Ixekizumab in the Treatment of Bullous Pemphigoid
Condition: Bullous Pemphigoid; Pemphigoid
MeSH terms: Pemphigoid, Bullous
Intervention: Ixekizumab
Intervention description: Subcutaneous injection
Intervention MeSH terms: Ixekizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: This is a single center, exploratory, open-label, single-arm design study of 12 patients with BP. Treatment naïve and treatment refractory patients with BP will be treated with Ixekizumab. Patients who are non-responders, to physician choice standard of care, will undergo a washout period and will be enrolled in the study.
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Ixekizumab; Bullous Pemphigoid; Pemphigoid; IL17; IL-17; Interleukin 17

Summary:

      Recently, Interleukin (IL)-17 has been identified as a key driver of chronic inflammation in
      Bullous Pemphigoid (BP). Ixekizumab is a recombinant high-affinity fully human monoclonal
      antibody that targets IL-17A Immunoglobulin gamma-1 (IgG1)/kappa-class. The purpose of this
      study is to determine the effect of Ixekizumab on BP patients.
    

Eligibility criteria:

        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