Full Press Release Details
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| Alnylam Pharmaceuticals, Inc. | ||
| Christine Regan Lindenboom | ||
| (Investors and Media) | ||
| +1-617-682-4340 |
Alnylam Announces Receipt of Complete Response Letter from U.S. FDA for
Supplemental New Drug Application for Patisiran for the Treatment of the
Cardiomyopathy of ATTR Amyloidosis
FDA Cites Insufficient Evidence of Clinical Meaningfulness
No Clinical Safety, Study Conduct, Drug Quality or Manufacturing Issues Identified
CRL Does Not Pertain to, nor Impact Commercial Availability of, ONPATTRO
(patisiran) for Existing Indication for the Treatment of the Polyneuropathy of Hereditary ATTR Amyloidosis in Adults
Alnylam to Host Investor Conference Call Today, Monday, October 9, 2023
CAMBRIDGE, Mass. October 9, 2023 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today
announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) in response to the Company s supplemental New Drug Application (sNDA) for patisiran for the treatment of the cardiomyopathy of
transthyretin-mediated (ATTR) amyloidosis.
Patisiran is the established name for ONPATTRO ,
which is approved by the FDA for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults. The CRL does not pertain to, nor does it impact commercial availability of, ONPATTRO for this existing indication.
The CRL indicated that the clinical meaningfulness of patisiran s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established,
and therefore, the sNDA for patisiran could not be approved in its present form. The CRL did not identify any issues with respect to clinical safety, study conduct, drug quality or manufacturing.
As a result of the CRL, the Company will no longer pursue an expanded indication for patisiran in the U.S. The Company remains dedicated to the ATTR
amyloidosis community and will continue to focus on the HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi
therapeutic subcutaneously administered once every three months in development for the treatment of the cardiomyopathy of ATTR amyloidosis, and
ALN-TTRsc04, which utilizes the Company s IKARIA technology, with the potential for greater than 90% TTR knockdown with once annual dosing.
First and foremost, our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating
and fatal disease and face significant unmet need. While we are disappointed by this decision, we are committed to supporting them and are well positioned to address their needs with continued innovation that can potentially help improve their
outcomes and treatment experience, said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam Pharmaceuticals. We remain confident in the HELIOS-B Phase 3 study of vutrisiran and look
forward to sharing topline results in early 2024. If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits. Beyond vutrisiran,
we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen.
The sNDA for patisiran was supported by positive results from the APOLLO-B Phase 3 study. In APOLLO-B, patisiran met the primary endpoint as well as the first secondary endpoint at Month 12, demonstrating a significant difference compared to placebo in 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 Overall Summary
(KCCQ-OS) score, respectively.
New results from an interim analysis of the ongoing open-label extension
(OLE) period of the APOLLO-B Phase 3 study were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting (ASM) 2023, which demonstrate the sustained treatment effect of patisiran on
functional status, health status and quality of life and cardiac biomarkers over 24 months. These findings reinforce the long-term treatment effect of TTR silencing by an RNAi therapeutic in patients with ATTR amyloidosis and provide strong support
for the Company s continued evaluation of vutrisiran and ALN-TTRsc04.
As previously announced, the
FDA s Cardiovascular and Renal Drugs Advisory Committee met on September 13, 2023 to discuss the sNDA for patisiran and voted 9:3 that the benefits of patisiran outweigh its risks for the treatment of the cardiomyopathy of ATTR
The Company intends to maintain availability of patisiran for patients with the cardiomyopathy of ATTR amyloidosis who are enrolled in the
OLE period of the APOLLO-B Phase 3 study and patisiran U.S. expanded access protocol (EAP).
Alnylam management will discuss the CRL via conference call on Monday, October 9, 2023 at 8:30 a.m. ET. To access the call, please
register online at https://register.vevent.com/register/BI8567d631e94e4c1eaa8da3a1ae2fcf69. Participants are requested to register a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after
the call and archived on the same webpage for six months.
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.
ONPATTRO (patisiran) 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
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
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%).
For additional information
about ONPATTRO, please see the full U.S. Prescribing Information.
ONPATTRO (patisiran)
ONPATTRO is an RNAi therapeutic that is approved in the United
States and Canada for the treatment of the polyneuropathy of hereditary ATTR (hATTR) amyloidosis in adults.
ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of
hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is
made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.
About ATTR Amyloidosis
Transthyretin-mediated (ATTR) amyloidosis is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR)
proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different
forms of ATTR amyloidosis hereditary ATTR (hATTR) amyloidosis, which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant and
impacts an estimated 200,000 300,000 people worldwide.
About the APOLLO-B Phase 3 Study
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 treatment period. After 12 months, all patients received
patisiran in a 36-month open-label extension period.
Alnylam s IKARIA platform takes advantage of more than two decades of
experience in developing RNAi therapeutics. IKARIA enables an extended duration of activity in preclinical studies, with potential for annual dosing in humans, and has design features which provide exquisite specificity, further widening the
potential therapeutic index, with enhanced target reduction levels.
About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using 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 potently silencing messenger RNA (mRNA) the genetic
precursors that encode for disease-causing or disease pathway 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 Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding
transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam s commercial RNAi therapeutic products are ONPATTRO (patisiran), AMVUTTRA (vutrisiran), GIVLAARI (givosiran), OXLUMO (lumasiran), and Leqvio (inclisiran), which is being developed and commercialized by Alnylam s partner, Novartis. Alnylam has a deep
pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its Alnylam P5x25 strategy
to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in
Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or
Alnylam Forward Looking Statements
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the
Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam s aspiration to
become a leading biotech company and the planned achievement of its Alnylam P5x25 strategy, the potential for Alnylam to identify new potential drug development
candidates and advance its research and development programs, Alnylam s ability to obtain approval for new commercial products or additional indications for its existing products, Alnylam s projected commercial and financial performance,
should be considered forward-looking statements. 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: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam s business, results of operations and financial condition; Alnylam s ability to