Additional Relevant Details The results demonstrated an absolute mean change from baseline of 69 meters on the six-minute walk test (6MWT) at week 12, the study's primary endpoint (baseline 6MWT ranged from 246 to 412 meters). This magnitude of improvement exceeded historical benchmarks for 6MWT that have served as the basis for recent approvals of other drugs in other rare diseases. ARRY-797 administration also resulted in sustained improvements in N-terminal pro-brain natriuretic peptide (NT-proBNP), functional capacity and cardiac function through 48 weeks in LMNA-related DCM patients. Patients who rolled over to a continuing treatment protocol maintained improvements in the 6MWT and NT-proBNP levels through 72 weeks of treatment. Other secondary endpoints measured including echocardiographic measures of left and right ventricular function and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ), both mirrored the favorable improvements seen with the 6MWT.

In this open label Phase 2 trial, patients were randomized to ARRY-797 100 mg twice daily (n=6) or 400 mg twice daily (n=6). Prior to enrollment, all patients were identified as having stable New York Heart Association class II–IIIa congestive heart failure and eleven patients had an implantable cardioverter defibrillator. All patients were receiving multiple heart failure medications. In addition to the 12-week primary endpoint measure, the study also evaluated secondary endpoints, which mirrored the improvements seen with the 6MWT. A trend for greater improvement in functional capacity and cardiac function were observed with the 400 mg dose level of ARRY-797 compared to the 100 mg dose level. ARRY-797 was well tolerated at both dose levels, with most patients experiencing mild to moderate adverse events, including stomatitis, acne and upper respiratory tract infection. None of the grade 3 / 4 adverse events were considered to be related to ARRY-797 by the investigators. Four patients discontinued the study. One patient discontinued due to availability of a heart for transplant, two patients for interventional cardiovascular procedures and one patient due to grade 2 stomatitis.