Alnylam and Sanofi Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR (hATTR) Amyloidosis Patients with Polyneuropathy
- Investigational RNAi Therapeutic Patisiran Meets Primary and All Secondary Endpoints, with Highly Significant Reduction In Neuropathy Progression and Improvement in Quality of Life at 18 Months Relative to Placebo -
- Alnylam Intends to File New Drug Application (NDA) in Late 2017 and Marketing Authorisation Application (MAA) in Early 2018 -
- Full Results to be Presented at 1st European ATTR Amyloidosis Meeting in November -
- Alnylam to Host Conference Call Today at
"We are very proud to report the first ever positive Phase 3 results for
an RNAi therapeutic, marking the potential arrival of an entirely new
class of medicines. This moment is the culmination of a 15-year journey
of tireless work by countless contributors who have overcome enormous
scientific and business challenges to make RNAi therapeutics a reality,"
The APOLLO trial enrolled 225 hATTR amyloidosis patients with polyneuropathy, representing 39 genotypes, at 44 study sites in 19 countries around the world. Patients were randomized 2:1 to patisiran or placebo, with patisiran administered intravenously at 0.3 mg/kg once every three weeks for 18 months. For both the mNIS+7 and Norfolk QOL-DN endpoint measures provided below, a lower score indicates a better clinical result.
At 18 months, the mean change from baseline in mNIS+7 was
significantly lower in the patisiran group as compared with placebo (p
less than 0.00001).
- The mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline.
Patients in the patisiran group experienced improvement in quality of
life compared to placebo, as assessed by the Norfolk Quality of Life
Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) (p less than
- The mean and median changes in QOL scores for patisiran also both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline.
All 5 other secondary endpoints also demonstrated statistically
significant favorable differences in the patisiran arm compared to
placebo (p less than 0.001). These were:
- NIS-W, the subdomain of mNIS+7 assessing muscle strength;
- Rasch-built Overall Disability Scale (R-ODS), a patient reported outcome measure of daily living and disability;
- 10-meter walk test, assessing gait speed;
- Modified body mass index (mBMI), assessing nutritional status; and
- COMPASS-31, a questionnaire to assess autonomic symptoms.
The overall safety profile of patisiran was encouraging.
- The patisiran and placebo arms had similar frequencies of adverse events (AEs) (96.6 percent and 97.4 percent, respectively) and serious adverse events (SAEs) (36.5 percent and 40.3 percent, respectively).
- The frequency of deaths in the study was similar in the patisiran (4.7 percent) and placebo (7.8 percent) arms.
- Patisiran treatment was associated with fewer discontinuations from treatment compared with placebo (7.4 percent and 37.7 percent, respectively) and discontinuations from treatment due to AEs (4.7 percent and 14.3 percent, respectively).
- AEs reported in greater than 10 percent of patients and seen more frequently with patisiran compared with placebo were peripheral edema (29.7 percent vs. 22.1 percent, respectively) and infusion-related reactions (18.9 percent vs. 9.1 percent, respectively), both of which were generally mild-to-moderate in severity.
"Patients living with hATTR amyloidosis face an inevitable and painful
advancement of their debilitating disease," said
Based on these positive results, Alnylam expects to file its first New
Drug Application in late 2017 and first Marketing Authorisation
Application shortly thereafter. Sanofi Genzyme is currently preparing
for regulatory filings for patisiran in
"This is a significant milestone that supports our belief that RNAi
therapeutics have the potential to become an innovative new class of
medicines for patients with rare genetic diseases," said
Full results, including data from an exploratory analysis of the
subgroup of patients with cardiac involvement, will be presented at the 1st
European ATTR Amyloidosis Meeting for Patients and Doctors, on
APOLLO is the largest randomized study ever completed in this disease. Nearly all eligible patients who completed APOLLO have rolled over to the APOLLO-Open Label Extension (OLE) study and continue to receive patisiran.
Conference Call Details
Alnylam management will discuss these results via conference call on
About the APOLLO Phase 3 Study
The APOLLO Phase 3 study is 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 efficacy endpoint was change from baseline in the mNIS+7
composite neuropathy impairment score at 18 months. Modified
Patisiran is an investigational medicine that uses the body's natural
processes to lower the levels of the TTR protein that causes TTR
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 enable the clearance of TTR amyloid deposits in
peripheral tissues and potentially restore function to these tissues.
The safety and efficacy of patisiran have not been evaluated by the
About hATTR amyloidosis
Hereditary transthyretin (TTR)-mediated (hATTR) amyloidosis is an
inherited, progressively debilitating, and often fatal disease caused by
mutations in the TTR gene. TTR protein is produced primarily in the
liver and is normally a carrier of vitamin A. Mutations in TTR 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. hATTR amyloidosis represents a major unmet medical need
with significant morbidity and mortality, affecting approximately 50,000
people worldwide. hATTR amyloidosis patients have a life expectancy of
2.5 to 15 years from symptom onset, and the only approved treatment
options are liver transplantation for early stage disease and tafamidis
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 revolution in biology, representing a breakthrough in understanding protein synthesis in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of 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, target the cause of diseases by potently silencing specific mRNAs, with the goal of preventing disease-causing proteins from being made.
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 patients who have limited or inadequate treatment options. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of 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 three product candidates that are in late-stage development or will be in 2017. 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. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam.
Sanofi Genzyme focuses on developing specialty treatments for debilitating diseases that are often difficult to diagnose and treat, providing hope to patients and their families. Learn more at www.sanofigenzyme.com.
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 topline results from its APOLLO
Phase 3 clinical trial for patisiran, its plans for and the expected
timing of regulatory filings seeking approval for patisiran from
regulatory authorities in
Patisiran has not been approved by the U.S. Food and Drug Administration, European Medicines Agency, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of this investigational therapeutic.
Sanofi Forward Looking Statements
This press release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, as amended.
Forward-looking statements are statements that are not historical facts.
These statements include projections and estimates regarding the
clinical development of and potential marketing approvals for the
product. Forward-looking statements are generally identified by the
words "expects", "anticipates", "believes", "intends", "estimates",
"plans", "would be" and similar expressions. Although Sanofi's
management believes that the expectations reflected in such
forward-looking statements are reasonable, investors are cautioned that
forward-looking information and statements are subject to various risks
and uncertainties, many of which are difficult to predict and generally
beyond the control of
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