Date: 2016-08-30
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the European Society of Cardiology Congress
Company: Array BioPharma (USA - CO)
Product: ARRY-797
Action
mechanism: p38 mitogen-activated protein kinase inhibitor. ARRY-797 is an oral, p38 mitogen activated protein kinase (MAPK) inhibitor discovered by Array scientists. Compared to other p38 MAPK inhibitors ARRY-797 has unique and differentiated properties: it is highly selective, retains exceptional potency in whole blood and possesses a favorable pharmacokinetic profile.
Disease: lamin A/C-related dilated cardiomyopathy
Therapeutic area: Cardiovascular diseases - Rare diseases
Country:
Trial details:
Latest
news: * On August 30, 2016, Array BioPharma announced results from a Phase 2 study of ARRY-797, an oral, selective p38 mitogen-activated protein kinase inhibitor, 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. The chart shows that the improvements on the 6MWT were sustained over time with ARRY-797 treatment. Taken together, the data to date suggest a path forward for this program, and Array has met with regulators to discuss the design of a study that could be the basis for marketing approval. Array is evaluating different options to advance the ARRY-797 program, including advancing it on its own, partnering the program for further development and commercialization or creating a separate company based on this asset. The Phase 2 trial results demonstrated an absolute change from baseline of 69 meters on the 6MWT at week 12, the study's primary endpoint in 12 patients receiving 400 mg or 100 mg of ARRY-797. These results exceed historical benchmarks set by drugs for other rare diseases, including pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension and mucopolysaccharidoses, trials for which also used the 6MWT as a primary endpoint. Secondary endpoints assessed at weeks 4, 12, 24, 26 and 48 included changes from baseline in 6MWT over time, changes from baseline in levels of NT-proBNP, echocardiographic measures of left and right ventricular function, and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ), all of which mirrored the favorable improvements seen with the 6MWT. ARRY-797 was generally well tolerated, and adverse events for most patients were mild to moderate, including stomatitis, acne and upper respiratory tract infection.
