Target: p38 | Indication: LMNA-DCM
Introduction / Brief Description
ARRY-797 is an oral, selective p38 mitogen-activated protein kinase inhibitor. ARRY-797 is being studied In a Phase 2 trial in patients with lamin A/C-related dilated cardiomyopathy (LMNA-related DCM), a rare, degenerative cardiovascular disease caused by mutations in the LMNA gene and characterized by poor prognosis. The trial results were presented at the European Society of Cardiology Congress 2016 in Rome, Italy. 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.
LMNA-related DCM is a rare, degenerative cardiovascular disease caused by genetic mutations in the lamin A/C gene. These mutations lead to loss of functional lamin proteins resulting in activation of the p38 MAPK pathway and leading to structural changes in cardiac tissue such as: alterations to cardiomyocyte and A/V nodal cell nuclei, which leads to apoptosis and cardiac tissue remodeling, and sarcomere reorganization, which affects the heart’s contractile function. LMNA-related DCM is estimated to occur in about 6,000 – 10,000 patients in the US. The number of patients currently identified with a molecular diagnosis is likely to be less than this estimate because of underutilization of genetic testing. Patients with LMNA-related DCM typically begin experiencing symptoms in their twenties or thirties and by age 45, nearly 70 percent of patients have had a heart transplant, have experienced a major cardiac event or have died. By comparison, only 25 percent of DCM patients who do not have LMNA mutations experience similar events by age 45. Currently, there are no disease-specific treatments approved for LMNA-related DCM.
Status: Active, not recruiting
Disease: LMNA-related dilated cardiomyopathy
Trial Information: NCT02057341
ARRY-797 / LMNA DCM
European Society of Cardiology Congress 2016
Phase 2 Study of A797, an Oral, Selective p38 Mitogen-Activated Protein Kinase Inhibitor, in Patients With Lamin A/C–Related Dilated Cardiomyopathy
ARRY-797 / LMNA DCM
Human Molecular Genetics
Abnormal p38 mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation
ARRY-797 / LMNA DCM
Inhibition of Site Specific Phosphorylation of Retinoblastoma Protein by a p38 Inhibitor Decreases Apoptosis, Improves Survival and Prevents Cardiomyopathy Caused by a Mutation in LMNA gene
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