CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the pivotal study results from the APOLLO Phase 3 trial of patisiran were published online today in The New England Journal of Medicine (NEJM). The study showed that patisiran improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status, and autonomic symptoms relative to placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis, an inevitably progressive and generally fatal disease. Patisiran treatment also led to favorable effects on exploratory endpoints related to cardiac structure and function in patients with cardiac involvement. Further, the frequency and severity of adverse events (AEs) were similar in patients receiving patisiran and placebo, with the exception of peripheral edema and infusion-related events which were higher in patisiran-treated patients and generally mild to moderate in severity. The full manuscript, titled "Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis," will appear in the July 5, 2018 issue of NEJM.
“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 David Adams M.D., Ph.D., Department of Neurology, Coordinator of the national reference center for Familial Amyloid Polyneuropathy (FAP) and rare neuropathies, Bicêtre Hospital, Greater Paris University Hospitals, AP-HP, Principal Investigator for the APOLLO trial, and lead author of the manuscript. “The positive impact on both neurologic impairment and quality of life in patients treated with patisiran was in marked contrast to the disease progression seen in placebo-treated patients in just 18 months. In fact, we observed improvement in neuropathy manifestations and quality of life in a majority of patisiran-treated patients, with some patients showing evidence of halting or reversal of neuropathy progression during the study, including a transition from assisted to unassisted walking. The broad, international patient population recruited to APOLLO is characteristic of the wide disease spectrum seen in clinical practice, supporting the relevance of the potential beneficial effects of patisiran for patients worldwide afflicted with this progressive and generally fatal disease.”
“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.
About Patisiran
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 U.S. Food and Drug Administration (FDA) and under accelerated
assessment by the European Medicines Agency (EMA) for the treatment of
patients with hATTR amyloidosis. The FDA has set a PDUFA date of August
11, 2018. The safety and efficacy of patisiran have not been evaluated
by the FDA or any other health authority.
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 Europe, and certain countries in Asia and Latin
America, specific indication varies by region). As such, there is a
significant need for novel therapeutics to help treat patients with
hATTR amyloidosis.
About RNAi
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.
About Alnylam Pharmaceuticals
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 Europe and is headquartered in
Cambridge, MA. For more information about our people, science and
pipeline, please visit www.alnylam.com
and engage with us on Twitter at @Alnylam
or on LinkedIn.
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 the United States and Europe, its
expectations regarding the potential for patisiran to improve the lives
of hATTR amyloidosis patients and their families, its plans for the
commercialization of patisiran if approved by regulatory authorities,
and expectations regarding its "Alnylam 2020" guidance for the
advancement and commercialization of RNAi therapeutics, constitute
forward-looking statements for the purposes of the safe harbor
provisions under The Private Securities Litigation Reform Act of 1995.
Actual results and future plans may differ materially from those
indicated by these forward-looking statements as a result of various
important risks, uncertainties and other factors, including, without
limitation, Alnylam's ability to discover and develop novel drug
candidates and delivery approaches, successfully demonstrate the
efficacy and safety of its product candidates, the pre-clinical and
clinical results for its product candidates, which may not be replicated
or continue to occur in other subjects or in additional studies or
otherwise support further development of product candidates for a
specified indication or at all, actions or advice of regulatory
agencies, which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for additional
pre-clinical and/or clinical testing, delays, interruptions or failures
in the manufacture and supply of its product candidates, obtaining,
maintaining and protecting intellectual property, Alnylam's ability to
enforce its intellectual property rights against third parties and
defend its patent portfolio against challenges from third parties,
obtaining and maintaining regulatory approval, pricing and reimbursement
for products, progress in establishing a commercial and ex-United States
infrastructure, competition from others using technology similar to
Alnylam's and others developing products for similar uses, Alnylam's
ability to manage its growth and operating expenses, obtain additional
funding to support its business activities, and establish and maintain
strategic business alliances and new business initiatives, Alnylam's
dependence on third parties for development, manufacture and
distribution of products, the outcome of litigation, the risk of
government investigations, and unexpected expenditures, as well as those
risks more fully discussed in the "Risk Factors" filed with Alnylam's
most recent Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission (SEC) and in other filings that Alnylam makes with
the SEC. In addition, any forward-looking statements represent Alnylam's
views only as of today and should not be relied upon as representing its
views as of any subsequent date. Alnylam explicitly disclaims any
obligation, except to the extent required by law, to update any
forward-looking statements.
Patisiran has not been approved by the FDA, EMA, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of this investigational therapeutic.
