Alnylam Reports Positive Topline Results from Phase 3 Study of Patisiran in ATTR-CM

Alnylam Pharmaceuticals reported positive results from its APOLLO-B phase 3 study that showed its experimental RNAi therapy patisiran met the primary endpoint and first secondary endpoint in the study in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy.

Photo: Pushkal Garg, chief medical officer of Alnylam

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR amyloidosis (wtATTR), which occurs without a TTR gene variant.

Patisiran, which is marketed as Onpattro, is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. It is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It 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.

APOLLO-B is a phase 3, 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 to receive 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.

“ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. These patients have limited treatment options, and disease progression is common,” said Pushkal Garg, chief medical officer of Alnylam. “As such, we are encouraged to see the potential of patisiran to improve the functional capacity and quality of life of patients living with this fatal, multi-system disease.”

He said the study results validate Alnylam’s approach to treat the condition with an RNAi therapeutic to silence TTR.

The study met its primary endpoint of change from baseline in the 6-Minute Walk Test (6-MWT) at 12 months compared to placebo. 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).

The study also included additional secondary composite outcome endpoints to be tested in a hierarchical manner. A non-significant result 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, and in the overall population. Patisiran also demonstrated an encouraging safety and tolerability profile, with deaths numerically favoring the patisiran arm.

The company said the overall safety profile of patisiran during the 12-month double-blind period was encouraging. Five patients (2.8 percent) on patisiran and 8 patients (4.5 percent) on placebo died. 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.

The patisiran and placebo arms had similar frequencies of adverse events (AEs) (91.2 percent in the patisiran arm and 94.4 percent in the placebo arm) and serious adverse events (SAEs) (33.7 percent in the patisiran arm and 35.4 percent in the placebo arm).

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.

Author: Rare Daily Staff