≥30% and ≥1 unit lower than baseline) at each planned follow-up visit after baseline. • Bivariate response status of participants with a baseline pruritus NRS score ≥3 (defined as a pruritus NRS score ≥30% and ≥1 unit lower than baseline) at each planned follow-up visit after baseline. • PGIC score at each planned follow-up visit after baseline. • Bivariate response status of PGIC response at each planned follow-up visit after baseline. • Changes in PGIS relative to the baseline at each planned post-baseline visit. • Binary response status of DLQI4 (defined as a DLQI score decreasing by ≥4 points relative to the baseline) at each planned post-baseline visit. • Binary response status of CDLQI6 (defined as a CDLQI score decreasing by ≥6 points relative to the baseline) at each planned post-baseline visit. • Changes in HiSQoL relative to the baseline and percentage change at each planned post-baseline visit. • Changes in HiSQoL-AA relative to the baseline and percentage change at each planned post-baseline visit. • Changes in EQ-5D-5L scores relative to the baseline at each planned post-baseline visit. Evaluate the safety and tolerability of 1.5% ruxolitinib cream BID in participants with HS. • Acute extremities (AEs) are assessed through changes in vital signs and evaluation of clinical laboratory samples.

Participants are eligible to be included in the study only if they meet all of the following criteria:

(1) Can understand and be willing to sign a written informed consent form for the study.

(2) The age at the time of screening is 12 years or older.

(3) Screening should be conducted by a dermatologist at least 6 months prior to the visit, based on clinical history and physical examination diagnosis of HS.

(4) The diagnosis is mild to moderate HS (Herrei stage I or II), with at least 4 abscesses and inflammatory nodules at screening and day 1 visit, without drainage channels, and affecting at least 2 different anatomical areas.

Note: Anatomical areas include (but are not limited to) the left or right axilla, the left or right groin fold, and the area under the left or right breast.

(5) Agree not to use local or systemic antibiotics to treat HS during the DBVC and OLE periods of this study from week 16 to week 20.

(6) Agree not to use topical disinfectants containing ingredients such as chlorhexidine gluconate, povidone-iodine, sodium hypochlorite, diluted bleach or benzoyl peroxide in areas affected by HS lesions during the DBVC and OLE periods of this study from week 16 to week 20.

Note: Soap and water are permitted.

(7) Willing to avoid pregnancy or childbirth according to the following criteria.

(a) Male participants of fertility potential must agree to take appropriate preventative measures to avoid fathering a child from the time of selection until 90 days (one spermatogenesis cycle) after the last application of the study cream, and must refrain from donating sperm during this period. Permissible methods of contraception should be communicated to participants and their understanding confirmed.

(b) Female participants in the WOCBP program must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first application on Day 1. They must agree to take appropriate precautions to avoid pregnancy for 30 days (one menstrual cycle) from screening until the last application of the study cream, and must avoid donating oocytes during this period. Permitted methods of contraception should be communicated to participants and their understanding confirmed.

(c) Female participants who are considered to have no reproductive potential are eligible.

Participants are excluded from the study if they meet any of the following criteria:

(1) The body area to be treated exceeds 20% BSA during screening or baseline.

(2) Acute abscesses are present during screening or baseline, requiring incision and drainage or intralesional injection of corticosteroids.

(3) Any drainage channels exist during screening or baseline.

(4) Any of the following symptoms:

(a) The presence of any skin condition other than HS that may confuse the assessment of HS.

(b) Any other coexisting skin condition that may interfere with or confuse HS assessments or endanger the safety of participants.

(c) Active tuberculosis; or current latent tuberculosis and/or a history of latent tuberculosis, unless adequately treated.

Note: Tuberculosis-related medical history will be collected in the EDC.

(d) Decreased immune function (e.g., lymphoma, immunosuppression related to organ transplantation, Wiskott-Aldrich syndrome).

(e) Chronic or acute infection requiring treatment with systemic antibiotics, antiviral drugs, antiparasitic drugs, antiprotozoal drugs or antifungal drugs within two weeks prior to day 1.

(f) An active acute bacterial, fungal, or viral skin infection (e.g., herpes simplex, herpes zoster, chickenpox, clinically infectious adenosis, pustules) within two weeks prior to day 1.

(5) Currently have any of the following symptoms or have any of the following medical histories:

(a) Clinically uncontrolled cardiovascular disease or history of cardiovascular disease, including unstable angina, myocardial infarction, coronary artery disease, ischemic heart disease, or New York Heart Association Class III or IV congestive heart failure, and uncontrolled arrhythmias or irregularities requiring treatment or uncontrolled hypertension (including elevated blood pressure (systolic > 150 mmHg or diastolic > 100 mmHg at screening and/or on day 1)), unless approved by the medical monitor/trial commissioner.

(b) Venous and arterial thrombosis, deep vein embolism, pulmonary embolism, or stroke.

(c) Currently has severe anemia, severe thrombocytopenia or severe neutropenia or a history thereof.

(d) Any malignant disease or history of malignancy within 5 years prior to day 1, except for non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin that has been adequately treated or removed, or cervical carcinoma in situ.

(e) Unstable asthma or COPD requiring systemic treatment (such as intravenous endothelial steroids) or hospitalization or emergency room treatment within 3 months prior to Day 1; or stable asthma or COPD requiring budesonide more than 720 µg daily (e.g., BID, 180 µg twice a day) or fluticasone more than 440 µg daily (e.g., BID, 110 µg twice a day) or other equivalent inhaled corticosteroids.

(f) Any serious illness or medical, physical, or mental condition that, in the researcher's view, would interfere with full participation in the study, including application of the study cream and participation in required study visits, pose a significant risk to the participant, or interfere with the interpretation of the study data. When in doubt, the researcher should consult a medical monitor to determine eligibility.

(6) Any of the following clinical laboratory test results appear during the screening:

Excluding laboratory values: Laboratory parameters Exclusion criteria Hematology a platelets < 100 × ^10⁹ /L b Heme < 9 g/dL c Absolute neutrophil count (ANC) < 1.5 × ^10⁹ /L liver f ALT > 2.5 × ULN g AST > 2.5 × ULN h Total bilirubin > 1.5 × ULN (Note: For participants clinically diagnosed with Gilbert's syndrome, direct bilirubin can be measured, and the criteria are met as long as direct bilirubin < ULN) kidney i Estimate glomerular filtration rate The estimated glomerular filtration rate is < 30 mL/min/1.73 ^m2 (using the chronic kidney disease epidemiological co-equation).

(a) HIV antibody positive.

(b) Currently having acute or chronic active HBV or HCV infection. Participants who have recovered or have been successfully treated and show no signs of active HBV or HCV infection, as well as participants who are immune due to hepatitis B vaccination, are eligible for enrollment. Participants who are HBsAg positive are eligible if they are HBV DNA negative; participants who are anti-HCV antibody positive are eligible if they are HCV RNA negative.

(c) Any other clinically significant laboratory results that, in the researcher's view, pose a significant risk to the participants.

(7) History of failure to treat HS (or any other inflammatory condition) with any systemic or local JAK or TYK2 inhibitor (e.g., abrocitinib, baricitinib, brepocitinib, deucravacitinib, filgotinib, lestaurtinib, pacritinib, ruxotinib, tofacitinib, upadacitinib) (assessed by the investigator through participant interviews).

(8) Use any of the following treatments during the washout period prior to day 1:

(a) For systemic immunosuppressive or immunomodulatory biologics (e.g., adalimumab, anakinra, bermekimab, bimekizumab, brodalumab, certolizumab, dupilumab, etanercept, golimumab, gusecubitumab) (guselkumab), infliximab, iscalimab, ixekizumab, risankizumab, rituximab, secukinumab, vilobelimab, ustekinumab), 12 weeks or 5 half-lives (if known), whichever is longer.

(b) For any local or systemic JAK or TYK2 inhibitor (e.g., abrutinib, baricitinib, brepotinib, delgocitinib, deuterocelecitinib, frigidinib, lintatinib, paritinib, ruxotetinib, tofacitinib, uropatinib), 4 weeks.

(c) For systemic corticosteroids or adrenocorticotropic hormone analogs, cyclosporine, methotrexate, azathioprine or other systemic immunosuppressants or immunomodulators (e.g., mycophenolate mofetil, tacrolimus), 4 weeks.

Note 1: The use of corticosteroid inhalers and nasal sprays is permitted.

Note 2: If the researcher and the trial commissioner (or designated personnel) deem it acceptable, oral corticosteroids may be used to treat non-skin conditions (such as asthma exacerbation, bronchitis) for no more than 7 days.

(d) For areas with HS lesions, surgery, laser or any phototherapy intervention, 4 weeks.

(e) For other systemic therapies for HS that may have therapeutic effects (e.g., rhodopsin, antihypertensive drugs, antiglycemic drugs and antiandrogens, such as atratin, isotretinoin, metformin, spironolactone and finasteride), 2 weeks.

(f) For the treatment of HS, systemic anti-infective agents (e.g., antibiotics, antiviral agents, antifungal agents) for 2 weeks.

(g) Internal therapy for HS lesions, 2 weeks.

(h) For any topical treatment of HS (e.g., topical disinfectants such as chlorhexidine, benzoyl peroxide, sodium hypochlorite, povidone-iodine or benzoyl peroxide; topical antibiotics; topical corticosteroids; topical calcineurin inhibitors; other topical medications), 2 weeks.

(i) For potent systemic CYP3A4 inhibitors, 2 weeks or 5 half-lives (whichever is longer).

(j) For immunization with live attenuated vaccine, 2 weeks.

Note: Inactivated/inactivated vaccines (such as influenza, COVID-19, etc.) are permitted.

(k) For any type of opium treatment, 2 weeks.

(l) Currently receiving treatment, or having been treated with another investigational drug for 30 days or 5 half-lives (whichever is longer) prior to day 1, or currently enrolled in another investigational drug study.

(9) Had a major trauma or major surgery within 30 days prior to the screening visit due to HS or any other indication (as assessed by the investigator).

(10) Known allergy or reaction to any component of the study cream formulation and/or similar products.

(11) Those with a history of voluntary alcohol or drug addiction within the year prior to screening, or those currently drinking alcohol or using drugs, are considered by the researchers to have a history that would interfere with the participants’ ability to adhere to the drug administration schedule and the research evaluation.

(12) Pregnancy or lactation.

(13) Currently hospitalized for mental health adjustment disorder or has been hospitalized within the past 12 months.

(14) Participants who, in the researcher’s view, are unable or unlikely to comply with the smearing schedule, research evaluation, or procedures (e.g., electronic diary compliance).

(15) In the EU, participants are considered incapacitated under Article 31 of the CTR.

(16) The employees of the experiment commissioner or researcher or their family members.

Research and treatment of the drug

Apply 1.5% ruxolitinib cream or matching mediator cream as a thin film, twice daily, for at least 30 minutes in the morning and before bedtime, with an interval of approximately 8 hours.

During outpatient visits, the amount of study cream used for each application will be determined by weighing the tube before and after the participant applies the study cream to the affected area. All study cream tubes (including caps) will be weighed before dispensing. All returned study cream tubes (including caps) will also be weighed. Participants should be instructed not to use more than 60 grams of tubes per week.

Efficacy evaluation

Although clinical trial endpoints have not yet been established in adolescents, the efficacy endpoints studied in this study are applicable to both groups (adolescents and adults) because the clinical performance of HS is consistent in adolescents and adults.

Number of lesions

During each study visit, researchers assessed the number of lesions in suppurative hidradenitis and used them to calculate the following efficacy parameters: HiSCR and HiSCR75, AN number, and IHS4.

The number of lesions and their assessments will be recorded in the lesion count worksheet, including assessments of anatomical regions, including (but not limited to) the left and right axillae, the left and right inguinal folds, and the left and right submammary regions.

Clinical response to suppurative hidradenitis

HiSCR was initially developed based on a baseline Phase 2 study of adalimumab and validated based on meaningful changes in pain scores and DLQI. HiSCR was defined as a reduction of at least 50% in the number of arterial fistulas (ANs) relative to baseline, with no increase in the number of abscesses or draining fistulas (channels). In this study, the higher improvement threshold of HiSCR75 was used as the primary endpoint. Participants with draining channels were excluded from this study. If a randomly assigned participant developed a draining channel during the study, that participant was withdrawn from the study.

Number of abscesses and inflammatory nodules

The number of abscesses and inflammatory nodules will be recorded at all visits. These numbers will be used to calculate the change in AN number relative to the baseline, and AN50, AN75, AN90, and AN100, which are defined as a decrease in AN number relative to the baseline of at least 50%, 75%, 90%, and 100%, respectively.

International Severity Rating System for Hidradenitis Suppurativa

The IHS4 is a comprehensive, dynamic, and validated tool for determining the severity of HS. It uses a weighted scale with the number of inflammatory nodules, abscesses, and drainage channels (fungi or sinuses) as weighting factors of 1, 2, and 4 (e.g., an IHS4 score equals the number of inflammatory nodules [multiplied by 1] plus the number of abscesses [multiplied by 2] plus the number of drainage channels [multiplied by 4]).

Outbreak rate

The measurement of outbreaks is an important component of treatment, and their incidence is associated with a decline in patients' quality of life.

In this study, the definition of an outbreak is summarized below, proposed by Zouboulis et al.:

Compared to the baseline, the total number of abscesses and inflammatory nodules increased by at least 25%; and

Compared to the baseline, the total number of abscesses and inflammatory nodules increased by at least 2.

The proportion of participants in the outbreak will be assessed during this study.

Heli's stage of suppurative hidradenitis

The Hearley classification is a static assessment and was initially designed to select appropriate treatment for a specific body location: Stage I is medical therapy, Stage II is local surgery, and Stage III is extensive surgical resection. Participants diagnosed with HS (Hearley Stage I or II) according to the inclusion criteria will be enrolled in the study. Due to the heterogeneity of Hearley Stage II, participants with scarring are eligible to participate, while those with drainage channels will be excluded. Researchers (or designated personnel) will determine the Hearley stage in each affected anatomical region during visits, as indicated in Table 34 .

surface 34 Hurley's disease describe I Abscesses may form, single or multiple, without sinuses or scarring/scarring. II One or more widely separated recurrent abscesses, with channel (draining or non-draining) formation and scarring/growth. III The area is characterized by multiple interconnected pathways (draining or non-draining) and abscesses, exhibiting diffuse or near-diffuse invasion.

Body surface area

The total BSA% affected by HS and requiring regional treatment will be used to determine the number of study cream tubes allocated at each visit. As outlined in the SoA, the total BSA% affected will be estimated at each visit. The body surface area assessment of body parts receiving regional treatment can be roughly estimated using the palmar method as a guide, with the closest estimate being 0.5%, where the palm plus 5 fingers (fingers together and thumb folded to the side (handprint)) is considered 1% BSA and the thumb is considered 0.1% BSA.

Patient Report Results

The collected patient reports will be evaluated as outlined in the SoA.

All PROs will be collected electronically. Itching NRS and skin pain NRS will be collected daily via electronic diaries; additional PROs will be collected during field visits. For PROs collected during field visits, to avoid participant bias regarding questionnaire responses, assessments should be completed before any other assessment or research procedures and before treatment-related discussions with the researcher or research site staff.

Electronic Diary Assessment: Skin Pain and Itching Rating Scale

Participants will be instructed to complete and record their skin pain NRS and itching NRS every night in an electronic diary from the day of screening until week 52 or the ET visit.

Participants will be assessed based on a 24-hour memory period:

NRS for skin pain: the most severe skin pain caused by HS, ranging from 0 (no pain) to 10 (the most severe skin pain imaginable).

NRS: The most severe pruritus caused by HS, ranging from 0 (no pruritus) to 10 (the most severe pruritus imaginable).

The baseline skin pain NRS and itching NRS were determined before the first application of the cream to be the average of the NRS scores 7 days prior to the baseline visit (data from at least 4 days of the 7 days were required).

Pain relief treatment

From the day of selection until week 52 or the ET visit, participants will answer a questionnaire on painkiller (non-opioid) use in an electronic diary every evening.

Suppurative hidradenitis quality of life

HiSQoL will be used for quality of life assessment, and adult participants will complete the questionnaire during a designated visit. HiSQoL is a 17-item HS-specific health-related quality of life tool with a 7-day recall period, used to assess HS symptoms and the impact of HS problems on quality of life.

Suppurative hidradenitis quality of life - teenagers

The HiSQoL-AA was used to assess quality of life. Adolescents (12 to <18 years old) completed the questionnaire during their visit. The HiSQoL-AA contains 15 items and has a 7-day recall period, and is used to assess HS symptoms and HS experiences in adolescent patients.

Skin disease quality of life index

The DLQI is a simple, validated 10-question questionnaire used to measure the impact of skin problems on adult participants over the past 7 days, across symptoms and feelings, daily activities, leisure, work and school, personal relationships, and therapy. Adult participants will complete the DLQI during study visits.

Childhood skin disease quality of life index

CDLQI is a validated 10-question questionnaire used to measure the impact of a skin condition on a child's life over the past 7 days. The measurements were collected from adolescent participants at the time of their self-visit.

Patient Global Impression of Severity

PGIS is a single-item self-reported test in which participants rate the severity of their symptoms using a 7-point scale: (1) absent, (2) very mild, (3) mild, (4) moderate, (5) moderate to severe, (6) severe, and (7) very severe. Participants will complete PGIS during their visit.

Changes in overall patient impression

PGIC is a self-reported measurement that reflects participants’ beliefs about the efficacy of treatment since the start of the study. PGIC is a 7-point scale ((1) very improved, (2) much improved, (3) slightly improved, (4) no change, (5) slightly worsened, (6) severely worsened, and (7) very severely worsened) that describes participants’ assessment of overall improvement and will be collected during on-site visits, as outlined in SoA.

EQ-5D-5L

All participants will complete the EQ-5D-5L questionnaire during the visit. These measurements will provide data for economic modeling and analysis, including developing health benefits or quality-adjusted life years.

Impaired work efficiency and activity - suppurative hidradenitis

Participants will complete the WPAI-HS questionnaire during the visit. The WPAI-HS questionnaire is a tool for measuring impairment in paid and unpaid work. It measures absences and false attendance, as well as impairment in unpaid activities, caused by HS and other health problems over the past 7 days. The least clinically significant difference is defined as half the standard deviation of the baseline score for the overall population. Absences, false attendance, and overall impairment will be assessed only for the participants used.

Figure 1 graphically shows the mean and standard error of the number of abscesses and inflammatory nodules (ANs) from baseline to week 32 during the treatment period.

Figure 2 shows the ratio of the number of participants to the AN50 response at each visit. AN50 responders are individuals whose AN number decreased by >=50% relative to the baseline.

Figure 3 shows the proportion of participants to the AN75 response at each visit. AN75 responders are individuals whose AN number decreased by >= 75% relative to the baseline.

Figure 4 shows the proportion of patients who achieved the Hidradenitis Suppurativa Clinical Response (HiSCR) during the treatment period.

Figure 5 graphically illustrates the mean and standard error of the NRS for skin pain during visits during the treatment period.

Figure 6 graphically illustrates the mean and standard error of the itch NRS score at visits during the treatment period.

Figure 7 graphically illustrates the mean and standard error of the IHS4 score during the visit.

Claims (64)

A method for treating hidradenitis suppurativa (HS) in a human patient in need, the method comprising: topically administering to the affected skin area of the patient a topical preparation comprising 1.5% (w/w) of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free alkali, wherein the patient has no drainage access. The method described in Request 1, wherein the preparation is administered twice daily. The method of claim 1 or 2, wherein the ruxotinib or a pharmaceutically acceptable salt thereof is ruxotinib phosphate. The method of any one of claims 1 to 3, wherein the local formulation is a cream formulation. The method described in any of the requests 1 to 4, wherein the patient has Hurley stage I or Hurley stage II HS. The method described in any of the requests 1 to 5, wherein the patient has a total number of abscesses and inflammatory nodules (AN number) of less than 10. The method of any one of claims 1 to 6, wherein the body surface area (BSA) invaded by the HS is ≤ 20%. The method of any one of the requests 1 to 4, wherein the patient is diagnosed with HS at baseline and has a total number of 3 to ≤10 abscesses and inflammatory nodules (AN) without drainage channels. If any of the methods in requests 1 to 8 are used, the total AN number at baseline changes after the patient has been treated for at least 2, 4, 8, 12, or 16 weeks. The method described in any of requests 1 to 9, wherein the total number of ANs decreases after the patient has been treated for at least 16 weeks. As in Request 10, the total AN number decreases by at least 2 from the baseline to week 16. As in Request 10, the total AN number decreases by at least 3 from the baseline to week 16. The method of any of the requests 1 to 12, wherein at the baseline, the patient has a baseline pain-NRS score ≥ 1. The method described in any of the requests 1 to 13, wherein the patient’s pain-NRS score changes relative to baseline after at least 2, 4, 8, 12 or 16 weeks of treatment. The method described in any of the requests 1 to 13, wherein the patient has received treatment for at least 16 weeks and the pain-NRS score has decreased relative to baseline. The method described in claim 14 or 15, wherein the pain-NRS score is reduced by at least about 1 relative to the baseline. The method described in claim 14 or 15, wherein the pain-NRS score is reduced by at least about 2 relative to the baseline. The method of any of the requests 1 to 17, wherein at the baseline, the patient has a baseline pruritus-NRS score ≥ 1. The method described in any of the requests 1 to 18, wherein the patient’s itch-NRS score changes relative to baseline after at least 2, 4, 8, 12 or 16 weeks of treatment. The method described in any of the requests 1 to 19, wherein the patient’s itch-NRS score decreased relative to baseline after at least 16 weeks of treatment. The method of claim 20, wherein the itching-NRS score is reduced by at least about 1 relative to the baseline. The method of any of claims 1 to 21, wherein the local formulation is administered for at least 16 weeks. The method described in any of the requests 1 to 22, wherein the patient is 18 years of age or older. If any of the methods described in requests 1 to 23 applies, wherein the patient achieves a Hidradenitis Suppurativa Clinical Response (HiSCR) and/or a modified Hidradenitis Suppurativa Clinical Response (mHiSCR) before the administration of the drug at week 2, week 4, week 8, week 12, or week 16. The method described in any of the requests 1 to 24, wherein the patient achieved AN50 at least 16 weeks prior to administration. The method described in any of the requests 1 to 24, wherein the patient achieved AN75 at least 16 weeks prior to administration. The method described in any of the requests 1 to 26, wherein the patient achieved an International Hidradenitis Suppurativa Severity Score System (IHS4) score at least 16 weeks prior to administration. The method described in any of the requests 1 to 26, wherein the patient has achieved a reduction of ≥55% in total ISH4 score relative to baseline using the International Hidradenitis Severity Rating System (IHS4-55) at least 16 weeks prior. The method described in any of the requests 1 to 26, wherein the patient achieved IHS4-55 at least 32 weeks prior to administration. If any of the methods described in requests 1 to 29 are used, the abscesses show a relative decrease in baseline after the patient has been treated for at least one of 2, 4, 8, 12, or 16 weeks. The method described in claim 30, wherein the abscess is reduced relative to baseline after 12 or 16 weeks of treatment in the patient. If any of the methods described in requests 1 to 29 are used, in which the patient receives treatment for at least one of 2, 4, 8, 12, or 16 weeks, and the inflammatory nodules show a relative reduction in baseline. The method described in claim 32, wherein after 12 or 16 weeks, the patient’s inflammatory nodules are reduced relative to the baseline. If any of the methods described in requests 1 to 29 are used, in which the patient, after administration of at least one of the following 2, 4, 8, 12, or 16 weeks, showed a relative reduction in abscesses and inflammatory nodules compared to the baseline. The method described in claim 34, wherein after 12 or 16 weeks, the patient’s abscesses and inflammatory nodules are reduced relative to the baseline. A method for treating hidradenitis suppurativa (HS) in a human patient in need, the method comprising: topically administering to the affected skin area of the patient a topical preparation comprising 0.75% to 1.5% (w/w) of ruxolitinib or a pharmaceutically acceptable salt thereof, based on free alkali, wherein the patient has no drainage access. The method of claim 36, wherein the ruxolitinib or its pharmaceutically acceptable salt comprises about 0.75% ruxolitinib or its pharmaceutically acceptable salt as free base. As in the method of request item 36 or 37, the preparation is administered twice daily. The method of any of claims 36 to 38, wherein the ruxotinib or a pharmaceutically acceptable salt thereof is ruxotinib phosphate. The method of any of claims 36 to 38, wherein the local formulation is a cream formulation. The method described in any of the requests 36 to 40, wherein the patient has Helix stage I or Helix stage II HS. The method described in any of the requests 36 to 41, wherein the patient has a total number of abscesses and inflammatory nodules (AN number) of less than 10. The method of any of claims 36 to 41, wherein the body surface area (BSA) of the HS invasion is ≤20%. The method described in any of the requests 36 to 43, wherein the patient achieved AN50 at least 16 weeks prior to administration. The method described in any of the requests 36 to 43, wherein the patient achieved AN75 at least 16 weeks prior to administration. The method described in any of the requests 36 to 45, wherein the patient achieved IHS4 at least 16 weeks prior to administration. The method described in any of the requests 36 to 45, wherein the patient has achieved a reduction of ≥55% in total ISH4 score relative to baseline using the International Hidradenitis Severity Rating System (IHS4-55) at least 16 weeks prior to administration. The method described in any of the requests 36 to 45, wherein the patient achieved IHS4-55 at least 32 weeks prior to administration. If any of the methods in requests 36 to 48 is used, the abscesses decrease relative to baseline after the patient is given at least one of 2, 4, 8, 12, or 16 weeks. As in claim 49, the abscesses decreased relative to baseline after 12 or 16 weeks of treatment in the patient. If any of the methods in requests 36 to 48 is used, in which the patient receives treatment for at least one of 2, 4, 8, 12, or 16 weeks, and the inflammatory nodules show a relative reduction in baseline. The method of claim 51, wherein after 12 or 16 weeks, the patient’s inflammatory nodules are reduced relative to the baseline. If any of the methods in requests 36 to 48 are used, the patient experiences a relative reduction in abscesses and inflammatory nodules after administration for at least one of 2, 4, 8, 12, or 16 weeks. The method described in claim 53, wherein after 12 or 16 weeks, the patient’s abscesses and inflammatory nodules are reduced relative to the baseline. A method for reducing pain in human patients with suppurative hidradenitis (HS), the method comprising: topically administering to the affected skin area of the patient a topical preparation containing 1.5% (w/w) ruxolitinib or a pharmaceutically acceptable saline thereof, based on free base; wherein the patient has no drainage pathway, and wherein the patient is ≥18 years of age and, after 16 weeks of administration, the analgesic number (AN) has decreased relative to baseline. A method for reducing pain in human patients with suppurative hidradenitis (HS), the method comprising: topically administering twice daily to the affected skin area of the patient a topical preparation containing 1.5% (w/w) ruxolitinib or a pharmaceutically acceptable saline thereof, based on free base; wherein the patient has no drainage access, and wherein the patient is ≥18 years of age and, at baseline, has a baseline pain-NRS score ≥1, and the patient's pain-NRS score changes relative to baseline after at least 2, 4, 8, 12, or 16 weeks of topical administration. A method for reducing itching in human patients with suppurative hidradenitis (HS), the method comprising: topically applying twice daily to the affected skin area of the patient a topical preparation containing 1.5% (w/w) ruxolitinib or a medically acceptable saline thereof, based on free base, where the patient has no drainage pathways, and where the patient has achieved an AN50 at least 16 weeks prior. A method for treating hidradenitis suppurativa (HS) in human patients of need, the method comprising: topically administering twice daily to the affected skin area of the patient a topical preparation comprising 1.5% (w/w) of ruxolitinib or a pharmaceutically acceptable saline thereof, based on free base; wherein the patient has no drainage pathway; wherein the patient is ≥18 years of age at baseline; and wherein the patient achieves a hidradenitis suppurativa clinical response (HiSCR) and/or a modified hidradenitis suppurativa clinical response (mHiSCR) after administration for at least 2, 4, 8, 12, or 16 weeks. A method for treating hidradenitis suppurativa (HS) in human patients of need, the method comprising: topically administering twice daily to the affected skin area of the patient a topical preparation comprising 1.5% (w/w) of ruxolitinib or a pharmaceutically acceptable saline thereof, based on free base; wherein the patient has no drainage pathway; wherein the patient is ≥18 years of age at baseline; and wherein the patient experiences a reduction in abscess and/or inflammatory nodules relative to baseline after at least one of 2, 4, 8, 12, or 16 weeks of administration. A method for treating hidradenitis suppurativa (HS) in human patients of need, the method comprising: topically administering to the affected skin area of the patient a topical formulation comprising 1.5% (w/w) ruxolitinib or a pharmaceutically acceptable salt thereof, based on free alkali, wherein the patient achieves a reduction of ≥55% in the International Hidradenitis Severity Rating System (IHS4-55) relative to baseline total ISH4 score. The method of claim 60, wherein the ISH4-55 score is reduced by approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, or approximately 85% relative to the baseline total ISH4 score. The method of request item 61, wherein the patient achieves a reduction in IHS 4-55 score at least before week 2, week 4, week 8, week 12, week 16, week 20, week 24, week 28 or week 32. The method described in Request 60, wherein the patient achieved a reduction in the IHS 4-55 score at least 16 weeks prior. The method described in Request 60, wherein the patient achieved a reduction in the IHS 4-55 score at least 32 weeks prior.