Tolerability and encouraging clinical activity of SHP-141, a topical skin-restricted HDAC inhibitor, in a phase 1B study in cutaneous t-cell lymphoma Y. H. Kim1, M. S. Krathen1, M. Duvic2, H. Wong3, P. Porcu3, J. Tacastacas4, N. J. Korman4, J. Guitart5, S. B. Landau7, J. E. Bradner6 1. Stanford U, Palo Alto, CA, United States. 2. MD Anderson CC, Houston, TX, United States. 3. Ohio State U, Columbus, OH, United States. 4. UH Case Med Center, Cleveland, OH, United States. 5. Northwestern U, Chicago, IL, United States. 6. Dana Farber Cancer I, Boston, MA, United States. 7. Shape Pharma, Cambridge, MA, United States. Shape Pharmaceuticals provided financial support with a grant from the Leukemia and Lymphoma Society Abstract Methods Results (contd) Results (contd) The efficacy of histone deacetylase inhibitors (HDACi) as systemic therapy in CTCL is well-established, but class-associated toxicities have limited use to advanced or refractory disease. SHP-141 is a novel firstin-class topical HDACi intentionally designed to maximize activity in the skin but limit systemic exposure by rendering the drug inactive via endogenous serum esterases. A phase 1b multi-center, double-blind, placebo (PBO)-controlled, randomized trial in stage IA-IIA CTCL was conducted to assess safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy with SHP-141 applied twice daily for 28 days. Six patients were enrolled (5 SHP-141: 1 PBO) at each dose level (0.1%, 0.5%, 1.0%) in the dose-escalation phase. Of 18 total patients enrolled, the SHP-141 arm had 3 stage IA, 11 IB, 1 IIA; PBO arm had 2 stage IA and 1 IB. No discontinuations, DLTs, or serious adverse events (AEs) were recorded. Most AEs were mild; SHP-141 related AEs were limited to skin without any systemic toxicities. IHC of skin biopsy specimens confirmed evidence of a dose dependent augmented HDACi activity using a specific acetyl–lysine antibody. PK results confirmed lack of SHP-141 exposure in peripheral blood supporting the higher exposures. Notably, 4 of 15 patients randomized to SHP-141 attained an objective response (> 50% improvement by CAILS) and 6 had weekly incremental CAILS improvement over 28 days; neither feature was observed in the PBO arm. This initial clinical study of a skin-optimized topical HDACi demonstrates excellent tolerability and encouraging early clinical efficacy, even with dosing limited to 28 days. SHP-141 may address an important unmet medical need in early stage CTCL by providing a topical HDACi devoid of systemic toxicities. Study Design • This is a randomized, double-blind, placebo-controlled, dose-escalating, multi-center study. • Patients were randomized on a 5:1 basis to receive either SHP-141 or the placebo. • A Data Safety Monitoring Board reviewed safety data for each cohort to confirm sufficient safety of that dose. • Patients were treated to maximum of 5% BSA. • Serial evaluations of skin lesions were conducted to determine potential pharmacodynamic effects and evaluate histological and clinical effects. Each patient was evaluated on Days 1, 7, 14, 21 and 28 of treatment and at the final study visit at Day 42. Safety • No Patients with Dose Limiting Toxicities • No Serious Adverse Events or Discontinuations • All adverse events were mild or moderate; only skin related events were considered “possibly related” to SHP-141 COMPOSITE ASSESSMENT OF INDEX LESION SEVERITY(CAILS)1 • Has been applied in Mycosis Fungoides clinical studies • Four Parameters are measured: Introduction • • • CTCL is a rare, life-altering form of Non-Hodgkins Lymphoma where therapeutic options for patients with advanced disease have expanded; however systemic toxicity has limited options for early stage patients Current treatment for early stage treatments have slow onset of action, poor symptomatic relief and some may not be used over large body surface areas because of local toxicity SHP-141 is a HDACi that inhibits isoforms1,2,3 and 6. SHP-141 is a soft drug that is active in skin and breaks down to inactive metabolites Key Inclusion Criteria: • 18 years of age or older with histopathologically confirmed MF; a documented verifiable biopsy report required. • Documented clinical stage IA, IB, or IIA MF. • Skin lesion involvement of at least 3% of BSA • ECOG performance status of 0-2. Key Exclusion Criteria: • Histologic evidence of folliculotropic variant or large cell transformed MF. • Severe pruritus requiring systemic or topical treatment. • Prior Treatment within the specified timeframes: • • • • • • Table: Adverse events possibly or definitely related to SHP-141 All targeted treated areas were evaluated and summed for Parameters Percent reduction based on change at specific time-point from baseline Particular interest at Day 28 (last treatment visit) and Day 42 (follow-up) PR is defined as >50 % and CR is 100% reduction from baseline to endpoint Stage IB IB IB IB IB Lysine Staining (Pharmacodynamic),Photography and PK • At baseline, Day 14 (4h post) and Day 28 (random), skin sections were formalin-fixed, paraffin embedded, and stained for acetylated chromatin (Rabbit polyclonal acetyllysine antibody). Staining completed at BWH Pathology • • Brown staining is consistent with augmented acetylation Prominent staining in the 1.0% dosing group (3/5 patients) Stage IA IB IA IA IIA Stage IB IB IB IB IB Stage IB IA IA • No SHP141 systemic exposure (not shown) Table: All patients by Dosing Cohort; placebos separated A Table: Summary of CAILS responses across all groups; • Four SHP-141 patients had “PR”: 003-001,001-004,005-001,002-002 • Two SHP-141 patients were “close” at Day 42: 006-001 (46%), 006-004 (41%) • No placebo patient had a PR Results Discussion-Conclusions B • Majority of Patients were IB for active; IA for placebo • All active Stage IA patients were in 0.5% group • • • • Scaling, Erythema and Plaque Elevation each scored 0-8 Index Lesion Area measured and scored from 0-18 1 Olsen et al, J Clin Oncol. 2011; 29(18): 2598–2607. Any histone deacetylase inhibitors within 4 weeks. Steroids or chemotherapy within 4 weeks (eg retinoids). Nitrosoureas, mitomycin C or 7-hydroxystaurosporine at any time. Phototherapy (i.e., PUVA or UVB) within 4 weeks. Radiation or electron beam therapy within 3 months; local radiation treatment of non-study lesions is allowed. Topical treatment, including retinoids, carmustine, corticosteroids or nitrogen mustard, within 4 weeks. Table: Selected Demographics • • Figure: Example of (A)Augmented Lysine Staining and (B) Photograph of treated area (biopsies taken from this site) • SHP-141 demonstrates excellent tolerability through 28days of dosing • SHP-141 has promising early efficacy even with dosing limited to 28 days. Clinical response was maintained in some patient at 2-weeks post dosing • SHP-141 has evidence for local HDACi activity using a novel skin-based IHC assay • At Day 42 40% (6/15) were PRs or trending towards a PR. • Further studies with larger BSA and longer term dosing are justified.