WO2025235561A1 - Venetoclax oral drugs and uses thereof - Google Patents

Abstract

The present disclosure relates to Venetoclax oral drugs and uses thereof. In some aspects, the present disclosure provides for a pharmaceutical composition for oral administration, which comprises an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier or excipient. In some aspects, the present disclosure provides for uses of the above pharmaceutical compositions.

Description

VENETOCLAX ORAL DRUGS AND USES THEREOF

I. Related Applications

[0001] The present application claims priority to U.S. provisional patent application No. 63/644,383, filed on May 8, 2024, U.S. provisional patent application No. 63/722,988, filed on November 20, 2024, and U.S. provisional patent application No. 63/782,488, filed on April 2, 2025. The disclosures of the above-referenced applications are incorporated by reference in their entireties for all purposes.

II. Field of the Invention

[0002] The present disclosure relates to Venetoclax oral drugs and uses thereof. In some aspects, the present disclosure provides for a pharmaceutical composition for oral administration, which comprises an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier or excipient. In some aspects, the present disclosure provides for uses of the above pharmaceutical compositions.

III. Background a. Clinical significancy of Venetoclax

[0003] Venetoclax is a highly selective, potent, orally bioavailable small molecule inhibitor of BCL-2 that has demonstrated significant clinical efficacy in the treatment of various hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and multiple myeloma (MM). BCL-2 is a key regulator of apoptosis (programmed cell death) and is overexpressed in many cancer cells, contributing to their survival and resistance to therapy. By selectively inhibiting BCL-2, Venetoclax promotes apoptosis in cancer cells, leading to tumor regression.-

[0004] Venetoclax is a lipophilic compound with a molecular weight of approximately 868.44 g/mol. It is practically insoluble in water, with a log P value of 8.1.- These physicochemical properties contribute to its poor aqueous solubility and influence its permeability in the GI tract. Venetoclax is a permeable compound, with absorption characteristics in the gastrointestinal tract. However, its permeability is influenced by various factors such as molecular size, lipophilicity, and the presence of efflux transporters.

[0005] Venetoclax is a substrate for efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)¹, which can limit its absorption and distribution in the body. Inhibition or inducing of these transporters can alter Venetoclax bioavailability. Venetoclax is primarily metabolized by enzyme CYP3A4, which can lead to the formation of inactive metabolites. Drug-drug interactions with CYP3A4 inhibitors or inducers can significantly impact Venetoclax metabolism and bioavailability.

[0006] The bioavailability of current marketed Venetoclax tablets (Trademark: VENCLEXTA®, Marketed by both Abbvie and Genentech USA) can vary among patients due to differences in the type of food intake and coadministration of other medicines. Personalized dosing strategies based on patient characteristics and drug-drug interactions are essential to optimize Venetoclax therapy and minimize the risk of toxicity. Physicians must be aware of potential drug interactions when prescribing Venetoclax and adjust the dosage as needed.- b. Challenges in bioavailability of the marketed Venetoclax Tablets i. Significant food effects

[0007] The absolute bioavailability for Venetoclax Tablets (Trademark: VENCLEXTA®) was estimated at 5.4% under fasting conditions.- When taken with a low-fat meal, Venetoclax exposure increases by about 3.4-fold, and with a high-fat meal, exposure increases up to 5.3-fold compared to fasting-. Therefore, the patients are instructed to take VENCLEXTA tablets with a meal and water at approximately the same time each day. The absorption of Venetoclax is significantly affected by food intake, impacting both its effectiveness and safety. This food effect is primarily due to Venetoclax's poor solubility in water and its slow dissolution from the tablets, a characteristic of its formulation of VENCLEXTA®. -

[0008] Additionally, Venetoclax is a substrate for efflux transporters like P-glycoprotein (P- gp), which actively transports it out of cells. Consequently, Venetoclax is more readily absorbed in the upper gastrointestinal (GI) tract, specifically the stomach and duodenum, compared to the lower GI tract regions such as the small intestines and colon.

[0009] Understanding this food effect is crucial for optimizing Venetoclax formulation to ensure patients receive maximum benefits with minimal side effects. Overall, these findings highlight the importance of considering the complex interactions between the dissolution of the drug from its formulation, the absorption mechanisms of P-gp substrate, and lipophilicity of the drug molecule when designing drug delivery approaches for patients receiving Venetoclax therapy. ii. Drug-drug interaction

[0010] Given its status as a substrate for efflux transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), as well as being metabolized by CYP3A4, Venetoclax poses a risk for drug-drug interactions that could lead to toxicity in patients.

[0011] For patients that are taken other medicines, they are instructed to avoid using VENCLEXTA with strong CYP3A inhibitors at the start and during the dose escalation period. This combination can increase Venetoclax levels, potentially raising the risk of TLS (tumor lysis syndrome). For patients who have completed dose escalation and are on a stable daily dose of VENCLEXTA, they need to reduce the VENCLEXTA dose by at least 75% when strong CYP3A inhibitors are needed. Also, patients must consider other treatments and do not use VENCLEXTA with moderate CYP3A inhibitors or P-gp inhibitors if possible. If moderate CYP3A inhibitors or P-gp inhibitors must be used, reduce the VENCLEXTA dose by at least 50% and monitor patients closely for side effects. Resume the original VENCLEXTA dose 2 to 3 days after stopping the CYP3A inhibitor or P-gp inhibitor was recommended.¹ iii. Blood-brain barrier (BBB) crossing

[0012] Central nervous system involvement (CNSi) is a rare complication of CLL, occurring in approximately 0.4% of patients-. In pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the incidence is 5% and 10%, respectively, with higher rates in the relapse setting-. Venetoclax is approved for the treatment of CLL and adult AML. It is also investigated for other hematological malignancies, including ALL, multiple myeloma (MM), mantle cell lymphoma (MCL), and pediatric AML. While the plasma pharmacokinetics (PK) of Venetoclax are well-characterized, information on its penetration into the CNS is limited.

[0013] For Venetoclax to enter the CNS, it must overcome both physicochemical and physiological barriers. Venetoclax, with a molecular weight of 868.44 g/mol, faces challenges passing through the tight junctions of the blood-brain barrier (BBB). Additionally, Venetoclax is a substrate of several efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are expressed within the Blood Brain Barrier (BBB) and can actively pump Venetoclax out of the CNS. c. Sodium dodecyl sulfate (SDS) as solubilizer and permeability enhancer [0014] SDS is an anionic surfactant and commonly used as a wetting agent and solubility enhancing agent in solid oral dosage forms. It is also used as a permeation-enhancing agent in various studies-. SDS has been demonstrated that it can reversibly open tight junctions-. The permeability enhancement effect of SDS on P-gp substrates has been the subject of investigation for decades, yet conclusive findings remain elusive, with outcomes largely dependent on the specific molecule under study.- For instance, numerous studies have noted that SDS can increase the permeability of drugs with low permeability. However, when tested in vivo, SDS did not show any enhancement in drug permeability. Thus, enhancing drug absorption has been a long-standing objective in drug absorption research, and as of now, no common excipient is known to enhance drug permeability in vivo.^2, —

[0015] SDS has shown potential in enhancing drug permeation across the blood-brain barrier (BBB). The mechanism behind this enhancement is believed to involve an interaction with membrane lipids, which could temporarily increase the BBB membrane's permeability. This interaction may facilitate a higher rate of passive permeation for drug molecules, effectively aiding their passage into the brain.— However, despite these promising effects, the impact of SDS on the BBB crossing of P-glycoprotein (P-gp) substrates, such as Venetoclax, remains unclear. The BBB is richly endowed with various transporters, including P-gp, which play a crucial role in limiting the movement of P-gp substrates between the blood vessels and the brain. It is plausible that the efflux effect of P-gp may still restrict the movement of these substrates, even in the presence of SDS-induced membrane permeability changes. Further research is needed to elucidate the precise effects of SDS on the BBB crossing of P-gp substrates, which could have significant implications for improving drug delivery to the brain and enhancing the efficacy of treatments targeting neurological illnesses.

[0016] Accordingly, there is a need for improved oral pharmaceutical compositions and methods for preventing and/or treating a diseases or disorder, e.g., a tumor or cancer, in a subject. The present disclosure addresses this and other related needs.

IV. Summary of the Invention

[0017] In one aspect or embodiment, the present disclosure provides for a pharmaceutical composition for oral administration, which comprises: a) an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and b) an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally, c) a pharmaceutically acceptable carrier or excipient. [0018] In another aspect or embodiment, the present disclosure provides for a method for inhibiting or reducing function of BCL-2 in a subject, which method comprises orally administering, to a subject in need, an effective amount of the above pharmaceutical composition.

[0019] In still another aspect or embodiment, the present disclosure provides for a method for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to central nervous system of a subject, which method comprises orally administering, to a subject in need, an effective amount of the above pharmaceutical composition.

[0020] In yet another aspect or embodiment, the present disclosure provides for a method for treating or preventing a cancer or tumor in a subject, which method comprises orally administering, to a subject in need, an effective amount of the above pharmaceutical composition.

[0021] In yet another aspect or embodiment, the present disclosure provides for a use of the above pharmaceutical composition for inhibiting or reducing function of BCL-2 in a subject.

[0022] In yet another aspect or embodiment, the present disclosure provides for a use of the above pharmaceutical composition for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to the central nervous system of a subject.

[0023] In yet another aspect or embodiment, the present disclosure provides for a use of the above pharmaceutical composition for treating or preventing a cancer or tumor in a subject.

V. Brief Description of the Drawings

[0024] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0025] Figure 1 illustrates an exemplary individual plasma concentration-time curve of test formulation #1 of Venetoclax in Wistar rats after a single dose of 30 mg/kg orally.

[0026] Figure 2 illustrates an exemplary individual plasma concentration-time curve of reference formulation of Venetoclax in Wistar rats after a single dose of 30 mg/kg orally.

[0027] Figure 3 illustrates an exemplary comparison of Average plasma concentrations from Test Formulation #1 and Reference Formulation.

[0028] Figure 4 illustrates an exemplary average plasma concentration-time curve of Venetoclax after a single intravenous dose. [0029] Figure 5 illustrates an exemplary plasma Concentration versus Time plot for Test Formulation #2.

[0030] Figure 6 illustrates an exemplary plasma Concentration versus Time plot for Reference Formulation.

[0031] Figure 7 illustrates an exemplary Venetoclax concentration in plasma and brain from Test Formulation #4.

[0032] Figure 8 illustrates an exemplary plot of the mean plasma concentrations of Venetoclax from the test formulation #5 and the reference formulation (Venclexta®) after a single oral administration in nine human subjects.

[0033] Figure 9 illustrates an exemplary plot of the mean plasma concentrations of Venetoclax following a single oral administration of the test formulation #5 under fasting and a Fed condition in nine human subjects.

[0034] Figure 10 illustrates an exemplary in vitro drug release profiles for Venetoclax Tablet (20 mg) of the test formulation #5.

[0035] Figure 11 illustrates an exemplary plot of the mean plasma concentrations of Venetoclax following a single oral administration of the test formulation No. 5 (Table 5) under fasting and co-administered with 600 mg of Rifampin capsules.

VI. Detailed Description

[0036] A detailed description of one or more embodiments of the claimed subject matter is provided below along with accompanying figures that illustrate the principles of the claimed subject matter. The claimed subject matter is described in connection with such embodiments, but is not limited to any particular embodiment. It is to be understood that the claimed subject matter may be embodied in various forms, and encompasses numerous alternatives, modifications and equivalents. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the claimed subject matter in virtually any appropriately detailed system, structure, or manner. Numerous specific details are set forth in the following description in order to provide a thorough understanding of the present disclosure. These details are provided for the purpose of example and the claimed subject matter may be practiced according to the claims without some or all of these specific details. It is to be understood that other embodiments can be used and structural changes can be made without departing from the scope of the claimed subject matter. It should be understood that the various features and functionality described in one or more of the individual embodiments are not limited in their applicability to the particular embodiment with which they are described. They instead can, be applied, alone or in some combination, to one or more of the other embodiments of the disclosure, whether or not such embodiments are described, and whether or not such features are presented as being a part of a described embodiment. For the purpose of clarity, technical material that is known in the technical fields related to the claimed subject matter has not been described in detail so that the claimed subject matter is not unnecessarily obscured.

[0037] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art.

[0038] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entireties for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, patent applications, published applications or other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference. Citation of the publications or documents is not intended as an admission that any of them is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0039] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

[0040] The practice of the provided embodiments will employ, unless otherwise indicated, conventional techniques and descriptions of organic chemistry, polymer technology, molecular biology (including recombinant techniques), cell biology, biochemistry, and sequencing technology, which are within the skill of those who practice in the art. Such conventional techniques include polypeptide and protein synthesis and modification, polynucleotide synthesis and modification, polymer array synthesis, hybridization and ligation of polynucleotides, and detection of hybridization using a label. Specific illustrations of suitable techniques can be had by reference to the examples herein. However, other equivalent conventional procedures can, of course, also be used. Such conventional techniques and descriptions can be found in standard laboratory manuals such as Green, et al., Eds., Genome Analysis: A Laboratory Manual Series (Vols. I-IV) (1999); Weiner, Gabriel, Stephens, Eds., Genetic Variation: A Laboratory Manual (2007); Dieffenbach, Dveksler, Eds., PCR Primer: A Laboratory Manual (2003); Bowtell and Sambrook, DNA Microarrays: A Molecular Cloning Manual (2003); Mount, Bioinformatics: Sequence and Genome Analysis (2004); Sambrook and Russell, Condensed Protocols from Molecular Cloning: A Laboratory Manual (2006); and Sambrook and Russell, Molecular Cloning: A Laboratory Manual (2002) (all from Cold Spring Harbor Laboratory Press); Ausubel et al. eds., Current Protocols in Molecular Biology (1987); T. Brown ed., Essential Molecular Biology (1991), IRL Press; Goeddel ed., Gene Expression Technology (1991), Academic Press; A. Bothwell et al. eds., Methods for Cloning and Analysis of Eukaryotic Genes (1990), Bartlett Publ.; M. Kriegler, Gene Transfer and Expression (1990), Stockton Press; R. Wu et al. eds., Recombinant DNA Methodology (1989), Academic Press; M. McPherson et al., PCR: A Practical Approach (1991), IRL Press at Oxford University Press; Stryer, Biochemistry (4th Ed.) (1995), W. H. Freeman, New York N.Y.; Gait, Oligonucleotide Synthesis: A Practical Approach (2002), IRL Press, London; Nelson and Cox, Lehninger, Principles of Biochemistry (2000) 3rd Ed., W. H. Freeman Pub., New York, N.Y.; Berg, et al., Biochemistry (2002) 5th Ed., W. H. Freeman Pub., New York, N.Y.; D. Weir & C. Blackwell, eds., Handbook of Experimental Immunology (1996), Wiley-Blackwell; Cellular and Molecular Immunology (A. Abbas et al., W.B. Saunders Co. 1991, 1994); Current Protocols in Immunology (J. Coligan et al. eds. 1991), all of which are herein incorporated in their entireties by reference for all purposes.

[0041] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the claimed subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the claimed subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the claimed subject matter. This applies regardless of the breadth of the range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6.

[0042] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

A. Definitions

[0043] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “a” or “an” means “at least one” or “one or more.” It is understood that aspects and variations described herein include “consisting” and/or “consisting essentially of’ aspects and variations.

[0044] The term “comprising,” which is used interchangeably with “including,” “containing,” or “characterized by,” is inclusive or open-ended language and does not exclude additional, unrecited elements or method steps. The phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The present disclosure contemplates embodiments of the invention compositions and methods corresponding to the scope of each of these phrases. Thus, a composition or method comprising recited elements or steps contemplates particular embodiments in which the composition or method consists essentially of or consists of those elements or steps.

[0045] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0046] As used herein, a composition refers to any mixture of two or more products, substances, or compounds, including cells. It may be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.

[0047] An “individual” or “subject” includes a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). An “individual” or “subject” may include birds such as chickens, vertebrates such as fish and mammals such as mice, rats, rabbits, cats, dogs, pigs, cows, ox, sheep, goats, horses, monkeys and other non-human primates. In certain embodiments, the individual or subject is a human.

[0048] As used herein, the term “sample” refers to anything which may contain an analyte for which an analyte assay is desired. As used herein, a “sample” can be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof. The sample may be a biological sample, such as a biological fluid or a biological tissue. Examples of biological fluids include urine, blood, plasma, serum, saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus, amniotic fluid or the like. Biological tissues are aggregate of cells, usually of a particular kind together with their intercellular substance that form one of the structural materials of a human, animal, plant, bacterial, fungal or viral structure, including connective, epithelium, muscle and nerve tissues. Examples of biological tissues also include organs, tumors, lymph nodes, arteries and individual cell(s).

[0049] In some embodiments, the sample is a biological sample. A biological sample of the present disclosure encompasses a sample in the form of a solution, a suspension, a liquid, a powder, a paste, an aqueous sample, or a non-aqueous sample. As used herein, a “biological sample” includes any sample obtained from a living or viral (or prion) source or other source of macromolecules and biomolecules, and includes any cell type or tissue of a subject from which nucleic acid, protein and/or other macromolecule can be obtained. The biological sample can be a sample obtained directly from a biological source or a sample that is processed. For example, isolated nucleic acids that are amplified constitute a biological sample. Biological samples include, but are not limited to, body fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine and sweat, tissue and organ samples from animals and plants and processed samples derived therefrom. In some embodiments, the sample can be derived from a tissue or a body fluid, for example, a connective, epithelium, muscle or nerve tissue; a tissue selected from the group consisting of brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, gland, and internal blood vessels; or a body fluid selected from the group consisting of blood, urine, saliva, bone marrow, sperm, an ascitic fluid, and subfractions thereof, e.g., serum or plasma.

[0050] As used herein, “treatment’ or ‘treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment includes preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; preventing re-occurring of the disease and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance.

[0051] The term “effective amount” or “therapeutically effective amount” refers to the amount of an active agent sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The term “therapeutically effective amount” is used herein to denote any amount of the formulation which causes a substantial improvement in a disease condition when applied to the affected areas repeatedly over a period of time. The amount will vary with the condition being treated, the stage of advancement of the condition, and the type and concentration of formulation applied. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.

[0052] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a subject or a patient, such as a mammal, such as human (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, malate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0053] The term “salt thereof’ means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0054] A “subject,” “individual,” or “patient,” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.

[0055] As used herein, the term “Venetoclax” refers to a compound of Formula (I) as follows:

In some embodiment, Venetoclax, or a pharmaceutically acceptable salt thereof, is sold with the tradename, Venclexta or Venclyxto. Other names of Venetoclax, or a pharmaceutically acceptable salt thereof, include GDC-0199, ABT-199 or RG-7601.

B. Pharmaceutical compositions for oral administration

[0056] In one aspect or embodiment, the present disclosure provides for a pharmaceutical composition for oral administration, which comprises: a) an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and b) an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally, c) a pharmaceutically acceptable carrier or excipient.

[0057] In some embodiment, the present pharmaceutical compositions comprise an effective amount of Venetoclax. In some embodiment, the present pharmaceutical compositions comprise an effective amount of a pharmaceutically acceptable salt of Venetoclax.

[0058] The present pharmaceutical compositions can comprise any suitable level or concentration of Venetoclax, or a pharmaceutically acceptable salt thereof. For example, the present pharmaceutical compositions can comprise from about 0.1% (w/w) to about 50% (w/w) Venetoclax, or a pharmaceutically acceptable salt thereof. In some embodiment, the present pharmaceutical composition can comprise from about 0.1% (w/w), 0.2% (w/w), 0.3% (w/w), 0.4% (w/w), 0.5% (w/w), 0.6% (w/w), 0.7% (w/w), 0.8% (w/w), 0.9% (w/w), 1% (w/w), 2% (w/w), 3% (w/w), 4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), 10% (w/w), 15% (w/w), 20% (w/w), 25% (w/w), 30% (w/w), 35% (w/w), 40% (w/w), 45% (w/w), 50% (w/w), or any subrange thereof, Venetoclax, or a pharmaceutically acceptable salt thereof. In some embodiment, the present pharmaceutical compositions comprise from about 0.1% (w/w) to about 1% (w/w) Venetoclax, or a pharmaceutically acceptable salt thereof.

[0059] The present pharmaceutical compositions can comprise any suitable level or concentration of an anionic surfactant, or a pharmaceutically acceptable salt thereof. For example, the present pharmaceutical compositions can comprise from about 20% (w/w) to about 99.9% (w/w) anionic surfactant, or a pharmaceutically acceptable salt thereof. In some embodiment, the present pharmaceutical composition can comprise from about 20% (w/w), 25% (w/w), 30% (w/w), 35% (w/w), 40% (w/w), 45% (w/w), 50% (w/w), 55% (w/w), 60% (w/w), 65% (w/w), 70% (w/w), 75% (w/w), 80% (w/w), 85% (w/w), 90% (w/w), 95% (w/w), 99% (w/w), 99.9% (w/w) or more, or any subrange thereof, anionic surfactant, or a pharmaceutically acceptable salt thereof. In another example, the present pharmaceutical compositions can comprise from about 20% (w/w) to about 99.9% (w/w) anionic surfactant that is an organosulfate or sodium dodecyl sulfate (SDS), or a pharmaceutically acceptable salt thereof. In some embodiment, the present pharmaceutical composition can comprise from about 20% (w/w), 25% (w/w), 30% (w/w), 35% (w/w), 40% (w/w), 45% (w/w), 50% (w/w), 55% (w/w), 60% (w/w), 65% (w/w), 70% (w/w), 75% (w/w), 80% (w/w), 85% (w/w), 90% (w/w), 95% (w/w), 99% (w/w), 99.9% (w/w) or more, or any subrange thereof, anionic surfactant that is an organosulfate or sodium dodecyl sulfate (SDS), or a pharmaceutically acceptable salt thereof.

[0060] The present pharmaceutical compositions can comprise any suitable anionic surfactant. For example, the present pharmaceutical compositions can comprise an anionic surfactant that is an organosulfate. Any suitable organosulfate can be used in the present pharmaceutical compositions. In some embodiment, the organosulfate in the present pharmaceutical compositions is a 5-carbon organosulfate, a 6-carbon organosulfate, a 7-carbon organosulfate, a 8-carbon organosulfate, a 9-carbon organosulfate, a 10-carbon organosulfate, a 11-carbon organosulfate, a 12-carbon organosulfate, a 13-carbon organosulfate, a 14-carbon organosulfate, a 15-carbon organosulfate, or a combination or mixture thereof. In some embodiment, the organosulfate in tire present pharmaceutical compositions is sodium dodecyl sulfate (SDS), sodium decyl sulfate or sodium octyl sulfate. In some embodiment, the organosulfate in the present pharmaceutical compositions is sodium dodecyl sulfate (SDS). [0061] The present pharmaceutical compositions can further comprise a soft gel filler. Any suitable soft gel filler can be used in the present pharmaceutical compositions. For example, the soft gel filler in the present pharmaceutical compositions can be polyethylene glycol (PEG). Any suitable polyethylene glycol (PEG) can be used in the present pharmaceutical compositions. For example, polyethylene glycol (PEG) can be polyethylene glycol 400 (PEG 400), PEG 1450, or PEG 8000.

[0062] The present pharmaceutical compositions can be in any suitable orally acceptable dosage form. For example, the present pharmaceutical compositions can be in an orally acceptable dosage form of a tablet, a capsule, an emulsion, an aqueous suspension, a dispersion or a solution. In some embodiment, the present pharmaceutical compositions is in an orally acceptable dosage form of a tablet. In some embodiment, the pharmaceutically acceptable carrier or excipient in the tablet is a filler, e.g., cellulose or microcrystalline cellulose.

[0063] The present pharmaceutical compositions can comprise any suitable unit dosage of Venetoclax, or a pharmaceutically acceptable salt thereof. For example, the present pharmaceutical compositions can comprise a unit dosage of Venetoclax, or a pharmaceutically acceptable salt thereof, in an amount ranging from about 1 mg to about 400 mg. In some embodiment, the present pharmaceutical compositions can comprise a unit dosage of Venetoclax, or a pharmaceutically acceptable salt thereof, in an amount of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or any subrange thereof.

[0064] The present pharmaceutical compositions can comprise another suitable active ingredient or drug. The other suitable active ingredient or drug can be a small molecule or large molecule active ingredient or drug. For example, the large molecule active ingredient or drug can be a protein or a polypeptide, e.g., an antibody. For example, the large molecule active ingredient or drug can be a polynucleotide or an oligonucleotide, e.g., a DNA, RNA, lipid, polysaccharide, a sugar, or a combination or mixture thereof. In another example, the present pharmaceutical compositions can comprise another anti-cancer or anti-tumor drug, e.g., a small molecule large molecule anti-cancer or anti-tumor drug. In some embodiment, the other suitable active ingredient or drug in the present pharmaceutical compositions is a protein or a polypeptide, e.g., an antibody or a monoclonal antibody. In some embodiment, other suitable active ingredient or drug in the present pharmaceutical compositions is obinutuzumab or rituximab.

[0065] The present pharmaceutical compositions can be configured for preventing and/or treating any suitable disease or disorder. For example, The present pharmaceutical compositions can be configured for preventing and/or treating cancer or tumor. In some embodiment, the present pharmaceutical compositions configured for preventing and/or treating acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL). In some embodiment, the present pharmaceutical compositions comprise Venetoclax, or a pharmaceutically acceptable salt thereof, as the sole active substance and are configured for preventing and/or treating acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0066] In some embodiment, the present pharmaceutical compositions configured for preventing and/or treating acute lymphoblastic leukemia, in relapse, acute myeloid leukemia arising from previous myelodysplastic/myeloproliferative neoplasm, acute myeloid leukemia post cytotoxic therapy, acute T-lymphocytic leukemia, AL amyloidosis, allogeneic hematopoietic stem cell transplantation, all-trans retinoic acid (ATRA) and arsenic (As) resistant acute promyelocytic leukemia (APL), B-cell acute lymphoblastic leukemia, B-cell lymphoma, chronic myelomonocytic leukemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hematologic malignancy, hemophagocytic lymph histiocytosis, HIV-1- infection, leukemia, lymphoblastic, acute, LI, leukemia, lymphoblastic, acute, L2, leukemia, myeloid, acute, lymphoblastic lymphoma (precursor B -lymphoblastic lymphoma/leukemia) recurrent, lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma/leukemia) recurrent, lymphoplasmacytic lymphoma, mantle Cell lymphoma (MCL), marginal zone lymphoma (MZL), minimal residual disease, mucosa associated lymphoid tissue, multiple myeloma, multiple myeloma in relapse, myelodysplasia-related acute myeloid leukemia, myelodysplastic syndromes (MDS), non-Hodgkin lymphoma, plasma cell myeloma, recurrent hairy cell leukemia, recurrent hairy cell leukemia variant, recurrent transformed chronic lymphocytic leukemia, refractory acute myeloid leukemia, refractory follicular lymphoma, refractory small cell lung carcinoma, refractory transformed chronic lymphocytic leukemia, relapsed acute myeloid leukemia, relapsed follicular lymphoma, relapsed small cell lung cancer, relapsed/refractory chronic lymphocytic leukemia, Richter syndrome, secondary acute myeloid leukemia, stem cell transplant complications, T-cell lymphoma refractory, T-cell lymphoma relapsed, T-cell or B-cell acute lymphoblastic leukemia, T-cell prolymphocytic leukemia (T- PLL), transformed chronic lymphocytic leukemia to diffuse large B-cell lymphoma, transformed small lymphocytic lymphoma to diffuse large B-cell lymphoma, or Waldenstrom's Macroglobulinemia.

[0067] In some embodiment, the present pharmaceutical compositions comprise Venetoclax, or a pharmaceutically acceptable salt thereof, and a second active substance(s), and are configured for preventing and/or treating acute lymphoblastic leukemia, in relapse, acute myeloid leukemia arising from previous myelodysplastic/myeloproliferative neoplasm, acute myeloid leukemia post cytotoxic therapy, acute T-lymphocytic leukemia, AL amyloidosis, allogeneic hematopoietic stem cell transplantation, all-trans retinoic acid (ATRA) and arsenic (As) resistant acute promyelocytic leukemia (APL), B-cell acute lymphoblastic leukemia, B-cell lymphoma, chronic myelomonocytic leukemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hematologic malignancy, hemophagocytic lymph histiocytosis, HIV- 1-infection, leukemia, lymphoblastic, acute, LI, leukemia, lymphoblastic, acute, L2, leukemia, myeloid, acute, lymphoblastic lymphoma (precursor B -lymphoblastic lymphoma/leukemia) recurrent, lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma/leukemia) recurrent, lymphoplasmacytic lymphoma, mantle Cell lymphoma (MCL), marginal zone lymphoma (MZL), minimal residual disease, mucosa associated lymphoid tissue, multiple myeloma, multiple myeloma in relapse, myelodysplasia-related acute myeloid leukemia, myelodysplastic syndromes (MDS), non-Hodgkin lymphoma, plasma cell myeloma, recurrent hairy cell leukemia, recurrent hairy cell leukemia variant, recurrent transformed chronic lymphocytic leukemia, refractory acute myeloid leukemia, refractory follicular lymphoma, refractory small cell lung carcinoma, refractory transformed chronic lymphocytic leukemia, relapsed acute myeloid leukemia, relapsed follicular lymphoma, relapsed small cell lung cancer, relapsed/refractory chronic lymphocytic leukemia, Richter syndrome, secondary acute myeloid leukemia, stem cell transplant complications, T-cell lymphoma refractory, T-cell lymphoma relapsed, T-cell or B-cell acute lymphoblastic leukemia, T-cell prolymphocytic leukemia (T- PLL), transformed chronic lymphocytic leukemia to diffuse large B-cell lymphoma, transformed small lymphocytic lymphoma to diffuse large B-cell lymphoma, or Waldenstrom's Macroglobulinemia.

C. Uses of the pharmaceutical compositions for oral administration [0068] In another aspect or embodiment, the present disclosure provides for a method for inhibiting or reducing function of BCL-2 in a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples.

[0069] In still another aspect or embodiment, the present disclosure provides for a method for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to central nervous system of a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples.

[0070] In yet another aspect or embodiment, the present disclosure provides for a method for treating or preventing a disease or a disorder, e.g., a cancer or tumor, in a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples.

[0071] The present pharmaceutical compositions can be administered to any suitable subject. For example, the present pharmaceutical compositions can be administered to a non-human subject, e.g., a non-human mammal. In some embodiment, the present pharmaceutical compositions can be administered to a non-human subject, e.g., a non-human mammal, in research, drug discovery and/or validation, preclinical study or clinical study or trial. In another example, the present pharmaceutical compositions can be administered to a human. In some embodiment, the present pharmaceutical compositions can be administered to a human in clinical study or trial, or for treatment and/or prevention of a disease or disorder.

[0072] The present pharmaceutical compositions can be administered to a subject to reach any suitable level of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject. For example, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level from about 50 mg/ml to about 4,000 mg/ml. In some embodiment, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level of 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 350 mg/ml, 400 mg/ml, 450 mg/ml, 500 mg/ml, 550 mg/ml, 600 mg/ml, 650 mg/ml, 700 mg/ml, 750 mg/ml, 800 mg/ml, 850 mg/ml, 900 mg/ml, 950 mg/ml, 1,000 mg/ml, 1,500 mg/ml, 2,000 mg/ml, 2,500 mg/ml, 3,000 mg/ml, 3,500 mg/ml, 4,000 mg/ml, or any subrange thereof.

[0073] In another example, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level that is about 2 fold to about 15 fold of plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject. In some embodiment, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level that is about 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 11 fold, 12 fold, 13 fold, 14 fold, 15 fold, or any subrange thereof, of plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

[0074] In still another example, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system of the subject reaches a level from about 10 ng/mL to about 70 ng/mL. In some embodiment, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system of the subject reaches a level of about 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL, 55 ng/mL, 60 ng/mL, 65 ng/mL, 70 ng/mL, or any subrange thereof.

[0075] In yet another example, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system (CNS) of the subject reaches a level that is about 2 fold to about 100 fold of CNS concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject. In some embodiment, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system (CNS) of the subject reaches a level that is about 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 11 fold, 12 fold, 13 fold, 14 fold, 15 fold, 16 fold, 17 fold, 18 fold, 19 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, or any subrange thereof, of CNS concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

[0076] The present pharmaceutical compositions can be administered to a subject at any suitable time. For example, an effective amount of the pharmaceutical composition can be administered to a subject within 1 hour or 60 minutes of having food intake, e.g., having a meal. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject within 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute of having food intake. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject with a meal. In another example, an effective amount of the pharmaceutical composition can be administered to a subject before or after 1 hour or 60 minutes of having food intake, e.g. , having a meal.

[0077] In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject before or after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours of having food intake. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject without a meal. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject at about the same time each day, e.g., within 1 hour or 60 minutes of a set time daily. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject within 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute of a set time daily. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject not at approximately the same time each day, e.g., before or after 1 hour or 60 minutes of a set time daily. In some embodiment, an effective amount of the pharmaceutical composition can be administered to a subject before or after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours of a set time daily.

[0078] The present pharmaceutical compositions can be administered to a subject to reach any suitable level of bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject. For example, after oral administration to a subject, the bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level that is about 2 fold to about 10 fold of the bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject. In some embodiment, after oral administration to a subject, the bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject can reach a level that is about 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or any subrange thereof, of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

[0079] The present pharmaceutical compositions can be administered to any suitable subject. For example, an effective amount of the pharmaceutical composition can be administered to a subject that also receives administration of posaconazole, a CYP3A inhibitor or a P-glycoprotein (P-gp) inhibitor. In some embodiment, the CYP3A inhibitor is a CYP3A4 inhibitor. In some embodiment, the CYP3A inhibitor is a strong CYP3A inhibitor, e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, telaprevir or voriconazole. In some embodiment, the CYP3A inhibitor is a moderate CYP3A inhibitor, e.g., is aprepitant, ciprofloxacin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole or verapamil. In some embodiment, the P-glycoprotein (P-gp) inhibitor is amiodarone, carvedilol, cyclosporine, dronedarone, quinidine, ranolazine or verapamil.

[0080] The present pharmaceutical compositions can be administered to a subject for any suitable uses. In some embodiment, the present pharmaceutical compositions can be administered to a subject for treating a cancer or tumor in the subject. In some embodiment, the present pharmaceutical compositions can be administered to a subject for preventing cancer or tumor in the subject.

[0081] Exemplary cancer or tumor to be treated or prevented by the present pharmaceutical compositions can be leukemia, multiple myeloma (MM) or lymphoma, allogeneic hematopoietic stem cell transplantation, hematologic malignancy, hemophagocytic lymph histiocytosis, HIV-1- infection, minimal residual disease, mucosa associated lymphoid tissue, myelodysplastic syndromes (MDS), plasma cell myeloma, refractory small cell lung carcinoma, relapsed small cell lung cancer, Richter syndrome, stem cell transplant complications, Waldenstrom's Macroglobulinemia. In some embodiment, cancer or tumor to be treated or prevented by the present pharmaceutical compositions can be chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). In some embodiment, cancer or tumor to be treated or prevented by the present pharmaceutical compositions can be lymphocytic lymphoma, e.g., small lymphocytic lymphoma (SLL).

[0082] In some embodiment, the present methods are used for preventing and/or treating acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL). In some embodiment, the present methods use Venetoclax, or a pharmaceutically acceptable salt thereof, as the sole active substance, and are used for preventing and/or treating acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0083] In some embodiment, the present methods are used for preventing and/or treating acute lymphoblastic leukemia, in relapse, acute myeloid leukemia arising from previous myelodysplastic/myeloproliferative neoplasm, acute myeloid leukemia post cytotoxic therapy, acute T-lymphocytic leukemia, AL amyloidosis, allogeneic hematopoietic stem cell transplantation, all-trans retinoic acid (ATRA) and arsenic (As) resistant acute promyelocytic leukemia (APL), B-cell acute lymphoblastic leukemia, B-cell lymphoma, chronic myelomonocytic leukemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hematologic malignancy, hemophagocytic lymph histiocytosis, HIV-l-infection, leukemia, lymphoblastic, acute, LI, leukemia, lymphoblastic, acute, L2, leukemia, myeloid, acute, lymphoblastic lymphoma (precursor B -lymphoblastic lymphoma/leukemia) recurrent, lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma/leukemia) recurrent, lymphoplasmacytic lymphoma, mantle Cell lymphoma (MCL), marginal zone lymphoma (MZL), minimal residual disease, mucosa associated lymphoid tissue, multiple myeloma, multiple myeloma in relapse, myelodysplasia-related acute myeloid leukemia, myelodysplastic syndromes (MDS), non-Hodgkin lymphoma, plasma cell myeloma, recurrent hairy cell leukemia, recurrent hairy cell leukemia variant, recurrent transformed chronic lymphocytic leukemia, refractory acute myeloid leukemia, refractory follicular lymphoma, refractory small cell lung carcinoma, refractory transformed chronic lymphocytic leukemia, relapsed acute myeloid leukemia, relapsed follicular lymphoma, relapsed small cell lung cancer, relapsed/refractory chronic lymphocytic leukemia, Richter syndrome, secondary acute myeloid leukemia, stem cell transplant complications, T-cell lymphoma refractory, T-cell lymphoma relapsed, T-cell or B-cell acute lymphoblastic leukemia, T-cell prolymphocytic leukemia (T- PLL), transformed chronic lymphocytic leukemia to diffuse large B-cell lymphoma, transformed small lymphocytic lymphoma to diffuse large B-cell lymphoma, or Waldenstrom's Macroglobulinemia.

[0084] In some embodiment, the present methods use Venetoclax, or a pharmaceutically acceptable salt thereof, and a second active substance(s), and are used for preventing and/or treating acute lymphoblastic leukemia, in relapse, acute myeloid leukemia arising from previous myelodysplastic/myeloproliferative neoplasm, acute myeloid leukemia post cytotoxic therapy, acute T-lymphocytic leukemia, AL amyloidosis, allogeneic hematopoietic stem cell transplantation, all-trans retinoic acid (ATRA) and arsenic (As) resistant acute promyelocytic leukemia (APL), B-cell acute lymphoblastic leukemia, B-cell lymphoma, chronic myelomonocytic leukemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hematologic malignancy, hemophagocytic lymph histiocytosis, HIV-l-infection, leukemia, lymphoblastic, acute, LI, leukemia, lymphoblastic, acute, L2, leukemia, myeloid, acute, lymphoblastic lymphoma (precursor B -lymphoblastic lymphoma/leukemia) recurrent, lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma/leukemia) recurrent, lymphoplasmacytic lymphoma, mantle Cell lymphoma (MCL), marginal zone lymphoma (MZL), minimal residual disease, mucosa associated lymphoid tissue, multiple myeloma, multiple myeloma in relapse, myelodysplasia-related acute myeloid leukemia, myelodysplastic syndromes (MDS), non-Hodgkin lymphoma, plasma cell myeloma, recurrent hairy cell leukemia, recurrent hairy cell leukemia variant, recurrent transformed chronic lymphocytic leukemia, refractory acute myeloid leukemia, refractory follicular lymphoma, refractory small cell lung carcinoma, refractory transformed chronic lymphocytic leukemia, relapsed acute myeloid leukemia, relapsed follicular lymphoma, relapsed small cell lung cancer, relapsed/refractory chronic lymphocytic leukemia, Richter syndrome, secondary acute myeloid leukemia, stem cell transplant complications, T-cell lymphoma refractory, T-cell lymphoma relapsed, T-cell or B-cell acute lymphoblastic leukemia, T-cell prolymphocytic leukemia (T- PLL), transformed chronic lymphocytic leukemia to diffuse large B-cell lymphoma, transformed small lymphocytic lymphoma to diffuse large B-cell lymphoma, or Waldenstrom's Macroglobulinemia.

[0085] In yet another aspect or embodiment, the present disclosure provides for use of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples, for inhibiting or reducing function of BCL-2 in a subject. [0086] In yet another aspect or embodiment, the present disclosure provides for use of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples, for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to central nervous system of a subject.

[0087] In yet another aspect or embodiment, the present disclosure provides for use of the pharmaceutical composition described in the present specifications, e.g., the pharmaceutical composition described in the above Section B and in the Examples, for treating or preventing a disease or a disorder, e.g., a cancer or tumor in a subject.

D. Formulations

[0088] Any suitable formulation of the present pharmaceutical compositions can be prepared. See generally, Remington's Pharmaceutical Sciences, (2000) Hoover, J. E. editor, 20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. A formulation is selected to be suitable for an appropriate route of administration. In cases where the present pharmaceutical compositions are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the present pharmaceutical compositions as salts may be appropriate.

[0089] Examples of pharmaceutically acceptable salts can be organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a- ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal e.g., calcium) salts of carboxylic acids also are made.

[0090] Preferably, the present pharmaceutical compositions are formulated for oral administration, typically as a tablet or capsule.

[0091] Where contemplated compounds are administered in a pharmacological composition, it is contemplated that the compounds can be formulated in admixture with a pharmaceutically acceptable excipient and/or carrier. For example, contemplated compounds can be administered orally as neutral compounds or as pharmaceutically acceptable salts, or intravenously in a physiological saline solution. Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skills in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, contemplated compounds may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished with minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skills of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present pharmaceutical compositions for maximum beneficial effect in a patient.

[0092] Illustrative examples of water soluble organic solvents for use in the present pharmaceutical compositions and the present methods include and are not limited to polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or a combination thereof. Examples of alcohols include but are not limited to methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0093] Illustrative examples of water soluble non-ionic surfactants for use in the present pharmaceutical compositions and the present methods include and are not limited to CREMOPHOR® EL, polyethylene glycol modified CREMOPHOR® (polyoxyethyleneglyceroltriricinoleat 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxy stearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol- 8 -glyceride), GELUCIRE® (glycerol ester), SOFTIGEN® (PEG 6 caprylic glyceride), glycerin, glycol-polysorbate, or a combination thereof.

[0094] Illustrative examples of water-soluble lipids for use in the present pharmaceutical compositions and the present methods include but are not limited to vegetable oils, triglycerides, plant oils, or a combination thereof. Examples of lipid oils include but are not limited to castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, a triglyceride of coconut oil, palm seed oil, and hydrogenated forms thereof, or a combination thereof. [0095] Illustrative examples of fatty acids and fatty acid esters for use in the present pharmaceutical compositions and the present methods include but are not limited to oleic acid, monoglycerides, diglycerides, a mono- or di-fatty acid ester of PEG, or a combination thereof.

[0096] Illustrative examples of cyclodextrins for use in the present pharmaceutical compositions and the present methods include but are not limited to alpha-cyclodextrin, betacyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutyl ether-beta-cyclodextrin.

[0097] Illustrative examples of phospholipids for use in the present pharmaceutical compositions and the present methods include but are not limited to soy phosphatidylcholine, or distearoyl phosphatidylglycerol, and hydrogenated forms thereof, or a combination thereof.

[0098] The present pharmaceutical compositions can be formulated for immediate release and quick absorption, or they can be formulated for delayed release. In some embodiments, the present pharmaceutical compositions are formulated for delayed release, using methods and compositions that promote delivery of the active ingredient in the lower gastrointestinal tract, after the administered formulation has passed through the stomach. Such methods include known enteric coatings that slow or prevent release of the contemplated compound or a pharmaceutically acceptable salt thereof in the stomach, so that the active drug is primarily released in the intestines, to enhance direct delivery to the tissues most affected by a disease or disorder, e.g., cancer or tumor. Some useful methods for delayed release formulations are described for example in B. Singh, Modified-release solid formulations for Colonic Delivery, Recent Patents on Drug Delivery and Formulations 2007, Vol. 1(1), 53-63. The contemplated compound or a pharmaceutically acceptable salt thereof can be formulated using such methods to reduce dissolution in the stomach, and/or to increase dissolution and absorption in the lower gastrointestinal (GI) tract, in order to increase availability of the active drug in the targeted tissues.

[0099] Methods to achieve delayed release can utilize a single or a combination of two or more of the following: pH-controlled (or delay ed-release) systems, time-controlled (or timedependent) systems, microbially-controlled systems, and pressure-controlled systems.

[00100] One of ordinary skills in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, the contemplated compound or a pharmaceutically acceptable salt thereof, may be modified to render them more soluble in water or other vehicle. It is also well within the ordinary skills of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the contemplated compound or a pharmaceutically acceptable salt thereof for maximum beneficial effect in a patient.

_ E. Examples

Goals

[00101] The aim of this exemplary project is to develop a Venetoclax formulation that enhances bioavailability and minimizes drug-drug interactions. The formulation will be assessed for absolute bioavailability and its response to food effects on gastrointestinal absorption. Additionally, we will co-administer the formulation with P-gp inhibitors and/or CYP 3A4 inhibitors to gauge potential drug interactions. Lastly, we will evaluate the formulation's ability to penetrate the blood-brain barrier (BBB) after oral administration. Material and Methods a. _ Material

[00102] FDA approved Venetoclax tablets 10 mg (VENCLEXTA® Lot# 1191682) was purchased from the market. Venetoclax was purchased from Macklin (Lot# C15397476, Lot C16081087). Sodium Dodecyl Sulfate (SDS) was purchased from Sigma-Aldrich (Lot MKCQ6608, Lot 102649625). Polyethylene Glycol 400 (PEG 400) was purchased from Dow Chemical (Lot D210K5HFD1). Sodium carboxymethyl cellulose (CMC-Na) was provided by Chengdu Kelong chemical Co. Ltd (Lot 2022052301). Quinidine was purchased from Rundu Pharmaceutical Co., Ltd. (Lot 57923080101). Saline was purchased from Shijiazhuang No.4 Pharmaceutical Co., Ltd. (Lot 2301273401). b. _ Wistar Rats

[00103] Wistar rats have been reported to as suitable animal models for research in small intestinal P-gp since the P-gp profile of Wistar rats reflect that of humans. —

[00104] Male Wistar rats (weighing 230-250 g) were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (animal license No. SCXK (Zhe) 2020-0002). The rats were acclimatized for at least 5 days under laboratory conditions prior to the initiation of the experiment. Before the administration, the rats were fasted for 12 hours with access to drinking water. The experimental protocol was approved by the Institutional Animal Care and Use Committee of Chengdu Gencore Pharmaceutical Technology Co., Ltd. (Located at No. 17, Huigu West Second Road, Shuangliu District, Chengdu, Sichuan, China). All experimental procedures were conducted according to “Laboratory Animals-General requirements for animal experiment” (National standards of People's Republic of China; GB/T35823-2018). c. _ Human subjects

[00105] According to the Technical Guidelines for Bioequivalence Studies of Generic Chemical Drugs with Pharmacokinetic Parameters as Evaluation Indicators, the 2020 Chinese Pharmacopoeia, Appendix 9011: Guidelines for Bioavailability and Bioequivalence Studies of Drug Formulations in Humans, the FDA guidance Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, the FDA Draft Guidance on Venetoclax, the animal toxicity characteristics of the product, and relevant GCP requirements, subjects were selected based on the following inclusion and exclusion criteria.

1. Age and Gender: Healthy female subjects aged 18 years or older (including 18 years old) with no fertility requirements within six months after the last dose.

2. Body Weight: Female subjects with a body weight of ^45 kg and a Body Mass Index (BMI) between 19 kg/m² and 26 kg/m² (inclusive). BMI is calculated as follows: BMI = weight (kg) / height² (m²).

3. Informed Consent: Subjects who fully understand the trial details, study drug, and procedures, can communicate effectively with the researchers, are willing to comply with study requirements, and voluntarily sign the informed consent form. d. _ Preparation of Test Formulations

[00106] Four test formulations have been developed and dosed in Wistar rats. The formulations dosed in Wistar rats are named as Test Formulation #1, Test Formulation #2, Test Formulation #3, and Test Formulation #4. One formulation had been developed and dosed in human subjects. The formulation dosed in human subjects is named Test Formulation #5.

[00107] i. Test Formulation #1: Oral solution for Venetoclax oral absorption study.

Preparation procedure: First, PEG 400 and SDS were carefully weighed and combined in an appropriate container, followed by mixing at 80°C for 2.5 hours to ensure thorough mixing and dissolution. Next, Venetoclax (MACKLIN) was weighed and added to the mixture, which was then mixed at 80°C until Venetoclax was completely dissolved. The temperature was then raised to 85-90°C and maintained for 15 minutes before cooling the solution to 40°C. In the subsequent step, a second portion of SDS was weighed and added to the solution, followed by mixing at 80°C until SDS was fully dissolved. Once dissolved, the solution was allowed to cool to 25°C. Before dosing the rats, water was added to the formulation. The Venetoclax concentration in the testing formulation is about 2-3 mg/mL.

[00108] The final composition of Test Formulation #1 is shown in Table 1.

Table 1. Test Formulation #1: Oral solution for Venetoclax oral absorption study

[00109] ii. Test Formulation #2: Oral solution for Venetoclax drug-drug interaction study. Preparation procedure: PEG 400 and SDS are carefully weighed and combined in an appropriate container, followed by mixing at 80°C for 2.5 hours to ensure thorough mixing and dissolution. Then, Venetoclax is weighed and added to the mixture, which is then mixed at 80 °C until Venetoclax is completely dissolved. Once dissolved, the solution is allowed to cool to 25 °C.

The final composition of Test Formulation #2 is shown in Table 2.

Table 2. Test Formulation #2: Oral solution for Venetoclax drug-drug interaction study

[00110] Before dosing the rats, a dosing formulation was obtained by mixing 6.0222g of the Test Formulation #2 with 60.0493 g of water. The Venetoclax concentration in the testing formulation is about 0.8 mg/mE.

[00111] iii. Test Formulation #3: Intravenous injectable solution for Venetoclax absolute bioavailability study. Preparation procedure: PEG 400 and Polysorbate 80 were carefully weighed and combined in an appropriate container, followed by mixing at room temperature to ensure thorough mixing. Then, Venetoclax was weighed and added to the mixture, which was then mixed until Venetoclax was completely dissolved. The temperature was then raised to 140 -150 °C and mixed for 1 hour before cooling the solution to room temperature. In the subsequent step, water was added to obtain a solution containing about 0.2 mg/mL of Venetoclax.

[00112] The final composition of Test Formulation #3 is shown in Table 3.

Table 3. Test Formulation #3: Intravenous injectable solution for Venetoclax absolute bioavailability study

[00113] iv. Test Formulation #4: Oral solution for Venetoclax BBB crossing study.

Preparation procedure: SDS and water were carefully weighed and combined in an appropriate container, followed by mixing at room temperature to ensure thorough mixing and dissolution. Then, Venetoclax was weighed and added to the mixture, which was then mixed until Venetoclax was completely dissolved. In the subsequent step, additional water was added to obtain a solution containing about 2-3 mg/mL of Venetoclax.

[00114] The final composition of Test Formulation #4 is shown in Table 4.

Table 4. Test Formulation #4: Oral solution for Venetoclax BBB crossing interaction study

[00115] v. Test Formulation #5: Oral tablets for Venetoclax bioavailability and food effects on drug oral bioavailability studies in human subjects.

[00116] Preparation procedure: SDS and water were carefully weighed and combined in an appropriate container, followed by mixing at room temperature to ensure thorough mixing and dissolution. Then, Venetoclax was weighed and added to the mixture, which was then mixed until Venetoclax was completely dissolved. In the subsequent step, the prepared Venetoclax solution was subjected to an air drying process, followed by compression into tablet form. During compression, microcrystalline cellulose and magnesium stearate were incorporated to facilitate the tableting process. The resulting Venetoclax tablets comprise 20 mg of Venetoclax per tablet. The final composition of Test Formulation #5 is shown in Table 5.

Table 5. Test Formulation #5: compositions for Venetoclax 20 mg tablets

*: Water has been substantially removed during the air drying process.

**: A trace amount of Magnesium Stearate was added for lubrication purposes during tableting.

[00117] vi. Venetoclax reference formulation: The Venetoclax reference formulation was prepared using FDA-approved Venetoclax tablets (VENCLEXTA®) at a strength of 10 mg (Lot# 1191682). An adequate amount of VENCLEXTA® 10 mg tablets was ground into fine powder, weighed, and then mixed with 0.5% CMC-Na solution based on the Venetoclax concentration specified in the rat study designs. The mixture was thoroughly mixed before dosing. e. in vivo Rat studies

[00118] In the realm of new drug development, pharmacokinetic methods play a crucial role in assessing how a tested compound is absorbed, distributed, metabolized, and eliminated in animal and human models. Research on laboratory animals can provide valuable insights into drug development since it's often easier to measure bioactive compound levels in animal’s plasma or tissues, and these findings can be extrapolated to humans.

[00119] i. Study 1 : Oral bioavailability of Venetoclax. Sixteen male Wistar rats weighing 230-250 g were, before the administration, fasted for 12 hours with access to drinking water. All rats were randomly divided into two groups (n = 8 per group). One group (n = 8) received a single dose (30 mg/kg) of the Test Formulation #1 through oral gavage, while the other group (n = 8) received the same single dose (30 mg/kg) of Venetoclax reference formulation through oral gavage. The blood samples were directly collected into K2EDTA tubes via the jugular vein before dosing (0 h) and at 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 h after administration. The plasma samples were obtained from the blood by centrifugation at 3000 g, under 2-8 °C for 5 min. All samples were stored at -75 ± 15 °C until analysis.

[00120] ii. Study 2: Absolute oral bioavailability. Six male Wistar rats weighing 230-250 g were, before the administration, fasted for 12 hours with access to drinking water. All rats received a single intravenous dose of 0.2 mg/kg of Test Formulation #3. The blood samples were directly collected into K2EDTA tubes via the jugular vein before dosing (0 h) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after i.v. administration. The plasma samples were obtained from the blood by centrifugation at 3,000 g, under 2 - 8 °C for 5 min. All samples were stored at -75 + 15 °C until analysis.

[00121] iii. Study 3: Drug-drug interaction with P-gp inhibitor. Twenty-four male Wistar rats (weighing 230-250 g) were, before the administration, fasted for 12 hours with access to drinking water. All rats were randomly divided into four groups (n = 6 per group). Group 1 and group 3 received saline (control) orally; group 2 and group 4 received a single oral dose (30 mg/kg) of quinidine (suspended in 0.5% sodium carboxymethyl cellulose (CMC-Na)). Thirty minutes later, 10 mg/kg Venetoclax test formulation # 2 was orally administered to groups 1 and 2, and 10 mg/kg Venetoclax reference formulation was orally administered to groups 3 and 4, respectively. The blood samples were directly collected into K2EDTA tubes via the jugular vein before dosing (0 h) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 h after administration. The plasma samples were obtained from the blood by centrifugation at 3,000 g, under 2-8 °C for 5 min. All samples were stored at -75 ± 15 °C until analysis.

[00122] iv. Study 4: Blood brain barrier crossing. Fifteen male Wistar rats (weighing 230- 250 g) were, before the administration, fasted for 12 hours with access to drinking water. All rats were randomly divided into five groups (n = 3 per group). All groups received a single oral dose (30 mg/kg) of Test Formulation # 4. The blood samples were directly collected from one of the five groups into K2EDTA tubes via the jugular vein at each of the predetermined sampling time. The five predetermined sampling times for this study are 2, 4, 6, 8, and 24 h after administration. The plasma samples were obtained from the blood by centrifugation at 3,000 g, under 2-8 °C for 5 min. All samples were stored at -75 ± 15 °C until analysis.

[00123] The brain tissue samples were collected at the same time as the blood samples. After collection, tissues were rapidly frozen in liquid nitrogen, then stored in the dark at -75±15°C until analysis. Before analysis, tissues stored at -75±15°C were homogenized using a methanoksaline (1:1, v/v) homogenization solution. f. _ Sample analysis for Rat studies

[00124] The concentration of Venetoclax in Wistar rat plasma was measured using a LC- MS/MS. The LCMS/MS system was a Shimadzu LC-20AD equipped with an Applied Biosystem Sciex 4000 QTRAP mass spectrometer. The tandem mass spectrometer was operated under multiple reaction monitoring (MRM) using an electrospray ionization (ESI) source in positive mode. g. _ in vivo Human studies

[00125] In this study, a total of nine (9) healthy human subjects were recruited and completed the study without any dropouts.

[00126] Participants in the study completed a three-dose regimen, including one T(Fasting) period, one T(Fed) period, and one R(Fasting) period. All participants were randomly assigned to one of three dosing sequence groups: T(Fasting)-T(Fed)-R(Fasting), T(Fasting)-R(Fasting)- T(Fed), or R(Fasting)-T(Fasting)-T(Fed).

[00127] In this context:

• T(Fasting): One 20 mg tablet of the test formulation #5 of Venetoclax was administered under fasting conditions.

• T(Fed): One 20 mg tablet of the test formulation #5 of Venetoclax was administered after a meal.

• R(Fasting): One 100 mg tablet of the reference formulation of Venetoclax (Venclexta®) was administered under fasting conditions.

[00128] The specific administration methods are as follows:

Fasting Test: For each period requiring fasting, participants fasted for at least 10 hours prior to dosing. On the morning of administration, while remaining in an upright position, participants took one 20 mg tablet for the Venetoclax test formulation #5 or one 100 mg tablet of the reference formulation (Venclexta®) with 250 mF of water. Fed Test: For each period requiring administration post-meal, participants fasted for at least 10 hours before consuming a high-fat meal. Thirty minutes before dosing (±1 minute), participants began eating the high-fat meal and completed it within 30 minutes. Thirty minutes after the meal (measured from the start of eating), while maintaining an upright position, participants took one 20 mg tablet of the Venetoclax test formulation #5 with 250 mL of water.

Table 6. Medication Administration Flowchart: a three way, three period crossover design

[00129] For each period of the fasting/Fed test, a baseline blood sample (Oh) had been collected prior to dosing. After dosing, blood samples were collected at 30 minutes, Ih, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, lOh, 12h, 24h, 48h, and 72h, for a total of 23 sampling points (including the baseline sample). No clinically significant abnormalities were detected during the exit examination. Neither early withdrawal had happened.

[00130] Approximately 4 mL of venous whole blood was collected each time into a vacuum blood collection tube containing EDTA-K2 as an anticoagulant. After blood collection, the sample was gently inverted several times to mix, placed upright on a test tube rack, and then centrifuged at 1,700g for 10 minutes at a temperature setting of 4°C. Centrifugation must begin within 1 hour after blood collection. After centrifugation, the plasma sample was aliquoted into pre-labeled vials. The plasma was placed in a freezer set at -60°C or lower within 1 hour after centrifugation, where it would be stored until transported to the analysis center. The time from blood collection to placing the plasma sample in the freezer should not exceed 2 hours, and all procedures were conducted at room temperature under white light conditions. h. _ Plasma Sample analysis for Human subjects

[00131] The concentration of Venetoclax in human plasma was measured using an LC- MS/MS. The LCMS/MS system is a Shimadzu LC-20AD equipped with an Applied Biosystem Sciex 4000 QTRAP mass spectrometer. The tandem mass spectrometer was operated under multiple reaction monitoring (MRM) using an electrospray ionization (ESI) source in positive mode. i. _ Pharmacokinetic analysis

[00132] Pharmacokinetic parameters of Venetoclax were calculated by Phoenix ™ WinNonlin software (version 8.1) with a non-compartmental model. Samples with concentrations below the lower limit of quantification (LLOQ) were not included in the calculation. The mean value and standard deviation (SD) were calculated with Microsoft Excel, and the parameter T_max was indicated by the median (range). The maximum plasma concentration (Cmax) and the time of maximum observed concentration (T_max) were determined from the observed plasma concentration-time curve. The terminal half-life (T1/2) was calculated as T1/2 ~ ln2/k_z (X_z: first-order rate constant associated with the terminal (log-linear) portion of the curve). The area under the plasma concentration time curve was calculated using the trapezoidal rale. AUCo-_t: The area under the curve from the time of dosing to the time of the last measurable concentration. AUCo-00: The area under the curve from time of dosing extrapolated to infinity, which was calculated as AUCo-00 = AUCo-t + C_E/X_Z (where Ct was the last plasma concentration measured) .

3. _ Results and discussions a. _ Study 1: Oral bioavailability of Venetoclax in Wistar Rats

[00133] Following oral administration of a single dose (30 mg/kg) to Wistar rats, the plasma drug concentrations were analyzed. The relationship between the plasma concentration and the time of both test formulation and reference formulation is compared in Table 7. The concentration-time curves are shown in Figure 1 and Figure 2.

Table 7. Plasma concentrations (mean ± SD) of Venetoclax test #1 and reference formulation after a single oral administration of 30 mg/kg in Wistar rats

1 818 + 154 195 + 87.3

2 1384 + 245 235 + 99.2

3 1891 + 479 198 + 61.4

4 2168 + 460 156 + 47.2

5 1903 + 777 102 + 34.1

6 1287 + 469 68.1 + 25.2

8 776 + 247 38.0 + 17.6

12 351 + 175 19.1 + 8.53

16 210 + 133 10.8 + 4.80

24 97.6 ± 105 5.21 + 1.53

[00134] The calculated pharmacokinetic parameters are summarized in Table 8. A notable 8.4-fold increase in Cmax and an 11.3-fold increase in AUCo-t were observed for the test formulation #1 compared to the reference formulation. T1/2 did not show a significant difference between the two formulations. However, test formulation #1 exhibited a later Tmax than the reference formulation in Wistar rats. The data suggests that while drug clearance rates (T1/2) were similar between the rat subjects, the rate and the extend of absorption (Cmax) was much faster for Test Formulation #1. Consequently, the bioavailability (AUCo-t) of Test Formulation #1 was significantly higher than that of the reference formulation. Average plasma concentrations from Test Formulation #1 and Reference Formulation are compared in Figure #3.

Table 8. Main pharmacokinetic parameters (mean ± SD) of test and reference formulation of Venetoclax in plasma following oral administration to Wistar rats. _ narmacokmctic . lest Formulation ff l Reference Formul

Umf raiamctcrs ~ (n ~ 8)

C_max ng/mL 2283 + 562 244 + 89.9

AUCo-t h*ng/mL 15470 + 4520 1255 + 441

AUCo-, h*ng/mL 15311 + 5084 1294 + 450

T1/2 h 4.53 + 1.60 5.28 + 0.964

Tmax* h 4 (3-5)* 2 (2-4)*

*: Median (range) [00135] The observed differences in the pharmacokinetic profiles between the two formulations suggest that Test Formulation #1 could potentially allow for a reduction in the dosage strength of the oral formulation while maintaining the same therapeutic outcome. This could have significant implications for patient care, as it may lead to lower dosages being required, potentially reducing the risk of side effects, and improving overall treatment adherence. Additionally, Test Formulation #1 may also offer the advantage of reducing the impact of food on the oral absorption of the drug. This is particularly important, as food interactions can often alter the efficacy and safety profile of medications. Overall, these findings highlight the potential benefits of Test Formulation #1 over the reference formulation and warrant further investigation to fully understand its clinical implications. b. _ Study 2: Absolute oral bioavailability in Wistar Rats

[00136] Six (6) rats received a single intravenous (i.v.) dose of 0.2 mg/kg Venetoclax. The blood samples were directly collected into K2EDTA tubes via the jugular vein before dosing (0 h) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after i.v. administration. The plasma concentrations and calculated pharmacokinetic parameters of Venetoclax after i.v. administration are shown in Table 9 and Table 10.

Table 9. The plasma concentrations of Venetoclax after i.v. administration of Test Formulation

#3 at a dose of 0.2 mg/kg.

Sampl

Time

.. ,

(h)

0 BQL BQL BQL BQL BQL BQL NA NA NA

0.083 522 288 431 485 355 282 394 101 25.7

0.25 170 127 117 111 82.0 99.1 118 30.0 25.5

0.5 121 92.6 80.2 128 64.0 73.2 93.2 26.1 28.0

1 77.9 39.6 62.7 81.9 43.9 47.5 58.9 18.1 30.7

2 35.1 32.8 32.2 38.0 30.0 38.2 34.4 3.31 9.62

4 11.2 19.7 12.0 14.8 10.1 15.7 13.9 3.55 25.5

6 10.8 11.6 6.99 8.21 9.32 9.26 9.36 1.68 17.9

8 8.98 11.8 4.14 6.18 5.17 8.85 7.52 2.86 38.1

12 5.24 5.55 BQL BQL BQL 3.73 4.84 0.974 20.1

24 BQL BQL BQL BQL BQL BQL NA NA NA

NA: Not applicable; BQL: Below the quantitation limit.

Table 10. Pharmacokinetic parameters of Venetoclax after i.v. administration at a dose of 0.2 mg/kg. PK Animal ID

Parame Rat 3 Rat 4

AUCo-oo h*ng/mL 417 342 295 359 253 302 328 57.5 17.5

AUCo-t h*ng/mL 376 307 280 344 238 280 304 49.8 16.4

Co ng/mL 912 433 824 1009 735 474 731 234 32.0

TI/2 h 5.47 4.07 2.61 1.69 2.00 4.07 3.32 1.46 44.0

CL mL/mm/k _{? C)C) 9 ?5 n 3 9 28 13 2 11 0 10.4} j _{81 17 4} g

V L/kg 1.81 2.60 1.29 0.982 1.69 2.42 1.80 0.627 34.8

[00137] Average plasma concentration-time curve of Venetoclax after a single intravenous dose of 0.2 mg/kg in Wistar rats is presented in Figure 4.

[00138] Absolute bioavailability is a measure that compares the amount of a drug that reaches systemic circulation after non-intravenous administration (such as oral (po), buccal, ocular, nasal, rectal, transdermal, subcutaneous, or sublingual administration) with the amount that reaches circulation after intravenous (iv) administration. The formula for calculating the absolute oral (po) bioavailability (F_abs) of a drug is as follows, where D represents the administered dose, AUC represents the area under the plot of plasma concentration of a drug versus time after dosing:

The absolute bioavailability of Test Formulation #1 and Reference Formulation are calculated and presented in Table #11.

Table 11 The absolute bioavailability of orally dosed Test Formulation #1 and Reference

Formulation [00139] According to the label insert of VENCLEXTA tablets-, the bioavailability of VENCLEXTA tablets under high-fat meal conditions is approximately five times higher than that taken on fast condition. This strong food effect on bioavailability could be related to the slow and poor dissolution process of the Venetoclax using the formulation of the marketed tablet product.

[00140] Test Formulation #1, developed as a Venetoclax solution, has shown a remarkable 10-fold improvement in bioavailability compared to the Reference Formulation, which uses the grounded powder of a commercially available Venetoclax tablet product. The improved bioavailability of Test Formulation #1 is particularly noteworthy as it suggests that the dissolution process of Venetoclax in each formulation may have critical impact on its bioavailability. This finding is significant because it indicates that Test Formulation #1 could offer consistent drug absorption, potentially leading to more predictable and reliable treatment outcomes.

[00141] The dissolution-impact-free formulation, like Test Formulation #1, represents an innovative approach to mitigate the influence of food intake on Venetoclax bioavailability. Creating a Venetoclax formulation that does not necessitate food intake could greatly improve patient compliance and treatment efficacy, marking a substantial advancement in Venetoclax therapy. c. _ Study 3: Drug-drug interaction with P-gp inhibitor in Wistar Rats

[00142] All rats were randomly divided into four groups (n = 6 per group). Group 1 and group 3 received saline solution (control) orally; group 2 and group 4 received a single oral dose (30 mg/kg) of quinidine (suspended in 0.5% CMC-Na). Thirty minutes later, 10 mg/kg Venetoclax Test Formulation #2 was orally administered to groups 1 and 2, and 10 mg/kg Venetoclax reference formulation (finely grounded tablet powder suspended in 0.5% CMC-Na) was orally administered to groups 3 and 4, respectively. The test article information and dosing information are shown in Table 12.

Table 12. The test article information and dosing information

[00143] The plasma concentrations of Venetoclax after coadministration of Venetoclax (Test Formulation #2 and reference formulation) with saline or quinidine suspension were determined (Table 13). The calculated pharmacokinetic parameters are summarized in Table 14.

Table 13. Plasma concentrations of Venetoclax of test formulation #2 and reference formulation coadministration with saline or quinidine in Wistar rats (mean ± SD, n = 6) ion (ng/mL Group .3

0.5 293 + 152 81.6 + 53.3 96.4 + 20.8 111 + 52.2

1 716 + 336 165 + 129 154 + 29.7 245 + 121

2 1086 + 459 427 + 299 155 + 35.0 458 + 328

3 988 + 438 536 + 338 151 + 78.1 398 + 219

4 678 + 361 624 + 343 124 + 73.6 349 + 186

6 300 + 154 374 + 148 51.6 + 29.6 243 + 128

8 178 + 120 188 + 81.1 26.4 + 13.4 129 + 65.2

12 69.1 + 60.6 75.2 + 35.6 12.0 + 5.86 63.1 + 31.6

24 16.1 + 16.3 15.6 + 8.07 3.39 + 1.71 28.0 + 35.2

48 4.62* NA NA 5.78*

Table 14. Pharmacokinetic parameters of Venetoclax of test formulation #2 and reference formulation coadministration with saline or quinidine in Wistar rats (mean ± SD, n = 6)

PK Parameters Unit Group I Group 2 Group 3 Group 4

C_max ng/mL 1165 ± 456 698 + 327 180 + 52.4 510 + 293

AUCo-t h*ng/mL 5705 + 2972 4073 + 1866 934 + 393 3397 + 1287 AUCo-oo h*ng/mL 5751 ± 2987 4173 + 1915 960 + 399 3841 + 1061

Ti/2 h 5.10 + 2.12 4.44 + 0.330 4.34 + 1.24 5.29 + 2.09 h 2.5 (2-3) 3.5 (2-4) 2 (1-4) 2.5 (2-6)

[00144] The mean concentration-time curves for Test Formulation #2 and Reference Formulation are shown in Figure 5 and Figure 6.

[00145] Assessment of pharmacokinetic drug-drug interactions (DDI) is crucial for understanding how medications may interact in the body. As shown in Table 8, when Venetoclax was coadministered with quinidine using the reference formulation, there were notable increases in Cmax, AUCO-t, and AUC0-<» compared to rats that received only saline. The fold changes for Cmax, AUCO-t, and AUC0-<» were 1.83, 2.64, and 3.00, respectively. These increases suggest that quinidine inhibited the P-gp efflux pump, leading to higher plasma concentrations of Venetoclax. In contrast, rats receiving Venetoclax with Quinidine using Test Formulation #2 showed less pronounced changes in these pharmacokinetic parameters. The fold changes for Cmax, AUCO-t, and AUC0-<» were 0.60, 0.71, and 0.73, respectively, compared to saline-pretreated rats.

[00146] These results suggest that Test Formulation #2 may possess properties that mitigate or counteract the DDI effects of P-gp inhibitors on Venetoclax. The potential advantage of Test Formulation #2 could be crucial in clinical settings, where minimizing the risk of adverse drug interactions is paramount for patient safety and treatment efficacy. Further studies are warranted to elucidate the mechanisms underlying this observed interaction and to assess its clinical relevance. d. _ Study 4: Blood brain barrier crossing in Wistar Rats

[00147] All rats were randomly divided into five groups (n = 3 per group). A single oral dose (30 mg/kg) of Venetoclax Test Formulation #4 was orally administered to each group.

[00148] The concentrations of Venetoclax in plasma and in brain from each group were collected and analyzed. The data are presented in Table 15 and Table 16, respectively. The mean Venetoclax concentration-time curves in plasma and brain are presented in Figure 7.

Table 15. The Venetoclax plasma concentration from Test Formulation #4

Table 16. The Venetoclax brain concentration from Test Formulation #4

[00149] Venetoclax plasma concentrations, Cmax and last plasma concentration (Ciast) at 8 and 24 hour after the oral dosing of Test Formulation #4, were 3103 ng/mL and 89.7 ng/mL. At the same times, the drug distributed in the brain reached concentrations of 41 ng/mL and 13 ng/mL. The corresponding percentages of Brain concentration to plasma concentration (brain-to-plasma ratio) were 1.3 % and 14.5 %. Venetoclax exhibits high protein binding, with less than 1% of the drug found in its unbound form in plasma.- Typically, the distribution of a drug to tissues is directly related to the unbound drug concentration. However, in this study the observed brain- to-plasma ratio of the Venetoclax was higher than the reported percentage of unbound drug in the blood. This finding suggests that the formulation of Test Venetoclax #4 used in this study may possess properties that either increase the levels of free, unbound drug in the plasma or enhance the ability of the drug molecule to traverse the blood-brain barrier (BBB).

[00150] Venetoclax is a potent BCL-2 inhibitor by its ability to induce cell death in the treatment of Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). In AML, studies have shown that the median half maximal inhibitory concentration (IC50) of Venetoclax treatment was well below 10 nM (8.7 ng/ml). In Chronic Lymphocytic Leukemia (CLL), the IC50 values were reported to be 1.9 nM and 1.6 ng/mL in vitro in a cultured CLL cell line exposed to Venetoclax for 24 hours.- The lowest brain concentration observed after a single dose of the investigated formulation was 13 ng/mL, a level significantly higher than the IC50 values reported for both AML and ALL.

[00151] The higher-than-expected brain-to-plasma ratio and brain drug concentration observed with Venetoclax after dosing the Test Formulation #4 could have significant implications for its clinical use, particularly in the treatment of CNS-involved malignancies or disorders. If the formulation indeed enhances the levels of free, unbound drug in the bloodstream or improves its ability to cross the BBB, it could lead to increased efficacy in targeting CNS tumors or leukemia cells that have infiltrated the CNS.

[00152] Further research is needed to fully understand the mechanisms underlying the observed brain-to-plasma ratio of Venetoclax and to determine whether this property can be exploited to improve the treatment outcomes of CNS-related diseases. Additionally, studies investigating the safety and potential side effects of formulations that enhance CNS penetration of Venetoclax will be essential to ensure its clinical utility. e. _ Study 5: Oral bioavailability of Venetoclax in human subjects

[00153] Following oral administration of a single dose (a 20 mg tablet of test formulation #5 or a 100 mg tablet of reference formulation, i.e., Venclexta® to human subjects, blood samples were collected and the drug concentrations in plasma were analyzed. The relationship between plasma drug concentration and the time of both test formulation and reference formulation is compared in Table 17. The concentration-time curves are shown in Figure 8.

Table 17. Mean Plasma concentrations of Venetoclax from the test formulation #5 and the reference formulation after a single oral administration in nine human subjects

[00154] The calculated pharmacokinetic parameters are summarized in Table 18 below. The ratios of these parameters demonstrate a similar oral bioavailability between the test and reference formulations, although the dosage strengths are significantly different. This finding indicates that the Test formulation #5 had a higher systemic absorption than that from the reference formulation after the oral dosing. Furthermore, the data confirms the pharmacokinetic findings from studies in the Wistar rats.

Table 18. Main pharmacokinetic parameter comparison between the test (#5) and reference formulations of Venetoclax following oral administration to human subjects (9 subjects) f. _ Study 6: Food effects on oral bioavailability of the Test formulation in human subjects

[00155] Nine (9) healthy human subjects received a single test formulation #5 of 20 mg Venetoclax tablet under both fasting and Fed conditions. The blood samples were collected and analyzed. The plasma concentrations of Venetoclax are shown in Table 19 below. The concentration-time curves are shown in Figure 9.

Table 19. Mean Plasma concentrations of Venetoclax for the test formulation #5 taken under the fasting and fed conditions in nine human subjects Table 20. Food effects on oral bioavailability of Test formulation #5 (Ratio = AUC from Fed studies / AUC from Fasting studies)

[00156] As shown in Tables 19 and 20, the impact of food on the oral bioavailability of the test formulation was found to be negligible. When the test formulation tablets were administered following a high-fat meal, drug absorption increased to about 1.5 times that observed under fasting conditions. g. _ Study 7: Drug-drug interaction on oral bioavailability of the Test formulation No. 5 in human subjects

[00157] Rifampin, an antimicrobial agent used to treat infectious diseases such as tuberculosis and methicillin-resistant Staphylococcus aureus infections, is commonly used as a probe drug to investigate the effects of CYP3A induction on the pharmacokinetics of CYP3A substrates. The inductive effects of rifampin on enzymes and transporters typically emerge after multiple doses, as time is required for changes in protein levels. Additionally, rifampin has been shown to exert acute inhibitory effects on P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP) 1B1 and 1B3, which occur almost immediately after a single dose¹³.

[00158] This drug-drug interaction study was a single-center, non-randomized, open-label, single-sequence, two-period, single-dose/multiple-dose trial conducted in healthy subjects. A total of 6 human healthy subjects were enrolled and assessed.

[00159] On day one of the first period, the subjects received a single oral dose of 40 mg of the test formulation of Venetoclax tablets (Test formulation No. 5, Table 5) after a standard meal. Following a washout period of at least 8 days, the second period commenced. On day one of the second period, the subjects received a single oral dose of 40 mg of the test formulation of Venetoclax tablets (Test formulation No. 5) along with 600 mg of rifampin capsules after a standard meal. Blood samples were collected at 12 time points during each period: within 60 minutes prior to dosing (0 h) and at 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose.

Table 21. Mean plasma concentrations of Venetoclax for the test formulation No. 5 (Table 5) measured following a single oral dose and a single oral dose co-administered with 600 mg of Rifampin capsules in six human subjects.

*: below quantitative limits.

Table 22. Main pharmacokinetic parameter comparison between a single oral administration of the test formulation No. 5 (Table 5) and co-administered with 600 mg of Rifampin capsules (6 human subjects) [00160] As shown in above Tables 21 and 22 and in Figure 11, the impact of 600 mg of Rifampin on the oral bioavailability of the test formulation No. 5 was minimal. Coadministration of the test formulation tablets (the test formulation No. 5) with 600 mg of Rifampin capsules resulted in approximately a 30% increase in Cmax. Meanwhile, both AUCo-t and AUCO-M showed a slight reduction of around 5%. These findings suggest or show that although Rifampin slightly enhanced the peak concentration of the test formulation, its overall exposure was only marginally affected. h. _ The in vitro drug release profiles of test formulation #5 of Venetoclax tablets (20 mg)

[00161] The drug release testing was conducted in 250 mL of 0.1N hydrochloric acid (HC1), pH 4.5 acetate buffer, and pH 6.5 phosphate buffer solutions over a period of 60 minutes respectively. A USP apparatus II setup was utilized for the study, with samples collected at 5, 10, 15, 30, 45 and 60 minutes following the introduction of Venetoclax tablets (test formulation #5) into the drug release media. The collected samples were subsequently analyzed, and the percentage of drug released over time is detailed in Table 23 below and plotted in Figure 10.

Table 23. Drug release data in different media

[00162] The in vitro drug release profiles presented in Figure 10 demonstrate that the rate and extent of drug release for Test Formulation #5 are independent of the pH of the drug release media. This observation is significant as it implicates that Test Formulation #5 might not be affected by the varying pH conditions encountered throughout the gastrointestinal (GI) tract.

[00163] The GI tract presents a dynamic pH environment, ranging from highly acidic conditions in the stomach (pH 1.0-2.5) to near-neutral and mildly alkaline conditions in the small intestine and colon (pH 6.6-7.5)¹⁴. A pH-independent release profile indicates that Test Formulation #5 is capable of delivering consistent drug release across the diverse pH conditions of the gastrointestinal (GI) tract. This characteristic is particularly beneficial for Venetoclax, a compound where reliable and predictable release is essential for achieving its therapeutic efficacy.

4. _ Conclusion

[00164] The oral bioavailability of Venetoclax is a crucial consideration in its approved therapeutic usage. Current Venetoclax tablets have demonstrated a notable food effect and susceptibility to drug-drug interactions. The formulations investigated in this study utilized Sodium Dodecyl Sulfate (SDS) as a stabilization agent and a potential permeation enhancer. The results were surprising, as they revealed a significant increase in oral bioavailability and minimized drug-drug interactions. Moreover, the concentrations of Venetoclax found in brain tissue were considerably higher than previously reported information in the literature-. These findings suggest that the formulations tested in this study have the potential to address key limitations associated with current Venetoclax formulations, offering improved bioavailability in both blood and brain, reduced food effects on drug absorption, and susceptibility to drug interactions, which could lead to more effective and safer treatments for patients.

References

[00165] References cited herein are listed below.

1. VENCLEXTA Tablets, Product label insert, approved by US FDA (Revised: 6/2022)

2. Alaargl. A. et al. A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold-labeled venetoclax, from chemistry to the clinic; Clin Transl Sci. 2022; 15 :244-254.

3. FDA review document: APPLICATION NUMBER: 2085730rigls000; CHEMISTRY REVIEW(S), p. 9 Badawi M. et al. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet; Clinical Drug Investigation (2022) 42:657—668 Reda G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chpenetratesytic leukemia with central nervous system involvement; Haematologica. 2019; 104: e222-e3. Badawi M. et al. Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients; Journal of Cancer 2023, Vol. 14:1151-1156 Boulenc X et al. Sodium lauryl sulfate increases tiludronate paracellular transport using human epithelial caco-2 monolayers; Int J Pharm 1995; 123: 71-83. Ates M. et al. Effect of permeability enhancers on paracellular permeability of acyclovir; Journal of Pharmacy and Pharmacology, 68 (2016), pp. 781-790. M Al-Mohizea. A. et al. Rhodamine- 123: A p-glycoprotein marker complex with sodium lauryl sulfate; Pak. J. Pharm. Sci., Vol.28, No.2, March 2015, pp.617-622 Vaithianathan S. et al. Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir; J Pharm Sci. 2016 Feb;105(2):996-1005. Saija A. et al. Changes in the permeability of the blood-brain barrier following sodium dodecyl sulphate administration in the rat; Exp Brain Res (1997) 115:546-551 Mai Y. et.al. Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter; Mol. Pharmaceutics 2021, 18, 1895-190 SK Agarwal, et.al. Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study; J Clin Pharmacol. 2016 Nov;56(l l):1335-1343. Evans D. F. et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects; Gut. 1988 Aug;29(8): 1035-1041.

Claims

1. A pharmaceutical composition for oral administration, which comprises: a) an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof; and b) an anionic surfactant, or a pharmaceutically acceptable salt thereof; and optionally c) a pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition of claim 1, which comprises an effective amount of Venetoclax.

3. The pharmaceutical composition of claim 1, which comprises an effective amount of a pharmaceutically acceptable salt of Venetoclax.

4. The pharmaceutical composition of any of claims 1-3, which comprises from about 0.1% (w/w) to about 50% (w/w) Venetoclax, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, which comprises from about 0.1% (w/w) to about 1% (w/w) Venetoclax, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of any of claims 1-5, wherein the anionic surfactant is an organosulfate.

7. The pharmaceutical composition of claim 6, wherein the organosulfate is a 5-carbon to a 15-carbon organosulfate, e.g., sodium dodecyl sulfate (SDS), sodium decyl sulfate or sodium octyl sulfate.

8. The pharmaceutical composition of claim 7, wherein the organosulfate, or a pharmaceutically acceptable salt thereof, is sodium dodecyl sulfate (SDS).

9. The pharmaceutical composition of any of claims 1-8, which further comprises a soft gel filler, e.g., polyethylene glycol (PEG).

10. The pharmaceutical composition of claim 9, wherein the polyethylene glycol (PEG) is polyethylene glycol 400 (PEG 400), PEG 1450, or PEG 8000.

11. The pharmaceutical composition of any of claims 1-10, which is in an orally acceptable dosage form of a tablet, a capsule, an emulsion, an aqueous suspension, a dispersion or a solution.

12. The pharmaceutical composition of any of claims 1-11, which comprises a unit dosage of Venetoclax, or a pharmaceutically acceptable salt thereof, in an amount ranging from about 1 mg to about 400 mg.

13. A method for inhibiting or reducing function of BCL-2 in a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition of any of claims 1-12.

14. A method for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to central nervous system of a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition of any of claims 1-12.

15. A method for treating or preventing a disease or a disorder, e.g. , a cancer or tumor in a subject, which method comprises orally administering, to a subject in need, an effective amount of the pharmaceutical composition of any of claims 1-12.

16. The method of any of claims 13-15, wherein the subject is a non-human subject, e.g., a non-human mammal.

17. The method of any of claims 13-15, wherein the subject is a human.

18. The method of any of claims 13-17, wherein, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject reaches a level from about 50 mg to about 4,000 mg.

19. The method of any of claims 13-18, wherein, after oral administration to a subject, plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject reaches a level that is about 2 fold to about 15 fold of plasma concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

20. The method of claim 14, wherein, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system of the subject reaches a level from about 10 ng/mL to about 70 ng/mL.

21. The method of claim 14, wherein, after oral administration to a subject, concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, in the central nervous system (CNS) of the subject reaches a level that is about 2 fold to about 100 fold of CNS concentration of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

22. The method of any of claims 13-21, wherein an effective amount of the pharmaceutical composition is administered to a subject with a meal.

23. The method of any of claims 13-21, wherein an effective amount of the pharmaceutical composition is administered to a subject without a meal.

24. The method of any of claims 13-23, wherein an effective amount of the pharmaceutical composition is administered to a subject at about the same time each day.

25. The method of any of claims 13-23, wherein an effective amount of the pharmaceutical composition is administered to a subject not at approximately the same time each day.

26. The method of any of claims 13-25, wherein after oral administration to a subject, absolute bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, in the subject reaches a level that is about 2 fold to about 10 fold of absolute bioavailability of Venetoclax, or a pharmaceutically acceptable salt thereof, from oral administration of same or comparable amount of VENCLEXTA®, to the same or a comparable subject.

27. The method of any of claims 13-26, wherein an effective amount of the pharmaceutical composition is administered to a subject that also receives administration of posaconazole, a CYP3A inhibitor, a CYP3A inducer, e.g., Rifampin, or a P-glycoprotein (P-gp) inhibitor.

28. The method of claim 27, wherein the CYP3A inhibitor is a CYP3A4 inhibitor.

29. The method of claim 27, wherein the CYP3A inhibitor is a strong CYP3A inhibitor.

30. The method of claim 29, wherein the strong CYP3A inhibitor is clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, telaprevir or voriconazole.

31. The method of claim 27, wherein the CYP3A inhibitor is a moderate CYP3A inhibitor.

32. The method of claim 31, wherein the moderate CYP3A inhibitor is aprepitant, ciprofloxacin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole or verapamil.

33. The method of claim 27, wherein the P-glycoprotein (P-gp) inhibitor is amiodarone, carvedilol, cyclosporine, dronedarone, quinidine, ranolazine or verapamil.

34. The method of any of claims 15-33, which is used for treating a cancer or tumor in a subject.

35. The method of any of claims 15-33, which is used for preventing a cancer or tumor in a subject.

36. The method of any of claims 15-33, wherein the cancer is leukemia, multiple myeloma (MM) or lymphoma, allogeneic hematopoietic stem cell transplantation, hematologic malignancy, hemophagocytic lymph histiocytosis, HIV- 1 -infection, minimal residual disease, mucosa associated lymphoid tissue, myelodysplastic syndromes (MDS), plasma cell myeloma, refractory small cell lung carcinoma, relapsed small cell lung cancer, Richter syndrome, stem cell transplant complications, Waldenstrom's Macroglobulinemia.

37. The method of claim 36, wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML).

38. The method of claim 36, wherein the lymphoma is lymphocytic lymphoma, e.g., small lymphocytic lymphoma (SLL).

39. Use of the pharmaceutical composition of any of claims 1-12 for inhibiting or reducing function of BCL-2 in a subject.

40. Use of the pharmaceutical composition of any of claims 1-12 for delivering an effective amount of Venetoclax, or a pharmaceutically acceptable salt thereof, to the central nervous system of a subject.

41. Use of the pharmaceutical composition of any of claims 1-12 for treating or preventing a cancer or tumor in a subject.