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Alnylam Pharma (ALNY) Presents Additional Results from the APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy at Heart Failure Society of America Annual Meeting

September 30, 2022 2:01 PM EDT

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced results from exploratory endpoints and additional analyses of prespecified patient subgroups for the primary and secondary endpoints in the APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy. The results were presented during a moderated poster session at the Heart Failure Society of America’s Annual Scientific Meeting on September 30, 2022. The Company previously announced that the 12-month study achieved its primary endpoint and met its first secondary endpoint at the 18th International Symposium on Amyloidosis in September 2022.

The 12-month findings across a comprehensive set of exploratory endpoints suggest that treatment with patisiran was associated with favorable impacts on key measures of cardiac stress and injury, NT-proBNP and Troponin I, respectively. In addition, favorable impact of patisiran relative to placebo was seen in several echocardiographic parameters and technetium scintigraphy uptake. Results from an analysis of prespecified patient subgroups were also presented, demonstrating generally consistent benefit across subgroups for the primary and secondary endpoints of 6-MWT and KCCQ-OS, respectively. As previously shared, patisiran also demonstrated an encouraging safety and tolerability profile in patients with ATTR amyloidosis with cardiomyopathy.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited,” said Parag Kale, M.D., Staff Cardiologist, Heart Transplant Department at Baylor University Medical Center. “It’s impressive to see that the effects of patisiran on functional capacity and quality of life in the APOLLO-B study were maintained across key patient subgroups, and corroborated by favorable changes in exploratory measures of NT-proBNP and Troponin I, cardiac biomarkers that are often used in clinical practice to assess patients with cardiomyopathy due to ATTR amyloidosis.”

APOLLO-B Study Results

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, health status 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 treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Exploratory Endpoints

At 12 months, the results of the exploratory endpoints presented today are as follows:

  • Results on NT-proBNP, a measure of cardiac stress, favored patisiran compared to placebo.
    • NT-proBNP adjusted geometric mean fold change from baseline at Month 12 was 1.11 for the patisiran group and 1.38 for the placebo group, with an adjusted geometric mean fold change ratio of 0.80 (nominal p equal to 1.825x10-5) in favor of patisiran.
  • Results on Troponin I, a biomarker of myocardial injury, favored patisiran compared to placebo.
    • Troponin I adjusted geometric mean fold change from baseline at Month 12 was 1.13 for the patisiran group and 1.30 for the placebo group, with an adjusted geometric mean fold change ratio of 0.87 (nominal p=0.0011) in favor of patisiran.
  • Results on several exploratory analyses of echocardiographic parameters at Month 12, including global longitudinal strain (p=0.0324), LV mass (p=0.0402), and LV end-diastolic volume (p=0.0508), favored patisiran (all nominal p values) compared to placebo. No significant differences were seen in mean or relative LV wall thickness or cardiac output.
  • Cardiac uptake of technetium on scintigraphy imaging was assessed in a planned cohort of patients, with 37 patients in the patisiran arm and 28 patients in the placebo arm evaluable at Month 12. Among evaluable patients with both baseline and Month 12 results (37 patisiran and 28 placebo), all patients in the patisiran arm (100%) reduced or demonstrated no change in the Perugini grading scale at Month 12 relative to baseline. Of the evaluable patients in the patisiran arm, 37.8% demonstrated a reduction of ≥1 Perugini grade, including 3 (8.1%) patients who reduced by ≥2 Perugini grades at Month 12. No evaluable placebo patients demonstrated a reduction from baseline in Perugini grade at Month 12.

Analyses of Prespecified Patient Subgroups

  • Prespecified patient subgroup analyses were conducted for the primary and first secondary endpoints, evaluating patisiran compared to placebo across baseline tafamidis use, age, ATTR amyloidosis type (hereditary and wild-type), New York Heart Association (NYHA) functional classification, baseline 6-MWT score, NT-proBNP level and region. At Month 12, a generally consistent benefit in 6-MWT and KCCQ-OS was observed with patisiran compared to placebo across the prespecified patient subgroups.
  • Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR of 87% in the full analysis set, 84% for patients receiving tafamidis at baseline and 88% for those not receiving tafamidis at baseline.
  • Composite outcomes secondary endpoints for the study did not achieve statistical significance over 12 months. In the overall population, the hazard ratio (95% CI) for time to first event (all-cause hospitalization, urgent HF visit, or a death event) was 0.839 (0.557, 1.263), directionally favoring patisiran over 12 months; subgroup analyses by baseline tafamidis use showed similar trajectories. In addition, all-cause mortality (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) directionally favored patisiran vs placebo. In the overall population, all-cause deaths were observed in 10 (5.6%) placebo vs 4 (2.2%) patisiran patients, resulting in a hazard ratio of mortality of 0.355 (0.110, 1.138); similar results were observed in subgroups of patients based on use of tafamidis at baseline.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, with 12 months of dosing. The majority of adverse events (AEs) were mild or moderate in severity. Treatment emergent AEs occurring in 5% or more patients in the patisiran group and observed at least 3% more commonly than in the placebo group included infusion-related reactions (12.2% vs 9.0%), arthralgia (7.7% vs 4.5%), and muscle spasms (6.6% vs 2.2%). In the safety analysis there were 5 deaths (2.8%) observed in patisiran-treated patients and 8 deaths (4.5%) observed in the placebo group.

“Data from the APOLLO-B exploratory endpoints, coupled with evidence of a generally consistent benefit across pre-specified patient subgroups in the 6-MWT and KCCQ-OS, reinforce our belief that TTR silencing with patisiran has the potential to address multiple aspects of ATTR amyloidosis, including cardiac manifestations of disease,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead at Alnylam Pharmaceuticals. “We remain steadfast in our commitment to develop impactful RNAi therapeutic options for patients living with all forms of ATTR amyloidosis as evidenced by today’s data and the recent approvals of AMVUTTRA® (vutrisiran) for adult patients with hATTR amyloidosis with polyneuropathy in the U.S., the European Union, and Japan.”

Alnylam plans to submit a supplemental new drug application (sNDA) for patisiran as a potential treatment for patients with ATTR amyloidosis with cardiomyopathy for review by the United States Food and Drug Administration (FDA) in late 2022.

To view the APOLLO-B data presented at HFSA, please visit Capella.

Investor Webcast Information

Alnylam Management and Mat Maurer, M.D., Arnold and Arlene Goldstein Professor of Cardiology at Columbia University, will discuss the APOLLO-B results via webcast on September 30, 2022, at 8:00 p.m. ET. The webcast 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.



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