Positive topline results reported from APOLLO-B phase III study of patisiran in patients with ATTR amyloidosis with cardiomyopathy
Alnylam Pharmaceuticals, Inc. announced that the APOLLO-B Phase III study of patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, met the primary endpoint of change from baseline in the 6-Minute Walk Test (6-MWT) at 12 months compared to placebo (p-value 0.0162)
The study also met the first secondary endpoint of change from baseline in quality of life compared to placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) (p-value 0.0397).
The study also included additional secondary composite outcome endpoints to be tested in a hierarchical manner. A non-significant result (p-value 0.0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo. As a result, formal statistical testing was not performed on the final two composite endpoints, which were not powered for statistical significance given the short duration of the study — all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (nominal p-value 0.9888), and in the overall population (nominal p-value 0.5609). Patisiran also demonstrated an encouraging safety and tolerability profile, with deaths numerically favoring the patisiran arm.
APOLLO-B is a Phase III, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month double-blind treatment period. After 12 months, all patients will receive patisiran in an open-label extension period.
The primary endpoint of APOLLO-B is the change from baseline in the 6-MWT at 12 months compared to placebo. The secondary endpoints evaluate the efficacy of patisiran vs. placebo over 12 months in a hierarchical manner with the following measures: Health-related quality of life with the KCCQ change from baseline at 12 months; i. Composite of all-cause mortality, frequency of cardiovascular (CV) events (CV hospitalizations and urgent heart failure (HF) visits) and change from baseline in 6-MWT; ii. Composite of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits in patients not on tafamidis at baseline; and iii. Composite of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits in the overall study population. Exploratory endpoints included cardiac biomarkers and various imaging tools to further characterize the potential burden of cardiac involvement in these patients.
The overall safety profile of patisiran during the 12-month double-blind period was encouraging. i. 5 patients (2.8 percent) on patisiran and 8 patients (4.5 percent) on placebo died. Furthermore, the number of deaths in the all-cause mortality efficacy analysis was 4 (2.2 percent) in the patisiran arm and 10 (5.6 percent) in the placebo arm, determined in accordance with the pre-defined statistical analysis plan, which excluded death due to COVID-19, and treated cardiac transplant as a death event consistent with other studies in the field. ii. The patisiran and placebo arms had similar frequencies of adverse events (AEs) (91.2 percent and 94.4 percent, respectively) and serious adverse events (SAEs) (33.7 percent and 35.4 percent, respectively). AEs reported in greater than or equal to 5 percent of patisiran patients and seen at least 3 percent more frequently with patisiran compared with placebo were infusion-related reactions (12.2 percent vs. 9 percent, respectively), arthralgia (7.7 percent vs. 4.5 percent, respectively), and muscle spasms (6.6 percent vs. 2.2 percent, respectively). No SAEs occurred at least 2 percent more frequently in patisiran versus placebo treated patients.
Full results of the APOLLO-B study will be presented as part of a late-breaker session at the 18th International Symposium on Amyloidosis on September 8, 2022, in Heidelberg, Germany.
Patisiran is the established name for Onpattro, which is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Onpattro is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy.
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