WO2014151648A1

WO2014151648A1 - Treatment of autoimmune disease using helminthic parasites

Info

Publication number: WO2014151648A1
Application number: PCT/US2014/026169
Authority: WO
Inventors: Karin Margareta HEHENBERGER
Original assignee: Coronado Biosciences Inc
Current assignee: Fortress Biotech Inc
Priority date: 2013-03-15
Filing date: 2014-03-13
Publication date: 2014-09-25
Anticipated expiration: 2015-09-15

Abstract

Methods are provided for treating autoimmune disorders using helminthic parasite preparations.

Description

TREATMENT OF AUTOIMMUNE DISEASE USING HELMINTHIC PARASITES

FIELD OF THE INVENTION

[0001 ] The present invention relates generally to methods of treatment of autoimmune disease. More particularly, the present invention relates to the use of helminthic parasite ova in pharmaceutical formulations to prevent onset and ameliorate symptoms of type 2 diabetes mellitus, eosinophilic esophagi tis, Behcets disease, vitiligo, atopic dermatitis, juvenile idiopathic arthritis, primary biliary cirrhosis and primary sclerosing cholangitis. This application claims priority to U.S. Provisional Application No. 61/799,732, filed March 15, 2013, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Autoimmune diseases take many forms, but axe each characterized by an inappropriate response of a body's immune system to a native substance or tissue mistaken for a foreign agent. There are more than 80 distinct disorders classified as "autoimmune," and a substantia! minority of the population suffers from an autoimmune disorder. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly- diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100,000 person-years. Prevalence rates range from less than 5 per 100,000 (e.g., chronic active hepatitis, uveitis) to more than 500 per 100,000 (Grave disease, rheumatoid arthritis, thyroiditis).

[0003] Safety and efficacy of helminthic therapy has been investigated in clinical studies with patients suffering from inflammatory bowel disease ( IBD). Further, results of previous studies indicate that helminthic therapy might be effective in both forms of IBD, Crohn's disease (CD) and ulcerative colitis (UC). Up to now, helminthic therapy has been administered in more than 150 patients for UC, CD, allergic rhinitis (AR) or multiple sclerosis (MS), some treated for more than four years. Numerous studies of IBD demonstrated improvement of disease activity, with remission observed in many patients, ie, the agent has been shown to be effective not only in treating active disease, but also in maintaining remission. [0004] However, there remains a need for helminthic therapy to he exploited fully to ameliorate other disease conditions.

SUMMARY OF THE INVENTION

[0005] The present invention relates to novel therapeutic methods for the treatment of autoimmune diseases.

[0006] in particular, one aspect of the present invention provides a method of treating type 2 diabetes meliitus comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceuticaliy-acceptabie carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient, in some embodiments, the helminthic parasite may be selected from the group consisting of T. suis, S. mansoni, II. polygyrus, T. spiralis, T. trichiura and A^,r. americanus.

[0007] The biologically active portion of the helminthic parasite may be selected from the group consisting of parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract, in preferred embodiments, the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis. In further embodiments, the treatment ma ameliorate insulin resistance, or, in further embodiments, the treatment may prevent the disruption of normal insulin action by proinflammatory cytokines, which may, in sti ll further embodiments, be selected from the group consisting of IKK-beta, NF-kappa-B, TNF-a, IL-2, IL-17, IL-21, IL-22, and IL-6. In still further embodiments, the treatment may ameliorate one or more symptoms or complications associated with type 2 diabetes meliitus selected from the group consisting of elevated HbAlc, cardiovascular disease, ischemic heart disease, poor circulation, stroke, diabetic retinopathy, kidney failure, cognitive dysfunction, dementia, vascular dementia, acanthosis nigricans, sexual dysfunction, and frequent infections. In still further embodiments, the therapeutically effective amount may be between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater. [0008] in another aspect, a method is provided for treating behcet's disease comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceuticaily-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient. The treatment may, in some embodiments, act to reduce autoinflammation of the blood vessels by inhibiting Thl 7 differentiation. In still further embodiments, the treatment ameliorates one or more symptoms of behcet^'s disease selected from the group consisting of skin lesions, iritis, uveitis, retinal vasculitis, genital ulcerations, erythema nodosum, cutaneous pustular vasculitis, and stomach or bowel inflammation. 0009J The helminthic parasite, in further embodiments, may be selected from the group consisting of T. suis, S. mansoni, H. polyg rus, T. spiralis, T. trichiura and N. americanm. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

(0010] In yet another aspect, the present invention provides a method of treating eosinophilic esophagitis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceuticaily-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

[0011 ] The helminthic parasite, in further embodiments, may be selected from the group consisting of T. suis, S. mansoni, H. polygyrus, T. spiralis, T. trichiura and N. americanus. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

[0012] In yet another aspect, the present invention provides a method of treating vitiligo comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient. The treatment may, in some embodiments, prevent autoimmune attacks on melanocytes, or, in further embodiments, may slow or prevent progression of vitiligo.

[0013J The helminthic parasite, in further embodiments, may be selected from the group consisting of T. suis, 8. mansoni, H. polygyrus, T. spiralis, T. trichiura and N, americanus. in preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

[0014J In another aspect, a method of treating atopic dermatitis is provided comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

[0015] The helminthic parasite, in further embodiments, may be selected from the group consisting of T, suis, S. mansoni, H. polygyrus, T. spiralis, T. trichiura and N. americanus. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater. [0016] in another aspect a method of treating juvenile idiopathic arthritis is provided comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutieally-aceeptabie carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient,

[0017] The helminthic parasite, in farther embodiments, may be selected from the group consisting of T. suis, S. mansoni, H. poly gyrus, T. spiralis, T. trichi ra and N. americanus. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

[0018] In another aspect, the present invention provides a method of treating primary biliary cirrhosis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutieally-aceeptabie carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

[0019] The helminthic parasite, in further embodiments, may be selected from the group consisting of T. suis, 8. mansoni, H. polygyrus, T. spiralis, T. trichiura and N. americanus. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

[0020{ In yet another embodiment, a method is provided for treating primary sclerosing cholangitis comprising administering to a huma patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biological ly active portion thereof and a pharmaceutieally-aceeptabie carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

[0021 ] The helminthic parasite, in further embodiments, may be selected from the group consisting of T. s is, S. mansoni, H. polygyrus, T. spiralis, T. trichiura and N. americanus. In preferred embodiments, the pharmaceutical formulation may comprise parasite eggs or parasite egg extract of T. suis. The therapeutically effective amount may, in some embodiments, be between about 500 and about 20,000 eggs, and the amount may be administered between about 1 and about 4 times per month for a duration of six months or greater.

[0022] As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to phis or minus 10% of the particular term.

[0023] As used herein, the term "active agent" is used to refer to a chemical material or compound that induces a desired beneficial effect when administered topically or orally, and includes agents that are therapeutically and/or prophylactically effective as pharmaceuticals ("pharmacologically active agents"). By an "effective" amount of an active agent is meant a nontoxic but sufficient amount of an active agent to provide the desired beneficial effect.

[0024] As used herein, the term ^uegg" refers to either embryonated or nonem br onated . viable helminth, ova.

[0025] Additional features, advantages, and embodiments of the present disclosure may be set forth from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the present disclosure and the following detailed description are exemplary and intended to provide further explanation without further limiting the scope of the present disclosure claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The methods of the present invention provide therapies for the fol lowing autoimmune disorders: T2DM, eosinophilic esophagitis, Behcets disease, vitiligo, atopic dermatitis, juvenile idiopathic arthritis, primary biliary sclerosis, and primary sclerosing cholangitis.

[0027] T2DM is characterized by insulin resistance and relative insulin deficiency due to beta cell dysfunction. Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus. Behcets disease is an immune-mediated systemic vasculitis. Vitiligo results due to autoimmune targeting of melanocytes. Atopic dermatitis is an inflammatory, relapsing form of eczema. Juvenile idiopathic arthritis is a subset of arthritis affecting approximately 1 in 1 ,000 children in any given year, with about 1 in 1 0,000 having a severe form.. Finally, primary biliary cirrhosis and primary sclerosing cholangitis are inflammatory autoimmune diseases of the bile ducts,

[0028] Tests may be conducted throughout the course of treatment to determine safety or efficacy of the treatment. As used herein, "clinical chemistry" comprises one or more of the tests selected from the group consisting of total protein, albumin, serum creatinine, blood urea nitrogen (BUN), uric acid, bilirubin (total & direct), alkaline phosphatase, alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT). creatine phosphokinase (CPK), glucose, calcium, phosphorus, sodium, potassium, chloride, and bicarbonate.

[0029] As used herein, ''hematology" refers to the fol lowing tests: white blood ceil (WBC) count, differential white ceil count (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell (RBC) count, hematocrit, hemoglobin and platelet count. As used herein, "urinalysis" refers to a group of tests comprising color, specific gravity, pH, glucose, ketones, blood, protein, nitrates, leukocyte esterase, R BC, WBC.

Helminthic Preparations [0030] Embryonated eggs of certain helminths, such as, for example, porcine whipworm Trichuris suis (Trichuris suis ova, TSO), have been shown to colonize the human intestine without invading or infecting. Safety of ISO has been demonstrated in clinical studies with patients suffering from 1BD, Multiple Sclerosis, allergies and other autoimmune diseases, as shown in Table 1 .

Table 1 : Number (%) of Patients Experiencing Treatment-Emergent Adverse Events MedDRA Preferred Term - Sorted by Descending Incidence in the Total TSO Coin (Study CNDO 201 -002)

m ss ng onset dates are considered treatment-emergent events.

[0031] Any immunomodulatory non-infective helminth species may be used in the methods described herein, such as, for example, T. suis, S. mansoni, H. polygyrus, T. spiralis, T, irichiura and N. americanus. The entire adult helminth may be used, or any therapeutically effective portion thereof, such as, for example, parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract, in a preferred embodiment, parasite ova are used.

[0032] Therapeutically effective amounts of the helminth or biologically active portion thereof can be empirically determined and will vary with the pathology being treated, the severity of the symptoms, and the subject being treated. The effective amount may be determined during pre-c!inica! trials and clinical trials by methods familiar to physicians and clinicians. An effective amount of a helminthic parasite preparation useful in the methods may be administered to a mammal in need thereof by any of a number of well-known methods for administering pharmaceutical compounds. The peptide may be administered systemically or locally or, in the case of a neonatal patient, may be administered to the mother, in a preferred embodiment, the administration is oral.

[0033] Oral compositions may also include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0034j The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compositions described herein can include a single treatment or a series of treatments.

[0035] in preferred embodiments, each dose may comprise from about 500 to about 20,000 eggs, or from about 2,000 eggs to about 10,000 eggs. In further embodiments, each dose may comprise about 1 ,000 eggs, about 1 ,500 eggs, about 2,000 eggs, about 2,500 eggs, about 3,000 eggs, about 3,500 eggs, about 4,000 eggs, about 4,500 eggs, about 5,000 eggs, about 5,500 eggs, about 6,000 eggs, about 6,500 egg, about 7,000 eggs, about 7,500 eggs, about 8,000 eggs, about 8,500 eggs, about 9,000 eggs, about 9,500 eggs, about 10,000 eggs, about 10,500 eggs, about 1 1 ,000 eggs, about 1 1 ,500 eggs, about 12,000 eggs, about 12,500 eggs, about 13,000 eggs, abou 13,500 eggs, about 14,000 eggs, about 14,500 eggs, about 15,000 eggs, about 15,500 eggs, about 16,000 eggs, about 16,500 eggs, about 17,000 eggs, about 17,500 eggs, about 18,000 eggs, about 18,500 eggs, about 19,000 eggs, or about 19,500 eggs.

[0036] Administration may take place as often or as rarely as necessary to be therapeutically effective. The amount administered may be between about I and about 4 times per month for a duration of six months or greater, depending on the pathology of the patient and the presence of acute symptoms. In preferred embodiments, the frequency of administration of the pharmaceutical formulation may be greater for a first period of time taking place at the outset of treatment, than the frequency of administration during a second period of time taking place after the first period of time. Alternatively or additionally, the frequency of administration of the pharmaceutical formulation may be increased for a period of time when acute symptoms of the condition appear or are expected to appear, followed by a return to the frequency of administration after the acute symptoms have subsided.

Examples

[0037] Example 1 : Treatment of Autoimmune Disease m Patients _λ Using Helminthic

Parasite Preparatiogs

[0038] In order to demonstrate the efficacy of helminthic preparations in treatment of autoimmune diseases, cohorts of at least ten subjects each with confirmed diagnoses of each of the following diseases are recruited: T2DM, EE, Behcets, vitiligo, atopic dermatitis, JIA, PBC, and PSC. Each cohort has the following inclusion criteria: males or females, 8-35 years old (inclusive) (with the exception of the JIA cohort, which has an age range of 6-16), with diagnoses confirmed by standard tests. If female, before entry she must be (1 ) surgically sterile: (2) if heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method, or male partner sterilization, consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study and for 2 months after receiving the last administration of any study agent, or (3 ) not heterosexually active. The subjects must be willing to comply with the schedule of study visits and protocol requirements, and have the ability to provide informed consent.

[0039] in addition, subjects may not have the following exclusion criteria: patients having received any of the following medications in the two weeks before screening: antibiotic, antifungal, antiparasitic, immunosuppressive, or other excluded medication; patients with positive stool culture for ova, parasites, or any enteric pathogens at screening; patients with history of drug or alcohol abuse within 6 months prior to screening; patients with evidence of poor compliance with medical advice and instructions including diet or medication; patients with significant medical conditions putting the patient at risk for study participation or put at risk by study procedures; patients having active hepatitis B virus, hepatitis C virus, cytomegalovirus, Epstein Barr Virus, or herpes simplex virus or is known to be HI V positive; patients who have participated in another clinical trial within 30 days of Screening for this trial and/or any experimental treatment for this population; females of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period; females who are pregnant or breastfeeding at the time of enrol lment; patients with a white blood cell count < 3,000/mra3 (< 3.0 x 109 L) or > 1 4,0Q0/mm3 (> 14 x 109/L); platelet count < Ι ΟΟ,ΟΟΟ/μΕ (<100 x 109/L); serum creatinine >2 x upper limit of normal (ULN); AST (SGOT) or ALT (8GPT) > 2 x ULN; total bilirubin >2 mg/dL (34 μηιοΙ/L); hemoglobin < 9 g/dL. [0040] The active drug product, Trichuris suis ova 7500 is a non-sterile, aqueous suspension of the viable, embryonated eggs of the whipworm Trichuris suis for oral use. Active TSO is administered in 15 mL of the suspension medium supplied in either one or two 30 rriL glass containers. The suspension medium is an aqueous solution containing phosphate buffer, pH 5 and 0.05% potassium sorbate as antimicrobial preservative. Each unit dose is supplied in a 30 mL amber glass container with black outer lacquer and is sealed with a white polypropylene screw cap and a blue tamper evident ring,

[0041| The TSO is prepared as delineated in Table 2. The formulation is at a temperature between 2°C (36 °F) and 8°C (46 °F) and are protected from any risk of freezing (i.e., not be placed directly on freezer packs or in ice that could be below 0°C or 32 °F) or temperature greater than 25° C (77 °F). TSO is agitated gently before use to disperse the ova. Following dosing, tap water is to be added to the glass container, agitated, and ingested to ensure administration of the full dose of TSO.

Table 2; TSO Product

[0042] Following informed consent, each patient from each cohort is screened on the basis of clinical laboratories and condition severity. Informed consent, inclusion and exclusion criteria, vital signs, clinical laboratories, urinalysis, stool culture, pregnancy scrum test in female patients, 12-lead ECG, concomitant medications, medical history and a physical examination wi l l be conducted. Treatment then proceeds according to the Schedule of Events shown in Table 3.

Table 3 :

Ao\ 7-5086-9913.1

[0043] Eligible subjects are randomized to treatment with TSO 7500, or placebo (in a ratio of 2: 1 by cohort). During the treatment phase, study drug will be provided in a liquid form and will be administered every 2 weeks, starting with the Baseline visit, through Month 6. The primary time point for assessment of efficacy is at 6 months. Patients return to the clinic every three months during the treatment period of 6 months and every 3 months during the follow-up period of 6 months for assessment of efficacy and safety indices as per the Schedule of Events.

[0044] At the screening assessments, the following evaluations are performed: informed consent, inclusion and exclusion criteria, vital signs, clinical laboratories, urinalysis, stool culture, pregnancy serum test in female patients, 12-Iead ECG, concomitant medications, efficacy testing (to vary by condition treated and cohort), medical history and a physical examination.

[0045] Subjects who satisfy eligibility requirements from screening will return to the clinic for their baseline (pre-treatment) assessments. The baseline visit may occur anytime between screening to five weeks provided all eligibility criteria have been met. if subjects are still deemed to be eligible, the subject will be randomized and treated with their first dose of study medication. Baseline assessments will include: inclusion and exclusion criteria to ensure subject still meets requirements, medical history to assess any changes since screening, physical examination to assess any changes since screening, clinical laboratories (including hematology, serum chemistry, C-reactive protein, LFTs), urinalysis, pregnancy urine test (female patients only), vital signs, prior medications and on-going medications, efficacy testing (to vary by condition treated and cohort). For patients who still meet eligibility criteria, the subject will be randomized and receive their first dose of medication.

[0046] Two weeks after baseline visit, patients are contacted by telephone to verify that patient has taken 2 week study drug as directed, arid to assess for any adverse events or serious adverse events, or any changes in concomitant medications. |0047J At month 1 , subjects return to the clinic for the following assessments: study medication accountability, adverse events, pregnancy urine test (female patients only), dosing with study medication, and dispensing study medication and study drug dosing instructions.

[0048] At month 3, subjects return to the clinic for the following assessments: study medication accountability, adverse events, concomitant medications, vital signs, clinical laboratories (including hematology, serum chemistry, C-reactive protein, LFTs), urinalysis, prior and ongoing medications, efficacy testing (to vary by condition treated and cohort), dosing with study medication, an dispensing study medication and study drug dosing instructions.

[0049] At month 6, subjects return to the clinic for the following end-of-treatment-peri od assessments: study medication accountabi lity, adverse events, concomitant medications, vital signs, clinical laboratories (including hematology, serum chemistry, C-reactive protein, LFTs), urinalysis, stool culture, pregnancy laboratory (female subjects only), physical examination, efficacy testing (to vary by condition treated and cohort).

[0050] At month 9, patients return to the clinic for the following post-treatment follow-up assessments: adverse events, clinical laboratories, urinalysis, pregnancy urine test (female patients only), vital signs, concomitant medications, efficacy testing (to vary by condition treated and cohort).

[0051] At month 12, patients return to the clinic for the following end of post-treatment follow- up assessments: adverse events, physical examination, clinical laboratories, urinalysis, pregnancy urine test (female patients only), stool culture, vital signs, concomitant medications, efficacy testing (to vary by condition treated and cohort),

[0052] Data analysis will be tabulated by treatment group and presented using both descriptive and inferential statistics. Efficacy outcomes wil l be evaluated using the !ntent-to-Treat population (all patients randomized and treated with at least one dose of study medication). All inferential tests are two-sided and pairwise between each active TSO arm and the placebo arm. Assessment of outcomes at each protocol-scheduled time point will be performed for each endpoint. [0053] Generally, categorical endpoints will be assessed using a 2-sided chi-square test. Changes and percent changes from pre-treatment to on-treatment time points will be calculated for continuous efficacy endpoints. Continuous data will be assessed via a mixed model; adjusted (LSMeans) estimates and standard errors will be presented for these values with their associated pair wise p-va!ues. The primary comparisons will be pairwise between the individual TSO treatment arms and placebo. Assessment of dose response will be performed where warranted. Longitudinal assessment of changes over time may be performed for select endpoints, utilizing longitudinal mixed effects model with effects for treatment, center, and time. Graphical displays of changes over time will be presented for select outcomes. All data captured on the case report form (and in the clinical laboratory and other electronic databases) will be presented in by-domain data listings.

[0054] For the purpose of analysis, two populations will be identified. The safety population wil l comprise all patients treated with the study treatment (i.e. TSO 7500 or placebo), The modified intent-to-treat population (mITT) will include all patients treated with at least one dose of study medication and who have at least one post-baseline assessment.

[0055] The foregoing description of illustrative embodiments has been presented for purposes of illustration and of description. It is not intended to be exhaustive or limiting with respect to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the disclosed embodiments. It is intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims

WHAT fS CLAIMED IS:

1 . A method of treating type 2 diabetes mellitus comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helm inthic parasite or a biological ly active portion thereof and a pharmaceutically-acceptabie carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially T^'h l immune activity over Th2 immune activity in the human patient.

2. The method of claim ^'· . wherein the helminthic parasite is selected from the group consisting of T. suis, S. mansoni, H. polyg rus, T. spiralis, T. irichiura and N, americanus.

3. The method of claim 1 , wherein the biologically active portion of the helminthic parasite is selected from the group consisting of parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract,

4. The method of claim 3, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

5 The method of claim 1 , wherein the treatment ameliorates insulin resistance.

6. The method of claim 4, wherein the treatment prevents the disruption of normal insulin action by proinflammatory cytokines.

7. The method of claim 6, wherein the proinflammatory cytokines are selected from the group consisting of IKK-beta, NF-kappa-B, TNF-a, IL-2, IL-17, IL-21 , IL-22, and IL-6.

8. The method of claim 1 , wherein the treatment further ameliorates one or more symptoms or complications associated with type 2 diabetes mellitus selected from the group consisting of elevated HbA l c, cardiovascular disease, ischemic heart disease, poor circulation, stroke, diabetic retinopathy, kidney failure, cognitive dysfunction, dementia, vascular dementia, acanthosis nigricans, sexual dysfunction, and frequent infections.

9. The method of ciairn 1 , wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

1 0. A method of treating behcet's disease comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaeeutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Th l immune activity over Th2 immune activity in the human patient.

1 1 . The method of claim 10, wherein the treatment acts to reduce autoinfiammation of the blood vessels by inhibiting Th l 7 differentiation.

12. The method of claim I S , wherein the treatment ameliorates one or more symptoms of behcet's disease selected from the group consisting of skin lesions, iritis, uveitis, retina! vasculitis, genital ulcerations, erythema nodosum, cutaneous pustular vasculitis, and stomach or bowel inflammation.

13. The method of claim 1 1 , wherein the helminthic parasite is selected from the group consisting of T. suis, S. mansoni, If. polygyrus, T. spiralis, T, trichiura and N. americanns.

14. The method of claim 13, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

15. The method of claim 10, wherein the therapeutically effective amount is between about 500 and about 2.0,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

16. A method of treating eosinophilic esophagitis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaeeutically-acceptable carrier, wherein the helm inthic parasite or portion thereof acts to enhance preferentially Th l immune activity over Tii2 immune activity in the human patient.

17. The method of claim 16, wherein the helminthic parasite is selected from the group consisting of T. suis, S. mansoni, H. polygyrus, T. spiralis, T. trichiura and N. americanus.

1 8. The method of claim 16, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

19. The method of claim 36, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

20. A method of treating vitiligo comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

21. The method of claim 20, wherein the treatment prevents autoimmune attacks on melanocytes.

22. The method of claim 20, wherein the treatment slows or prevents progression of vitiligo,

23. The method of claim 20, wherein the helm inthic parasite is selected from the group consisting of 71 suis, S. mansoni, H. polygyrus, 71 spiralis, 71 irichiura and N, americanus.

24. The method of claim 20, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of 71 suis.

25. The method of claim 20, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

26. A method of treating atopic dermatitis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Th l immune activity over Th2 immune activity in the human patient.

27. The method of claim 26, wherein the helminthic parasite is selected from the group consisting of T. s is, S. mamoni, H, polygyr s, T. spiralis, T. trichiura and N. americamis.

28. The method of claim 26, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

29. The method of claim 26, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

30. A method of treating juvenile idiopathic arthritis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a phariTsaeeuiicaiiy-aceeptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Thl immune activity over Th2 immune activity in the human patient.

31. The method of claim 30, wherein the helminthic parasite is selected from the group consisting of T. suis, S. mansoni, II. polygyrus, T. spiralis, T. trichiura and N. americanv.s.

32. The method of ciaim 30, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T. suis.

33. The method of claim 30, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

34. A method of treating primary biliary cirrhosis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Th l immune activity over Th2 immune activity in the human patient.

35. The method of claim 34, wherein the helminthic parasite is selected from the group consisting of T, .wis, S. mansoni, H. polygynis, T. spiralis. T. irichiura and N. americanus

36. The method of claim 34, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract of T, mis.

37. The method of claim 34, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.

38. A method of treating primary sclerosing cholangitis comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a helminthic parasite or a biologically active portion thereof and a pharmaceutically-acceptable carrier, wherein the helminthic parasite or portion thereof acts to enhance preferentially Th J immune activity over Th2 immune activity in the human patient.

39. The method of claim 38, wherein the helminthic parasite is selected from the group consisting of T. suis, S, mansoni, H. polygyrus, T. spiralis, T. irichiura and N. americanus.

40. The method of claim 38, wherein the pharmaceutical formulation comprises parasite eggs or parasite egg extract oi^' T. suis.

41 . The method of claim 38, wherein the therapeutically effective amount is between about 500 and about 20,000 eggs, and wherein the amount is administered between about 1 and about 4 times per month for a duration of six months or greater.