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 Wide Range of Disease Severity and TTR Mutations, Including 54 Percent with Cardiac Involvement, Enabling Assessment of Patisiran Effects on Broad Range of Disease Manifestations -

- 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, Friday, July 1, at 8:30 am ET to Discuss Results -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today preliminary results from its ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, both investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of hereditary TTR-mediated amyloidosis (hATTR amyloidosis). These new clinical data are being presented at the XV International Symposium on Amyloidosis held July 3 - 7, 2016 in Uppsala, Sweden. Data from the patisiran Phase 2 OLE study provided evidence of improvement or no change in the mean neuropathy impairment score (mNIS+7) following 24 months of dosing in hATTR patients with polyneuropathy (hATTR-PN, also known as Familial Amyloidotic Polyneuropathy, or FAP). These results support the therapeutic hypothesis that TTR knockdown with patisiran can potentially halt or improve neuropathy progression in patients with hATTR-PN. The Company also presented baseline demographics from its APOLLO Phase 3 study of patisiran in hATTR-PN patients, showing, among other things, that the majority of patients have evidence of cardiac disease, which should allow the evaluation of patisiran's potential effects on cardiac manifestations of hATTR amyloidosis. In addition, initial 12-month data from the revusiran Phase 2 OLE study continued to show robust and sustained knockdown of serum TTR, and 6-minute walk distance (6-MWD) results were found to be generally stable in the majority of evaluable hATTR patients with cardiomyopathy (hATTR-CM, also known as Familial Amyloidotic Cardiomyopathy, or FAC). Alnylam also announced today that it expects to complete enrollment in the ENDEAVOUR Phase 3 study of revusiran this summer, ahead of schedule, with data readout now expected in early 2018.

"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 Eric Green, Vice President, General Manager, TTR Program. "Accordingly, we look forward to reporting data from the APOLLO Phase 3 trial with patisiran in mid-2017, where, in addition to evaluating the effect on neuropathy progression, we also expect to evaluate patisiran's impact on other aspects of the disease, including cardiac manifestations, given the significant number of patients enrolled in the trial with cardiac involvement."

Patisiran Results Show Potential to Halt or Improve Neuropathy Progression
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 (Adams et al., Neurology, 2015;85:675-682; Berk et al., JAMA, 2013;310:2658-67). Similar results were seen in patients with or without concomitant use of TTR tetramer stabilizers. In a new analysis, over 70 percent of patients showed either improvement or no change in mNIS+7 at 24 months. The maximal improvement achieved was a robust 34.6 point decrease in mNIS+7. In addition, patisiran administration was associated with statistically significant mean improvements in nerve fiber density from sweat gland biopsy samples from both the distal thigh and distal leg (p less than 0.01 for both), as read histologically in a blinded manner by a central lab. Over the 24-month period, hATTR-PN patients with associated cardiac involvement (N=11) showed stability in their cardiac biomarkers, echocardiographic measures, and 10-meter walk test (i.e., gait speed). Serum TTR levels were also measured throughout the OLE study, and showed TTR knockdown of up to 97 percent, a mean maximal knockdown of 93 percent, and a mean knockdown of 84 percent at 24 months.

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 December 2013 and January 2016. Ninety-five patients (42 percent) have the Val30Met TTR mutation, the most prevalent genotype known to be associated with hATTR-PN; the remaining 130 patients (58 percent) span 57 other mutations. In terms of disease severity, 104 patients (46 percent) were FAP Stage 1 at baseline, and 119 (53 percent) patients were Stage 2; only 2 patients (1 percent) were Stage 3. The mean baseline mNIS+7 score was 78.8 (range 8.0 - 165.0). Additionally, baseline mNIS+7 and quality of life (QOL) scores were found to correlate with FAP Stage and polyneuropathy disability (PND) score, underscoring the clinical relevance of specific endpoints in the APOLLO Phase 3 study. A significant number of patients (N=122, 54 percent) had cardiac involvement at baseline. The Company believes this patient subset should allow for a controlled evaluation of effects of patisiran on cardiac parameters, including cardiac biomarkers NT-proBNP and troponin, left ventricular wall thickness, ejection fraction, and 10-meter walk test, all included as secondary or exploratory endpoints in the Phase 3 study protocol. Alnylam expects to report data from the APOLLO trial in mid-2017.

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 Eric Green. "Nevertheless, given the highly advanced patient population in the revusiran Phase 2 OLE study, we continue to believe that further assessment of clinical activity in hATTR-CM will need to await placebo-controlled results from the cardiac subgroup in APOLLO and from ENDEAVOUR. To this end, we are pleased to announce today that we expect to complete enrollment in the ENDEAVOUR Phase 3 study of revusiran later this summer, ahead of schedule, which should position us to report out data from this study in early 2018."

Preliminary results were presented for patients (N=16) who reached the 12-month endpoint as of a data cutoff of May 26, 2016. At 12 months, the majority of hATTR-CM patients evaluable for 6-MWD (5 of 9) showed generally stable results, with a mean change of -14 ± 8 meters in those patients. On average, all evaluable patients with hATTR-CM (N=9) exhibited a mean change of -73 ± 26 meters, and those with wild-type ATTR amyloidosis (wtATTR, also known as Senile Systemic Amyloidosis, or SSA) (N=6) exhibited a mean change of -152 ± 36 meters over 12 months. These results are generally in line with natural history data at 12 months. Finally, repeat dosing with revusiran achieved robust and sustained TTR knockdown out to 18 months, with an up to 98 percent maximal and 88 percent mean maximal knockdown of TTR.

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 May 26, 2016. Fourteen patients (56 percent) in the Phase 2 OLE presented with SAEs. One event, a case of lactic acidosis, was deemed possibly related to study drug. There were a total of seven deaths, all of which were unrelated to study drug. Time from ATTR diagnosis to first dose in the Phase 2 OLE study was found to be significantly correlated with death or disease progression, where patients who died or experienced disease progression (N=8) had a mean time of 48 months compared with patients (N=11) who remained on study who had a mean time of 25 months (p less than 0.05). The majority of AEs were mild or moderate in severity, and included injection site reactions (ISRs) in 12 patients (48 percent); the majority of reported ISRs were mild in severity. Beyond the three cases previously reported, there were no further discontinuations due to ISRs. There were no other notable changes in liver function tests, renal function or hematologic parameters, including platelets.

To view all the results presented by Alnylam at the ISA meeting, please visit

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,, 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.

Sanofi Genzyme Alliance
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 North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW.

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 (ESC)-GalNAc Conjugates
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.

About RNAi
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.

About Alnylam Pharmaceuticals
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, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam's pipeline of investigational RNAi therapeutics, please visit

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.

Alnylam Pharmaceuticals, Inc.
Investors and Media
Christine Regan Lindenboom, 617-682-4340
Josh Brodsky, 617-551-8276

Source: Alnylam Pharmaceuticals, Inc.

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