Positive data for cardiac assessments in the APOLLO Phase III study of patisiran. Alnylam.

Alnylam Pharmaceuticals, Inc. announced publication of data from exploratory cardiac assessments in the APOLLO Phase III study of patisiran, an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The results were published online today in the journal Circulation, and showed that patisiran improved markers of cardiomyopathy in patients with hATTR amyloidosis with polyneuropathy.

�Our publication highlights the potential for patisiran to favorably impact certain cardiac manifestations of hATTR amyloidosis,� said Scott D. Solomon M.D., Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, lead author of the paper. �The results on exploratory endpoints of NT-proBNP � an independent predictor of survival in patients with ATTR amyloidosis � and certain echocardiographic measures of cardiac structure and function are encouraging. Together, these data support the therapeutic potential of patisiran in patients with cardiac involvement due to hATTR amyloidosis, where there is a substantially reduced lifespan and limited treatment options.�

The publication presents data on the treatment effects of patisiran relative to placebo on certain measures of cardiac structure and function in patients with echocardiographic evidence of cardiac amyloid involvement at study entry with no confounding medical history (APOLLO cardiac subpopulation: n=126; 56 percent of total study population). In pre-specified analyses, left ventricular (LV) wall thickness was reduced by a mean of 0.9 mm (p=0.017) in patisiran-treated patients, compared to those receiving placebo. Global longitudinal strain was also significantly improved by an absolute value of -1.4 percent (p=0.015), suggesting improved systolic, or contractile, function. Differences in global longitudinal strain of this magnitude have been shown in other studies to be an independent predictor of survival in patients with ATTR and light-chain (AL) amyloidosis. In addition to the favorable impact on echocardiographic measures of cardiac structure and function, a treatment effect on NT-proBNP � a cardiac biomarker released in response to ventricular wall stress � was also observed in the cardiac subpopulation, with a significant 55 percent relative reduction in NT-proBNP levels compared to placebo. This effect was noted as early as 9 months of treatment, the first assessment time point in APOLLO. In post-hoc categorical analyses, a greater proportion of patients treated with patisiran versus placebo experienced reductions in LV wall thickness, decreases in global longitudinal strain and reductions in NT-proBNP relative to baseline, providing evidence for potential improvement in markers of cardiomyopathy.

In the overall study population, the proportions of patients with cardiac cardiac adverse events (AEs) and cardiac serious AEs (SAEs) were similar in the patisiran and placebo groups. The incidence of cardiac arrhythmia AEs was lower in the patisiran group compared with placebo (18.9 versus 28.6 percent). Deaths occurred in 4.7 percent of patients treated with patisiran (3.2 per 100 patient-years) and 7.8 percent of patients treated with placebo (6.2 per 100 patient-years). In a post-hoc analysis, the exposure-adjusted rates of all-cause death and/or hospitalization were 71.8 and 34.7 per 100 patient-years in the placebo and patisiran groups, respectively, representing an approximately 50 percent reduction in event rate. A similar trend was seen for reduction of all-cause death and/or cardiac hospitalizations. As described in U.S. prescribing information for Onpattro(patisiran), four serious adverse reactions of atrioventricular (AV) heart block (2.7 percent) occurred in Onpattro -treated patients, including three cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated patients.

See- "Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An Analysis of the APOLLO Study"- Scott D. Solomon , David Adams , Arnt Kristen , Martha Grogan , et al., Originally published 14 Sep 2018 Circulation. 2018;https://doi.org/10.1161/CIRCULATIONAHA.118.035831.