Alnylam Announces Publication of APOLLO Phase 3 Clinical Study Results for Investigational RNAi Therapeutic Patisiran in The New England Journal of Medicine
− In Patients with Hereditary ATTR Amyloidosis, Patisiran Treatment Improved Polyneuropathy and Quality of Life Relative to Placebo −
− Majority of Patients Receiving Patisiran Experienced Improvement in Polyneuropathy and Quality of Life Relative to Baseline −
“The publication of the APOLLO study results in NEJM underscores the
potential for clinical benefit and the encouraging safety profile of
patisiran, and reinforces the strong therapeutic potential of this
investigational medicine for people living with hATTR amyloidosis,” said
“We are extremely pleased with the publication of this landmark manuscript, the first-ever pivotal RNAi clinical trial to be published in a top-tier, peer-reviewed medical journal,” said Akshay Vaishnaw, M.D., Ph.D., President of Research and Development at Alnylam. “Publication of the APOLLO study results in NEJM is a testament to Alnylam's decade-long effort and unwavering commitment to patients with hATTR amyloidosis, and to the goal of advancing an innovative new class of medicines that harnesses the natural RNAi mechanism of action to silence production of disease-causing proteins. Further, publication of these comprehensive efficacy and safety results highlights our commitment to scientific and clinical excellence, and the importance we place on data transparency. This work would not have been possible without all the patients and investigators who participated in APOLLO, and we are deeply indebted to them.”
The APOLLO study publication presents robust evidence for patisiran’s potential to treat a broad constellation of hATTR amyloidosis clinical manifestations and their disabling effects. Relative to placebo, data from APOLLO showed that treatment with patisiran resulted in significant and clinically meaningful improvements in measures of polyneuropathy and quality of life. In addition, compared to baseline and after 18 months of patisiran treatment, improvement was observed in a majority of patients in the primary endpoint, mNIS+7 score (a composite measure of neuropathy), and in the key secondary endpoint, Norfolk QOL-DN (a quality of life questionnaire). The improvement in mNIS+7 was shown to be correlated with degree of TTR knockdown. Significant effects on muscle strength, activities of daily living, ambulation, nutritional status, and autonomic symptoms were also noted in patisiran patients relative to placebo. Moreover, patisiran patients with echocardiographic evidence of cardiac amyloid involvement at study entry demonstrated favorable effects on exploratory endpoints related to cardiac structure and function when compared to placebo.
A lower proportion of patients randomized to patisiran than placebo discontinued treatment (7 versus 38 percent) and discontinued the study (7 versus 29 percent). The incidence and severity of AEs and the frequency of serious AEs (SAEs) and deaths were similar in patisiran- and placebo-treated patients. Compared to placebo, patisiran treatment was associated with fewer treatment discontinuations (5 versus 14 percent) due to AEs. The AEs occurring more frequently with patisiran than placebo were peripheral edema (30 versus 22 percent) and infusion-related reactions (IRRs; 19 versus 9 percent) both of which were generally mild to moderate in severity. IRRs decreased over time and led to study withdrawal in one patient (0.7 percent). No clinically-relevant changes in laboratory values related to patisiran treatment, including platelet counts and liver and kidney function tests, were observed during the study.
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial was a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. The primary endpoint of the study was the change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) relative to placebo at 18 months. Secondary endpoints included: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness (NIS-W); Rasch-built Overall Disability Scale (R-ODS); timed 10-meter walk (10-MWT); modified BMI (mBMI); and the composite autonomic symptom score-31 (COMPASS-31). In addition, exploratory cardiac assessments included measurement of N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels and echocardiography. The trial enrolled 225 hATTR amyloidosis patients in 19 countries with 39 genotypes who were randomized 2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg intravenously once every three weeks for 18 months. All patients who completed the APOLLO Phase 3 study were eligible to screen for the Global OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
Patisiran is an investigational, intravenously administered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of hereditary ATTR amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it is made. This may help to reduce the deposition and facilitate the clearance of TTR amyloid in peripheral tissues and potentially restore function to these tissues. Patisiran is currently under Priority Review as a Breakthrough Therapy with the
About hATTR amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy. The only available treatment options for early stage disease are liver transplantation and, in some countries, tafamidis (approved in
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 major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently 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 (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, and hepatic infectious diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform and deep pipeline of investigational medicines, including four product candidates that are in late-stage development. Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam employs over 800 people in the U.S. and
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam's views with respect to the results from its APOLLO Phase 3 clinical trial for patisiran, the publication of such results, and the potential implications of such results for patients, its expectations concerning the review of patisiran by regulatory authorities in
Patisiran has not been approved by the
Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom, 617-682-4340
(Investors and Media)
Josh Brodsky, 617-551-8276