A version of this story first appeared on our sister site, Practical Cardiology.
Newly announced data from the phase 3 APOLLO-B study (NCT03997383) of patisiran (Onpattro; Alnylam Pharmaceuticals) in patients with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy suggest that the treatment has met both its primary and first secondary end points.1
For the primary end point—change from baseline at month 12 in 6-Minute Walk Test (6MWT)—those treated with patisiran (n = 180) reported significant improvement compared with those randomly assigned to placebo (n = 180; p = .0162). Additionally, significant improvements were reported in quality of life—measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ)—for those on treatment compared with placebo (p = .0397).
In its announcement, Alnylam noted its plans to use data from the study in a supplemental new drug application to be submitted to the FDA later in 2022. The full results from APOLLO-B are planned to be presented during a late-breaking session of the 18th International Symposium on Amyloidosis on September 8, 2022, in Heidelberg, Germany.
“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” Pushkal Garg, MD , chief medical officer, Alnylam, said in a statement.1 “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. 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, multisystem disease.”
For safety, Alnylam noted that the results were “encouraging,” with a similar incidence of adverse events (AEs) reported for the treatment (91.2%) and placebo (94.4%) arms. Serious AEs also displayed similar rates, with 33.7% of those on treatment and 35.4% of those on placebo reporting them. In total, the AEs occurring at a rate of at least 5%, and 3% more frequently than placebo, for those on patisiran were infusion-related reactions (patisiran: 12.2%; placebo: 9%), arthralgia (patisiran: 7.7% placebo: 4.5%), and muscle spasms (patisiran: 6.6%; placebo: 2.2%). No SAEs occurred at least 2% more frequently in patisiran versus placebo-treated patients.
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There were 5 patients (2.8%) treated with patisiran and 8 patients (4.5%) on placebo who died during the study. The number of deaths in the all-cause mortality efficacy analysis was 4 (2.2%) in the treatment arm and 10 (5.6%) in the placebo arm. The study’s predefined statistical analysis plan excluded death due to COVID-19 and treated cardiac transplant as a death event.
“I am delighted by the results of the APOLLO-B study, which suggest the potential for patisiran to be a treatment option for patients with ATTR amyloidosis with cardiomyopathy, assuming favorable regulatory review. In addition, the APOLLO-B data further strengthen our confidence in our phase 3 HELIOS-B study of vutrisiran in ATTR amyloidosis with cardiomyopathy, which is expected to report out in early 2024,” Yvonne Greenstreet, MBChB, chief executive officer, Alnylam, said in a statement.1
Vutisiran (Amvuttra) was approved by the FDA for the treatment of ATTR amyloidosis in June 2022.2 The decision came after the agency first extended its review of the therapy by an additional 3 months, approved based on positive 9-month results from the phase 3 HELIOS-A study (NCT03759379). Results from the study showed that the treatment met the primary end point of change from baseline in the modified Neuropathy Impairment Score (mNIS+7) at 9 months (p <.001). Additionally, vutrisiran achieved statistically significant results (p <.001) on secondary measures such as the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) and timed 10-meter walk test (10-MWT) as compared with historical placebo results.2
As for the study of patisiran, APOLLO-B was a randomized, double-blind, placebo-controlled trial launched in 2019 that included 69 sites in 21 countries. The trial enrolled a total of 360 adult patients randomly assigned 1:1 to receive either 0.3 mg/kg of patisiran or placebo intravenously every 3 weeks over a 12-month treatment period. Protocol required patients to be switched to patisiran for an open-label extension period following the 12-month randomized period.
Other secondary end points included a composite outcome of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-minute walking test score; a composite of all-cause mortality and frequency of all-cause hospitalizations, and urgent heart failure visits in patients not on tafamidis (Vyndamax; Pfizer) at baseline; and a composite of all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in the overall study population.
Patisiran is currently approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults and 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.
Previously, in late 2020, an interim, 12-month analysis was reported from the open-label extension study (NCT02510261) of patisiran, suggesting that the therapy maintains its efficacy and an acceptable safety profile in patients with hereditary ATTR with polyneuropathy. After the 12-month open-label period, those treated with patisiran from the phase 3 APOLLO (NCT01960348) and phase 2 open-label (NCT01961921) parent studies maintained their improvements on the modified Neuropathy Impairment Score +7 (mNIS+7), with mean changes of -4.0 (95% CI, -7.7 to -0.3) and -4.7 (95% CI, – 11.9 to 2.4), respectively. For those who were on placebo in APOLLO that switched in the open-label extension, the mean change from global OLE enrollment was -1.4 (95% CI -6.2 to 3.5).3
1. Alnylam Reports Positive Topline Results from APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy. news release. Alnylam. August 3, 2022. Accessed August 3, 2022. https://www.businesswire.com/news/home/20220803005528/en/Alnylam-Reports-Positive-Topline-Results-from-APOLLO-B-Phase-3-Study -of-Patisiran-in-Patients-with-ATTR-Amyloidosis-with-Cardiomyopathy
2. Alnylam announces FDA approval of Amvuttra (Vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. news release. Alnylam. June 13, 2022. Accessed August 3, 2022. https://investors.alnylam.com/press-release?id=26776
3. Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. 2021;20(1):49-59. doi:10.1016/S1474-4422(20)30368-9