Ixekizumab in the Treatment of Bullous Pemphigoid

BP is the most common auto-immune blistering disease of the skin and causes significant morbidity. BP disproportionally affects the elderly population and the current, non-specific immunosuppressive therapies, in addition to patient comorbidities, are associated with a high risk of infection related mortality. Neutrophils and their proteases have been shown to play a major role in the cleavage of Bullous Pemphigoid 180 Antigen (BP180) in BP. Mast cells and other cellular mediators also contribute to the pro-inflammatory environment within and surrounding blisters of BP. However, the prior targeting of mast cells and basophils has resulted in unpredictable disease control. Recently, IL-17 has been identified as a key driver of chronic inflammation in BP. With the increasing aged population in the United States, BP will increase in prevalence and the development of a more targeted approach will be necessary to decrease morbidity and mortality. IL-17 inhibition with Ixekizumab may have targeted, disease-modifying effects on BP. The primary objective is to test the effect of Ixekizumab in the treatment of the autoimmune blistering disease, BP.

Subjects eligible for inclusion in this study have to fulfill all of the following Inclusion criteria:

• Subjects must be able to understand and comply with the requirements of the study and communicate with the investigator. Subjects must give written, signed, and dated informed consent before any study related activity is performed. When appropriate, a legal representative will sign the informed consent according to local laws and regulation
• Both men and women must be at least 18 years of age at the time of screening
• Subjects must have clinical, histological, and serological features of BP
• Urticarial plaques and/or vesicles and bullae
• Characteristic eosinophilic spongiosis and/or subepidermal separation of the skin
• Positive direct immunofluorescence (IgG and or C3 at the basement membrane zone) or indirect immunofluorescence (IgG on the roof of salt- split skin) or positive serologies on ELISA for BPAG1 or BPAG2
• Subjects must have treatment naive BP or treatment refractory disease, as defined by failure of at least one established treatment for BP
• Candidate for systemic therapy, defined by
• involvement of greater than 5 percent body surface area or moderate to extensive disease as defined by: the mean number of new bullae and urticarial plaques that have appeared over the course of 3 days as determined by the investigator or referring physician (moderate disease defined by greater than 1 and less than 10 new bullae and greater than 5 urticarial plaques and extensive disease by greater than 10 new bullae)
• Failure of prior therapy
• Topical treatment
• Systemic immunosuppressant
• Oral antibiotics and/or niacinamide

Exclusion criteria

Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. In order to ensure the recruitment of a representative sample of all eligible subjects, the investigator may apply no additional exclusions.

• Forms of BP other than classic BP (e.g. mucous membrane BP, Brunsting-Perry BP, p200 BP, p105 BP, or BP with concomitant pemphigus vulgaris Drug-induced BP (e.g., new onset or current exacerbation from angiotensin converting enzyme inhibitors, penicillamine, furosemide, phenacetin)
• Subjects who are receiving treatments known to worsen BP and use of penicillamine or phenacetin and those on angiotensin converting enzyme inhibitors or furosemide who have not been on a stable dose at least 4 weeks prior to enrollment.
• Ongoing use of prohibited treatments.
• Previous exposure to Ixekizumab or any other biologic drug directly targeting IL-17A or IL-17 (receptor A)RA
• Use of any other investigational drugs within 5 half-lives of the investigational treatment before study drug initiation or until the pharmacodynamics effect has returned to baseline, whichever is longer
• Previous use of IL-20 monoclonal antibody
• Pregnant or nursing (lactating) women (pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test)
• Women of childbearing potential [Post-menopausal or not of child-bearing potential is defined by: 1 year of natural (spontaneous) amenorrhea or Surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. Oophorectomy alone must confirmed by follow up hormone level assessment to be considered not of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception which includes:
• Total abstinence (Periodic abstinence and withdrawal are not acceptable methods of contraception)
• Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. Oophorectomy alone requires follow up hormone level assessment for fertility.
• Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
• Barrier methods of contraception: condom or occlusive cap. Use of oral, injected or implanted hormonal methods of contraception or other forms or hormonal contraception that have complete efficacy (failure less than 1 percent). (The dose of the contraceptive should be stable for 3 months)
• Active ongoing inflammatory diseases of the skin other than BP that might confound the evaluation of the benefit of Ixekizumab
• Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions) which, in the opinion of the investigator, significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy Investigator discretion should be used for subjects with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders Significant medical problems, including but not limited to the following: uncontrolled hypertension, congestive heart failure (New York Heart Association (NYHA) status of class III or IV)
• Serum creatinine level exceeding 2.0 mg per dL (176.8 micro mol per L) at screening
• Total white blood cell (WBC) count less than 2,500 per microL, platelets less than 100,000 per microL, neutrophils less1500/microL or hemoglobin less than 8.5 g per dL, at screening
• Active systemic infections during the 2 weeks prior to randomization (common cold viruses not included) or any infection that reoccurs on a regular basis.
• Investigator discretion should be used regarding subjects who have traveled or resided in areas of endemic mycoses, such as histoplasmosis, coccidioidomycosis or blastomycosis and for subjects with underlying conditions that may predispose them to infection, such as advanced or inadequately controlled diabetes. Due to its endemic nature in Arizona, coccidioidomycosis screening is performed at baseline. A history of a disseminated coccidioidomycosis infection will exclude subjects.
• History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis infection as defined by a positive or indeterminate QuantiFERON Tuberculosis (TB)-Gold test (QFT) at screening.
• Subjects with a positive QFT test may participate in the study if a full tuberculosis work up (according to local practice/guidelines) is completed within 12 weeks prior to establishes conclusively that the subject has no evidence of active tuberculosis.

If the presence of latent tuberculosis is established, then treatment must have been initiated and maintained according to local country guidelines for at least 4 weeks prior to randomization.

• Past medical history of, or current infection with, human immunodeficiency virus (HIV), hepatitis B or hepatitis C prior to new diagnosis at screening
• History of lymphoproliferative disease and or any known malignancy and/or history of malignancy of any organ system within the past 5 years

Exceptions include:

For skin squamous cell carcinoma in situ and or well differentiate squamous cell carcinoma and/or basal cell carcinoma and or actinic keratosis and/or melanoma in situ that have been treated with no evidence of recurrence For the cervix carcinoma that has been removed For the colon non-invasive malignant colon polyps that have been removed

• Current severe progressive or uncontrolled disease which the investigator renders the subject unsuitable for the trial or puts the subject at increased risk Inability or unwillingness to undergo repeated venipuncture
• Any medical or psychiatric condition which, in the investigator's opinion, would keep the subject from adhering to the protocol or completing the study per protocol
• History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to the initiation of therapy
• Plans for administration of live vaccines during the study period or in the 12 weeks prior to the initiation of therapy
• Bacillus Calmette-Guerin (BCG) vaccination within 12 months of starting the study or with 12 months after completing the study