AN2728 Clinical Data in Atopic Dermatitis

Transcription

1 AN2728 Clinical Data in Atopic Dermatitis Karl Beutner, MD, PhD 1 Overview of AN2728 in Atopic Dermatitis Target Product Profile Safe and effective topical therapy for atopic dermatitis Efficacy in the range of topical calcineurin inhibitors Safer than topical corticosteroids and topical calcineurin inhibitors 14 clinical studies to date have demonstrated safety Demonstrated efficacy in atopic dermatitis in the range of topical calcineurin inhibitors Due to demonstrated safety and efficacy in atopic dermatitis, AN2728 seems well-suited as a topical therapy for treating this disease 2 1

2 14 Completed Studies for AN2728 Demonstrate Safety & Efficacy Dosing Trial Design Objectives Subjects AN2728 PSR 102 4QD treatments over 5 days Safety 20 AN2728 PSR 104 2% x7 days 10% BSA, 35% BSA Absorption Maximum blood levels at steady state 16 AN2728 PSR 105 MUSE AN2728 PSR 106 Local Tolerability AN2728 PSR b AN2728 PSR b AN2728 PSR b AN2728 PSR % BSA Single treatment 2% x 8 days >= 35% BSA 2% x 21 days 5%, Betnesol-V, Protopic, Vehicle 0.5, 2, 5%, Betnesol-V Protopic, Vehicle 0.3, 1, 2% Betnesol-V, Vehicle Safety and PK Safety and PK at Maximal Exposures Safety and tolerability in areas of sensitive skin Safety and efficacy in psoriasis Safety and efficacy in psoriasis of multiple doses Safety and efficacy in psoriasis of multiple doses Completed Studies for AN2728 Demonstrate Safety & Efficacy (cont (cont d) Dosing Trial Design Objectives Subjects b AN2728 PSR , 1, 2% Betnesol-V, Vehicle Safety and efficacy in psoriasis of multiple doses Phase 2a AN2728 PSR 201 5%, Vehicle 4 weeks Safety and efficacy in psoriasis OTPSS scale) 35 Phase 2 AN2728 PSR 202 5%, Vehicle weeks Optimal duration for psoriasis OTPSS scale) 30 Phase 2 AN PSR , 2%, Vehicle QD, wks Dose-ranging Optimal dose and duration for psoriasis OTPSS scale) 145 Phase 2b AN2728 PSR 204 (Pilot Phase 3) 2% Vehicle weeks Whole-body Safety, Efficacy and Duration in Psoriasis PGA scale) 68 Phase 2a AN2728 AD %, Vehicle 6 weeks Safety and efficacy in atopic dermatitis ADSI scale) 46 with Atopic Dermatitis 4 2

3 Phase 2a Initial Human Proof of Concept Study in Atopic Dermatitis Trial Design Multi-center, randomized, double-blind, vehiclecontrolled, bilateral trial 25 adults (18-75 years) with atopic dermatitis 35% BSA applied AN2728 ointment, 2% vs. Ointment vehicle, for 6 weeks Two target lesions ( cm2), each with ADSI 6 and, and erythema 2 Difference in ADSI between target lesions of 1 Outcomes: Atopic Dermatitis Severity Index (ADSI) at 2, 4, 6 weeks (primary endpoint at 4 wks) Sum of scores from 5 clinical features: 0 (none) to 3 (severe) [total 0-15] Erythema, pruritus, exudation, excoriation, lichenification Safety: Reported AE s, vital signs, safety labs 5 AN2728 Met Primary Endpoint in Phase 2a Study in Atopic Dermatitis % of Treated Area with Greater Improvement in ADSI than Vehicle at Day 28 (p=0.02) % Improvement in ADSI at Day 28 (p=0.01) % of Treated Area Achieving Total or Partial Clearance (ADSI 2) by Day 28 (p=0.0027) 68% 66% 39% 52% 20% 16% 6 3

4 AN2728 Reduces the Severity of Signs & Symptoms of Atopic Dermatitis at Day 28 % Improvement in Component Score from Baseline to Day 28 64% 73% 83% 74% 56% 35% 33% 47% 45% 24% (redness) (flaking) (oozing) (skin thickening) (itchiness) 7 Safety Summary from Phase 2a Study of AN2728 in Atopic Dermatitis No Serious Adverse Events (SAEs) or severe adverse events observed No subject discontinued from trial due to an AE AEs occurring at the application site(s) judged to be drug-related were experienced by only 4 subjects 8 4

5 Anacor Has Conducted a Maximal Use Study in Psoriasis with 30% - 80% BSA Treated Maximal Use Systemic Exposure (MUSE) study is required by FDA to calculate therapeutic margins of safety at upper limit of topical exposure Includes: Highest frequency of dosing in the proposed label Use of to-be-marketed formulation Maximum total involved surface area to be treated at one time per label Amount applied per square cm to be documented Method of application/site preparation should be documented Sensitive and validated analytical method to measure active and potential metabolite(s) 9 Results of MUSE Study Indicate High Therapeutic Margins Summary of MUSE results Treatment applied to higher body surface areas produced higher plasma exposure levels, but did not correlate with greater adverse events Local tolerability scores for burning/stinging and pruritus improved substantially and remained stable and low while on treatment; symptoms returned toward baseline levels 6 days following end of treatment No Serious Adverse Events No Early Terminations due to safety concerns Safety margins calculated from MUSE data remain wide compared with prior PK data Based on the MUSE Study Cmax-Based Safety Margin (calculated from the dog acute toxicology study) ~160X AUC-Based Safety Margin (calculated from the rat 3-month toxicology study) ~20X All safety margins were calculated based on mean NOEL or NOAEL values from the toxicology studies and mean PK parameters derived from the clinical studies AUC-based safety margin is not a concern since it is calculated from the 3-month rat study which is based on a NOAEL dose that produced only changes in some hematological parameters which are monitorable in the clinic if needed 10 5

6 AN2728 is Consistently Safe and Well Tolerated AN2728 does not display genotoxic liabilities AN2728 exhibits good safety pharmacology (CV and CNS) profile AN2728 is not a skin sensitizer In vivo toxicology profile for AN2728 establishes toxicity endpoints that can be monitored and are at high systemic doses Acute: Dog acute IV NOAEL* (Cmax) = 27,300 ng/ml Chronic: 3-month Rat NOAEL (AUC) = 15,300 ng.h/ml Thus, AN2728 demonstrates an excellent safety profile for the topical treatment of inflammatory skin disease * NOAEL = No Observed Adverse Effect Level 11 Conclusions AN2728 seems potentially well-suited as a topical therapy for treating atopic dermatitis Efficacy in the range of mid-potency steroids and topical calcineurin inhibitors Demonstrated safety, even when applied to large body surface areas Current development plan for AN2728 in atopic dermatitis Phase 2a: Safety/PK and efficacy in adolescents (-17y) ~40 patients; ; 2% AN2728 x 4 wks Phase 2: Dose-ranging, bilateral in adolescents (-17y) ~80 patients (~40 per treatment arm) 2% AN2728 to one lesion vs. 0.5% to another for 4 wks Two cohorts: QD vs. Phase 2a: Safety/PK and efficacy in children (2-y; US) ~20 patients Thorough QT Trial: Objective: to assess the ECG effects of AN2728 following multiple dose administration relative to vehicle in ~60 healthy adult subjects (M=F) 6