Sep 30, 2022 Press Release for Alnylam
Alnylam 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
Sep 30, 2022
– New Data Further Support Potential for Patisiran to be an Effective Treatment for Cardiomyopathy of ATTR Amyloidosis –
– Data from Exploratory Endpoints, Including Cardiac Biomarkers and Imaging, Suggest Favorable Impact of Patisiran on Measures of Cardiac Stress, Injury, Structure, and Function at Month 12 –
– Treatment with Patisiran Demonstrated Generally Consistent Benefit Across Prespecified Patient Subgroups on Functional Capacity as Measured by the 6 Minute Walk Test (6-MWT) and Health Status and Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-OS), Compared to Placebo at Month 12 –
– Patisiran Demonstrated Encouraging Safety and Tolerability Profile in Patients with ATTR Amyloidosis with Cardiomyopathy –
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
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.
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
To view the APOLLO-B data presented at HFSA, please visit Capella.
Investor Webcast Information
Alnylam Management and
About ONPATTRO® (patisiran)
ONPATTRO is an RNAi therapeutic that is approved in
ONPATTRO Indication and Important Safety Information
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 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 (wtATTR) amyloidosis, 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 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.
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