Alnylam Reports New Results from Investigational RNAi Therapeutic Programs for Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy (hATTR-PN) and Cardiomyopathy (hATTR-CM)
- At 24 Months, Patisiran Shows a Mean 6.7 Point Decrease in Modified Neuropathy Impairment Score (mNIS+7), Comparing Favorably with an Expected Mean 26-30 Point Increase Estimated from Historical Data -
- In New Individual Patient Analysis, Over 70 Percent of Patisiran Patients Show Improvement or No Change in mNIS+7 at 24 Months, Supportive of Therapeutic Hypothesis that Patisiran can Potentially Halt or Improve Neuropathy Progression -
- In APOLLO Phase 3 Study of Patisiran, Baseline Demographics Reveal
Enrollment of a Globally Representative Patient Population with a
- At 12 Months, Revusiran Achieves Generally Stable 6-Minute Walk Distance Results in Majority of Evaluable Patients with hATTR-CM -
- Alnylam also Guides that ENDEAVOUR Phase 3 Study of Revusiran will Complete Enrollment by End of Summer, Ahead of Schedule, with Data Now Expected in Early 2018 -
- Company to Host Conference Call Today,
"We believe that data from these ongoing Phase 2 OLE studies further
support the potential of patisiran and revusiran as innovative
investigational medicines for the treatment of hereditary ATTR
amyloidosis. With patisiran, we believe the mean 6.7 point decrease in
mNIS+7 seen over 24 months is a promising result in light of the rapid
increase in neuropathy impairment scores that would have been
anticipated based on analyses of other historical data sets. Moreover,
we're encouraged to see that individual patient mNIS+7 responses show
evidence for halting of or improvement in neuropathy progression in over
70 percent of patients," said
Patisiran Results Show Potential to Halt or Improve Neuropathy
In the patisiran single-arm Phase 2 OLE study, new results for patients (N=24) who reached the 24-month endpoint as of a data cutoff date of May 12, 2016, showed a mean decrease of 6.7 points from baseline in mNIS+7 after 24 months of treatment. This compares favorably to an estimated mean increase in mNIS+7 of 26 to 30 points at 24 months based upon analyses of historical data sets in untreated hATTR-PN patients with similar baseline neurologic impairment (
In addition, Alnylam also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, the degree of TTR knockdown on Day 17 after the first dose of patisiran was compared to changes in mNIS+7 at 6, 12, 18, and 24 months. There was a positive correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement; the strongest correlations were observed at 6 and 12 months (p less than 0.01), and a trend was observed at 18 and 24 months (p equal to 0.055 and 0.15, respectively). Over 24 months, patients with lesser degrees of initial TTR knockdown also had improvements in mNIS+7, suggesting that there may be an accrual of clinical benefit to even those patients with lesser degrees of TTR knockdown if treated over longer periods of time. Altogether the Company believes these data support the therapeutic hypothesis that reduction of mutant and wild-type TTR with patisiran has the potential to halt or improve neuropathy progression in patients with hATTR-PN.
Patisiran administration was also found to be generally well tolerated in hATTR-PN patients out to 25 months, with no drug-related serious adverse events (SAEs) reported through the data transfer date. The most common drug-related or possibly drug-related adverse events (AEs) were flushing (22.2 percent) and infusion-related reactions (18.5 percent), all of which were mild in severity and did not result in any discontinuations. There were nine reports of SAEs in six patients, all of which were unrelated to study drug, including two deaths as previously reported. There were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelet counts.
APOLLO Phase 3 Study with Patisiran is Largest Controlled Study of
Patients with hATTR-PN to Date and Represents Global Patient Population
Alnylam also presented baseline demographics from the APOLLO Phase 3 study of patisiran. A total of 225 patients with hATTR-PN were enrolled at 44 sites in 19 countries around the world between
12-Month Data with Revusiran Show Generally Stable 6-Minute Walk
Distance Results in Majority of Evaluable Patients with hATTR-CM
"With revusiran, we are pleased to see the robust and durable knockdown of TTR for up to eighteen months, representing our longest human dosing experience with a GalNAc-siRNA conjugate. We're also encouraged to see generally stable 6-minute walk distance results in the majority of evaluable hATTR-CM patients," said
Preliminary results were presented for patients (N=16) who reached the
12-month endpoint as of a data cutoff of
Baseline demographics for patients in the revusiran Phase 2 OLE revealed
a study population with advanced disease, with a mean time from
diagnosis to first dose of 35 months. This compares with a nearly
three-times shorter, 13-month mean time from diagnosis to first dose for
hATTR-CM patients (N=139) enrolled in the ongoing ENDEAVOUR trial to
date. All safety data from the revusiran Phase 2 OLE are through the
data transfer date of
To view all the results presented by Alnylam at the ISA meeting, please visit www.alnylam.com/capella.
Conference Call Information
Alnylam management will discuss these data in a webcast conference call on Friday, July 1 at 8:30 a.m. ET. A slide presentation will also be available on the Investors page of the company's website, www.alnylam.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 36431889. A replay of the call will be available beginning at 10:30 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 36431889.
About the Patisiran Phase 2 OLE Study
The ongoing patisiran OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration in patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN) that were previously enrolled in a Phase 2 study. Patisiran is being administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous infusion. The study is measuring a number of clinical endpoints every six months, including mNIS+7, which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time. The change in the mNIS+7 measurement from baseline to 18 months is the primary endpoint in the Company's APOLLO Phase 3 trial of patisiran in patients with hATTR-PN.
About the Revusiran Phase 2 OLE Study
The ongoing revusiran OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of revusiran administration in TTR cardiac amyloidosis patients that were previously enrolled in a Phase 2 study. Patients receive a fixed subcutaneous dose of 500 mg of revusiran once daily for five days, followed by once-weekly dosing. The study is measuring a number of clinical endpoints every six months, including effects on serum TTR and on mortality, hospitalization, and 6-minute walk distance (6-MWD). The changes in 6-MWD and serum TTR from baseline to 18 months are the co-primary endpoints in the Company's ENDEAVOUR Phase 3 trial of revusiran in patients with hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM).
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in patients with hATTR-PN. The primary endpoint of the study is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31 autonomic symptom score. The trial enrolled 225 hATTR-PN patients that were randomized 2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate was derived from an Alnylam analysis of natural history data from 283 hATTR-PN patients. All patients completing the APOLLO Phase 3 study are eligible to screen for the APOLLO-OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Sanofi Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline in the rest of the world (ROW) through the end of 2019, together with certain broader co-development/co-commercialization rights and global rights for certain products. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW. In the case of revusiran, Alnylam and Sanofi Genzyme will co-develop/co-commercialize the product in
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 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 represents a major unmet medical need with significant morbidity and mortality; hATTR with polyneuropathy (hATTR-PN) - also known as familial amyloidotic polyneuropathy (FAP) - affects approximately 10,000 people worldwide and hATTR with cardiomyopathy (hATTR-CM) - also known as familial amyloidotic cardiomyopathy (FAC) - is estimated to affect at least 40,000 people worldwide. hATTR-PN patients have a life expectancy of 5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, Japan, and certain countries in Latin America). hATTR-CM is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Wild-type amyloidosis (wtATTR) - also called senile systemic amyloidosis (SSA) - is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. There is a significant need for novel therapeutics to treat patients with hATTR.
About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline programs, including programs in clinical development.
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off 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, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Ionis, Novartis, Roche, Takeda, Merck, Monsanto, The Medicines Company, and Sanofi Genzyme. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell,
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 potential for RNAi therapeutics, including patisiran and revusiran, the potential implications of reported results from its ongoing Phase 2 OLE studies of patisiran and revusiran, its expectations regarding the timing of clinical studies and presentation of clinical data, including for the APOLLO Phase 3 trial of patisiran and the ENDEAVOUR Phase 3 trial of revusiran, its expectations regarding its STAr pipeline growth strategy, and its plans regarding 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 may differ materially from those indicated by these forward-looking statements as a result of various important 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 drug 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, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage operating expenses, Alnylam's ability to 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, marketing, sales and distribution of products, the outcome of litigation, 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 to update any forward-looking statements.
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