Study To Evaluate The Efficacy Of Tofacitinib In Moderate To Severe Alopecia Areata, Totalis And Universalis

Alopecia areata (AA) is a common disease of the immune system, known as an "autoimmune" disease. In the disease, the immune system mistakenly destroys the hair follicle, causing hair to fall out. Despite many people having this disease, research into its cause and new, better ways to treat AA has lagged far behind other similar diseases of the immune system. Currently, there are no Federal Drug Administration approved drugs for AA.

Tofacitinib (made by Pfizer) is an intervention known to effectively treat a disease of the joints, known as rheumatoid arthritis. It is also being studied in the treatment of psoriasis, another "autoimmune" disease, by fighting inflammation. There are some genetic and chemical similarities between those with active rheumatoid arthritis, psoriasis, and AA,suggesting that treatment with the same drug is likely to be effective. In mice specially designed for testing drugs for the treatment of human alopecia, this medication worked to prevent the disease AA from starting in mice that would have otherwise developed the disease. To test Tofacitinib, we are going to treat 15 patients with moderate to severe AA for up to 6 months. This is an "open label" study, meaning that there will not be a placebo group; all patients enrolled in the study will receive the active medication. The effectiveness of the medication will be measured by changes in hair re-growth as determined by physical exam and photography, as well as by patient and physician scoring. After the treatment period of up to 6 months is completed, There will be the option of increasing the treatment duration up to an additional 6 months beyond the initially scheduled 6 months of treatment, if clinically indicated, and at the discretion of the investigator. Patients will be followed for another 6 months off of the drug to see if the effects of treatment last and if there is delayed response. The safety of the medication, Tofacitinib, in patients with AA will also be evaluated. Blood work will be collected before medication is started, during the treatment period and after Tofacitinib is stopped in order to monitor for adverse effects of the medication. Small scalp biopsies and peripheral blood will be taken at the beginning of the study before treatment and at weeks 4 and 24. Additional, optional scalp biopsies and blood draws may be suggested at other important time points. The chemical analysis of these skin samples and blood will help us to understand how the disease happens, how the treatment works, and even guide us to better treatments in the future.

Inclusion criteria

• Patients between 18 and 65 years of age.
• Patients with a diagnosis of moderate to severe patch type alopecia areata.
• Patients with alopecia totalis or universalis may be enrolled.
• Patients have >30% and <95% total scalp hair loss at baseline as measured using the SALT score to qualify as moderate to severe patch type AA; and 95-100% scalp hair loss to qualify as alopecia totalis or universalis.
• Duration of hair loss greater than 3 months without an upper limit of duration as long as there is reason to believe that regrowth is possible in the opinion of the investigator.
• No evidence of significant active ongoing regrowth present at baseline.
• Patients with a history of alopecia totalis/universalis can be included as long as the current episode of hair loss meets the criteria of 30 to 95% hair loss (i.e. they are not currently AT or AU), and as long as in the opinion of the investigator there does appear to be potential for regrowth. Patients with current episodes of alopecia totalis/universalis may be included in this study.
• Vaccinations should be up to date in agreement with current immunization guidelines prior to start of tofacitinib. The patient will be asked to obtain verbal verification from their primary care provider that this is the case.
• Patients may be naïve to treatment or unresponsive to intralesional (IL) steroids or other treatments for alopecia areata.
• Women of childbearing potential (WOCBP) must use highly effective methods of birth control [for at least 12 weeks after the last dose of investigational product] to minimize the risk of pregnancy. WOCBP must follow instructions for birth control for the entire duration of the study including a minimum of 90 days after dosing has been completed.

Acceptable methods of highly effective birth control include:

• Condom with spermicide
• Diaphragm and spermicide
• Cervical cap and spermicide The use of intrauterine devices, (IUDs) shall be at the discretion of the investigator.

• Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
• Women must not be breastfeeding.

Exclusion criteria

• Sex and Reproductive Status

• WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of study drug.
• WOCBP using a prohibited contraceptive method.
• Women who are pregnant or breastfeeding.
• Women with a positive pregnancy test on enrollment or before administration of tofacitinib.
• Sexually active fertile men not using effective birth control if their partners are WOCBP.
• Target Disease Exceptions

• Patients with current alopecia totalis/universalis (i.e. 100% scalp or 100% scalp and body loss, respectively) may be enrolled.
• Patients with a history of or active skin disease on the scalp such as psoriasis or seborrheic dermatitis.
• Patients in whom the diagnosis of alopecia areata is in question or in whom the pattern of hair loss is such that quantification of hair loss and assessment of regrowth is difficult. E.g patients with diffuse alopecia areata. This assessment is at the investigator's discretion.
• Patients with active medical conditions or malignancies (except adequately treated basal or squamous cell carcinoma) that in the opinion of the investigator would increase the risks associated with study participation, including patients with a history of recurrent infections.
• Patients with hemoglobin levels <9 g/dL, lymphocyte count <500 cells/mm3, absolute neutrophil count (ANC) <1000 cells/mm3, at baseline.
• Patients known to be HIV or hepatitis B or C positive.
• Patients with history or evidence of moderate or severe hepatic and/or renal impairment.
• Patients with history of immunosuppression or history of recurrent serious infections.
• Coexisting disease or concurrent medications

• Patients taking potent inhibitors of CYP3A4 (e.g.ketoconazole).
• Patients receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
• Patients known to be HIV or hepatitis B or C positive.
• Patients with evidence of infection or active/untreated skin cancer.
• Patients who have been treated with intralesional steroids, systemic steroids, anthralin, squaric acid, diphenylcyclopropenone (DPCP), protopic, minoxidil or other medication which in the opinion of the investigator may affect hair regrowth within one month of the baseline visit.
• Patients who are impaired, incapacitated, or incapable of completing study-related assessments.
• Patients with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
• Female patients who have had a breast cancer screening that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded by additional clinical, laboratory, or other diagnostic evaluations.
• Patients with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ. Existing non-melanoma skin cell cancers should be removed, the lesion site healed, and residual cancer ruled out before administration of the study drug.
• Patients who currently abuse drugs or alcohol.
• Patients with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of human immunodeficiency virus (HIV) detected during screening.
• Patients with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months before the informed consent document was signed.
• Patients who have received any live vaccines within 3 months of the anticipated first dose of study medication. Subjects may not receive live vaccine concurrently with tofacitinib.
• Patients with a history or symptoms suggestive of gastrointestinal perforation or disorders that might increase the risk of GI perforation such as gastric ulcers or diverticulitis.
• Patients who take NSAIDs at high dose or on a frequent basis, which in the investigator's opinion might increase the risks of gastrointestinal perforation.
• Patients with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, osteomyelitis, or bronchiectasis).
• Patients at risk for tuberculosis (TB). Specifically excluded from this study will be subjects with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (4 weeks).