A Proof-of-Concept Study of Topical AC-203 in Patients With Bullous Pemphigoid

A Randomized, Open-Label, Controlled Trial of Topical AC-203 in Subjects With Bullous Pemphigoid

Bullous pemphigoid (BP) is a chronic, inflammatory, subepidermal, autoimmune blistering disease which mainly develops in the elderly, with onset usually in the late 70s and a substantial increase in incidence in people older than 80 years. If untreated, it can persist for months or years, with periods of spontaneous remissions and exacerbations. It has been found that blisters and sera of BP patients contain abnormally high levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and IL-8. Recently, it also has been demonstrated that NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome components (the NLRP3-caspase-1-IL-18 axis) were significantly up-regulated in peripheral blood mononuclear cells from BP patients and positively correlated with disease activity. AC-203 is a topical formulation of an oral modulator of inflammasome and IL-1beta pathways. In vitro studies have demonstrated that AC-203 significantly reduced secretion of IL-6 and moderately reduced IL-8 secretion in HaCaT cells treated with specific anti-BP180 IgG. This study is designed to test the safety, tolerability, efficacy, and pharmacokinetics of AC-203 ointment (vs. a topical steroid comparator representing standard of care) ointment in subjects with BP.

Inclusion Criteria:

1. Age 20 to 90 years old, inclusive, at enrollment.

2. Diagnosis of bullous pemphigoid confirmed by histopathology and one of following assessments:

   1. Direct immunofluorescence (DIF)
   2. Indirect immunofluorescence (IIF)
   3. ELISA test (ELISA detection of immunoglobulin G (IgG) anti-BP180 autoantibodies in serum more than 9 U/mL).

3. Localized or limited BP with the occurrence of <10 new blisters per day in the week prior to enrollment.

4. Is male, or is female and meets all the following criteria:

   1. Not breastfeeding
   2. If of childbearing potential (defined as non-post hysterectomy or non-post-menopausal [≥50 years of age and amenorrheic for at least 1 year]), must have a negative pregnancy test result (human chorionic gonadotropin, beta subunit [bhCG]) at Visit 1, and must practice and be willing to continue to practice appropriate birth control (abstinence, double barrier methods, hormonal contraceptives, intrauterine device, or tubal ligation) during the entire duration of the study

5. Is able to understand and sign the Informed Consent Form (ICF), communicate with the investigator, and understand and comply with protocol requirements.

Exclusion Criteria:

1. Diagnosis of pemphigus, dermatitis, eczema, psoriasis, or other skin condition which in the opinion of the investigator may confound diagnosis, treatment, or evaluation of bullous pemphigoid.
2. Use of oral steroids in the 2 weeks prior to enrollment at a dose greater than prednisolone equivalent dose (PED) of 10 mg/day.
3. Use of topical steroids for more than 3 consecutive days in the 2 weeks prior to enrollment.
4. Use of non-steroid immunosuppressants including but not limited to azathioprine, mycophenolate, cyclophosphamide, chlorambucil, methotrexate, tacrolimus, or cyclosporine in the 2 weeks prior to enrollment.
5. Use of systemic antibiotics in the 2 weeks prior to enrollment.
6. Use of oral dapsone in the 2 weeks prior to enrollment.
7. Treatment with intravenous immunoglobulin (IVIG) in the 8 weeks prior to enrollment.
8. Any prior use of approved or investigational biologic anti-inflammatory therapy within 6 months prior to enrollment, including but not limited to: anakinra, rilonacept, canakinumab, etanercept, adalimumab, infliximab, rituximab, certolizumab, golimumab, tocilizumab, bertilimumab, or abatacept.
9. Presence of active systemic infections.
10. Any clinically significant medical condition or laboratory value that could potentially affect study participation and/or personal well-being, as judged by the investigator.
11. History of allergy or hypersensitivity to any component of study medication or clobetasol.
12. Has participated in a clinical study within 30 days prior to enrollment.
13. Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the clinical study site, or is directly affiliated with the study at the clinical study site.
14. Is employed by the sponsor (i.e., is an employee, temporary contract worker, or designee responsible for the conduct of the study).