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Alnylam Reports Positive Results from Ongoing Phase 2 Open-Label Extension (OLE) Studies for Patisiran and Revusiran, in Development for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis)


Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today 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...