Alnylam presents positive ongoing phase 2 open-label extension data for Patisiran and Revusiran

Alnylam Pharmaceuticals, Inc. has announced new results from its ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis).

These new clinical data were presented at the 1st European Congress on Hereditary ATTR amyloidosis (EC-ATTR) held November 2 - 3, 2015 in Paris. Data from the patisiran Phase 2 OLE study provided continued evidence following 18 months of dosing that patisiran has the potential to halt neuropathy progression in patients with Familial Amyloidotic Polyneuropathy (FAP). The company is announcing today that it expects to complete enrollment in the APOLLO Phase 3 trial of patisiran over the next three to four months, supporting a potential New Drug Application (NDA) filing in 2017 if the study is positive. In addition, initial data from the revusiran Phase 2 OLE study showed robust and sustained knockdown of serum TTR, and was found to be generally well tolerated in the majority of patients with TTR cardiac amyloidosis - including patients with Familial Amyloidotic Cardiomyopathy (FAC) and Senile Systemic Amyloidosis (SSA) - out to 10 months of treatment.

"We believe that data from these ongoing Phase 2 OLE studies further support the potential of RNAi therapeutics targeting TTR as innovative investigational medicines for the treatment of ATTR amyloidosis," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "We are encouraged by the clinical profile demonstrated to date with these programs, and their potential to offer treatment alternatives for patients suffering from this rare and devastating disease."

"Few treatment options exist for patients suffering from ATTR amyloidosis. With patisiran, new data supporting the possibility of halting neuropathic progression over 18 months of treatment is promising in light of the rapid increase in neuropathy impairment scores observed in analysis of other historical data sets. Indeed, the progressive neuropathy associated with FAP leads to the inexorable loss in ambulation - amongst other neurological deficits - with patients becoming dependent on a cane or wheelchair as their disease advances," said Philip N. Hawkins, Ph.D., FRCP, FRCPath, FMedSci, Professor of Medicine and Head of the National Amyloidosis Centre, University College London Medical School. "In addition, while in a small number of patients at an early time point, the initial revusiran OLE data are encouraging, and I look forward to seeing future data from this ongoing clinical trial. ATTR cardiac amyloidosis represents a significant unmet medical need for which there is no approved therapy. Overall, I am hopeful that RNAi therapeutics that stop production of the disease-causing TTR protein have the potential to halt progression in patients with ATTR amyloidosis and provide an important treatment option for management of this disease."

Patisiran Results Show Continued Evidence for Potential Halting of Neuropathy Progression and Mark First-Ever Evidence for Positive Effect on Nerve Regeneration

New results for patients (N=20) who reached the 18-month endpoint as of a data cut off of September 22, 2015, showed that neuropathy impairment scores were essentially unchanged from baseline values after 18 months of treatment. Specifically, there was a mean increase in mNIS+7 of only 1.7 points, which compares favorably to an estimated increase in mNIS+7 of 22 to 26 points at 18 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics (Adams et al., Neurology, 2015;85:675-682; Berk et al., JAMA, 2013;310:2658-67; Tafamidis European Medicines Agency Assessment Report, 2011). At 18 months, patisiran administration was associated with a statistically significant and clinically meaningful mean 4.9 m/mm3 increase from baseline in sweat gland nerve fiber density from distal thigh skin biopsy samples (p less than 0.001) as read histologically by a central lab in a masked manner. Serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown of up to 96% and a mean maximal knockdown of 93% for over 21 months.

"With patisiran, we are pleased to see continued evidence for potential halting of neuropathy progression after 18 months of treatment in the ongoing OLE study. Indeed, we believe that the small 1.7-point increase in mNIS+7 is encouraging, since mNIS+7 measured at 18 months is the primary endpoint in our ongoing APOLLO Phase 3 trial with patisiran," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "Moreover, we're pleased to see a meaningful improvement in nerve fiber density, providing the first-ever evidence that TTR knockdown by patisiran can potentially have a positive effect on aspects of nerve regeneration."

"The increase in skin sweat gland nerve fiber density observed over 18 months in FAP patients treated with patisiran is an important finding, as it is the first reported demonstration of potential peripheral nerve regeneration in response to a therapeutic intervention in patients with polyneuropathy. The potential clinical significance of this finding is further underscored by a recent publication1 showing that a lower sweat gland nerve fiber density in FAP patients is associated with a greater degree of walking disability at the time of skin biopsy and shorter time to loss of ambulation," said Michael Polydefkis, M.D., Director, Cutaneous Nerve Lab, Professor of Neurology, Johns Hopkins Medical Center.

Patisiran administration was also found to be generally well tolerated in FAP patients out to nearly two years, with minimal drug-related adverse events reported. The most common drug-related or possibly drug-related adverse events were flushing (25.9%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations.

Sustained and Clamped TTR Knockdown out to 10 Months in Revusiran OLE Study Represents Longest Dosing Experience for a GalNAc-siRNA Conjugate Reported to Date

Initial results were presented for patients (N=18) who reached the 6-month endpoint as of a data transfer date of October 12, 2015. Repeat dosing with revusiran achieved robust and sustained TTR knockdown over the 6-month period, with an up to 98% maximal and 87% mean maximum knockdown of TTR. For patients with an evaluable 6-minute walk distance (6-MWD) measurement at 6 months (N=15), the majority exhibited stable performance compared to baseline. On average, evaluable patients with FAC (N=8) exhibited a mean decline of 20 ± 14 meters and those with SSA (N=7) exhibited a mean decline of 24 ± 20 meters over 6 months.

"We are pleased to report initial data from our Phase 2 OLE trial with revusiran, showing robust and sustained knockdown of serum TTR and a favorable tolerability profile in the majority of patients with TTR cardiomyopathy out to 10 months of treatment. Notably, the sustained and clamped TTR knockdown observed represents the longest dosing experience for a GalNAc-siRNA conjugate reported to date," said Dr. Vaishnaw. "Moreover, while early in this study and in a relatively small patient population, we're encouraged that the majority of evaluable patients at 6 months have stable 6-MWD and no clinically meaningful changes in other cardiac measures. We look forward to additional data from the ongoing revusiran Phase 2 OLE study, and plan to report data from the trial at least once a year hereafter."

Weekly dosing with revusiran appeared to be generally well tolerated in the majority of ATTR cardiac amyloidosis patients. Serious adverse events (SAEs) were observed in eight patients (32%), including one death due to infiltrative cardiomyopathy; none of the SAEs were deemed to be related to study drug. The majority of the adverse events (AEs) were mild or moderate in severity; injection site reactions (ISRs) were reported in 11 patients (44%). As previously reported, three patients discontinued due to recurrent localized reactions at the injection site or a diffuse rash; no further discontinuations due to ISRs have occurred.

Also at the meeting, Alnylam and collaborators presented initial results from the DISCOVERY study, a prospective, multi-center, observational study aimed at characterizing the frequency of TTR mutations in subjects with clinical features suggestive of cardiac amyloidosis. In over 600 patients suspected of having cardiac amyloidosis, TTR mutations were found in approximately 14% of patients. The primary pathogenic mutation was V122I (7% of total patients tested), with four other pathogenic mutations identified. Interestingly, two new, previously unreported TTR mutations were discovered. In addition, Alnylam and collaborators presented results from a natural history study of patients with Senile Systemic Amyloidosis (SSA), a form of cardiac amyloidosis caused by deposition of wild-type TTR in the heart.

Conference Call Information

Alnylam management will discuss these data in a webcast conference call on Tuesday, November 3 at 7:00 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 70778772. A replay of the call will be available beginning at 9:00 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 70778772.

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 FAP patients 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 Phase 3 APOLLO trial of patisiran in FAP patients.

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 (6MWD). The changes in 6MWD and serum TTR from baseline to 18 months are the co-primary endpoints in the company's ENDEAVOUR Phase 3 trial of revusiran in FAC patients.

Genzyme Alliance

In January 2014, Alnylam and Genzyme, a Sanofi company, 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 Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline in the rest of the world (ROW), including co-development/co-commercialization and/or global product rights for certain programs. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Genzyme will advance the product in the ROW. In the case of revusiran, Alnylam and Genzyme will co-develop/co-commercialize the product in North America and Western Europe, while Genzyme will advance the product in the ROW.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR 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. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) is estimated to affect at least 40,000 people worldwide. FAP 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). FAC is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. 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 TTR amyloid polyneuropathy and/or cardiomyopathy.

About LNP Technology

Alnylam has licenses to Tekmira 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 Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. 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 Pharmaceuticals, Inc.


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