Alnylam Reports Positive Topline Results from APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy
– Patisiran Met the Primary Endpoint with a Statistically Significant Improvement in 6-Minute Walk Test Compared to Placebo at 12 Months –
– Patisiran Also Met the First Secondary Endpoint with a Statistically Significant Improvement in Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire, Compared to Placebo at 12 Months –
– Patisiran Demonstrated Encouraging Safety and Tolerability Profile in Patients with ATTR Amyloidosis with Cardiomyopathy –
– Company Plans to File a Supplemental New Drug Application in
– Full Data Will Be Presented at the 18th International Symposium on Amyloidosis –
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.
“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,” said
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 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;
- 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;
- Composite of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits in patients not on tafamidis at baseline; and
- 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.
- 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.
- 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.
“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,” said
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
Patisiran is the established name for ONPATTRO, which is approved in
Conference Call Information
Management will discuss the APOLLO-B topline results via conference call on
A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events. An archived webcast will be available on the Company’s website approximately two hours after the event.
About ATTR Amyloidosis
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. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.
About ONPATTRO® (Patisiran)
ONPATTRO is an RNAi therapeutic that is approved in
ONPATTRO Indication and ISI
ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Important Safety Information
Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).
The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion‑related reactions (19%).
About LNP Technology
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
Alnylam Forward Looking Statements
Various statements in this release concerning
Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population.
(Investors and Media)