Abstract 12210: Long-Term Efficacy and Safety of ARRY-371797 (PF-0765803) in an Open-Label Rollover Study in Patients With Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation

Introduction: Dilated cardiomyopathy due to LMNA gene mutations ( LMNA -DCM) accounts for ~6% of DCM cases and is a life-threatening condition with a high unmet need. No disease-specific treatment targeting the underlying mechanism of disease is currently available. ARRY-371797 (PF-0765803), a potent, selective, oral, small-molecule inhibitor of the p38α MAPK pathway, improved exercise capacity (6MWT) in symptomatic LMNA -DCM patients (n=12) in a 48-week, open-label, Phase 2 study. Methods: This was an open-label rollover study of the long-term safety and efficacy of ARRY-371797 in symptomatic LMNA -DCM patients previously participating in the Phase 2 parent study, with eligible patients continuing on the same dose. Safety and efficacy assessments (6MWT, NT-proBNP, and KCCQ) were performed at Weeks 48, 72, 96, 120, and 144 from treatment initiation in the parent study. Results: Eight patients were enrolled (mean [SD] age, 51 [10] years; 4 males). There was a >30 m mean improvement and >10% mean increase in 6MWT distance from parent study baseline up to Week 120 ( Table ), with 3 patients (37.5%) having ≥10% improvement from baseline to Week 144. The decrease in mean NT-proBNP concentration in the parent study was maintained ( Table ). KCCQ Physical Limitation score increased at all visits except Week 48. Changes in KCCQ Clinical Summary and Overall Summary scores were variable. Treatment was generally well tolerated: 3 patients discontinued due to causes not considered treatment-related (UTI and nausea, CRT-D, and LVAD implantation); 2 experienced Grade 1 adverse events considered treatment-related. There were no deaths. Conclusions: ARRY-371797 was generally well tolerated, with evidence suggesting preserved exercise capacity over >2 years’ follow-up. Efficacy and safety of ARRY-371797 is being investigated in the REALM-DCM trial, an ongoing, pivotal, Phase 3, randomized, placebo-controlled study in LMNA -DCM.