Alnylam announces clinical data from patisiran Phase 2 OLE study for treatment of patients with FAP

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today initial 12-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) in patients with familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented at the 67th Annual Meeting of the American Academy of Neurology (AAN) being held April 18 - 25 in Washington, D.C. Study results showed a mean 2.5 point decrease in modified Neuropathy Impairment Score (mNIS+7) at 12 months in patients who had reached the 12-month endpoint (N=20) at the time of data cutoff. This decrease in neuropathy progression compares favorably to the 13 to 18 point increase in mNIS+7 at 12 months that can be estimated from the literature in untreated FAP patients with similar baseline characteristics. In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for approximately 16 months, with an up to 88% mean knockdown achieved between doses. In aggregate, these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. Patisiran was also found to be generally well tolerated out to 17 months of drug administration, with no drug-related serious adverse events to date; all 27 patients enrolled in the study continue to receive patisiran. Alnylam has also announced today that it plans to report 18-month OLE data in late 2015.

"In this ongoing open-label study with patisiran, we are very encouraged to see what we believe to be continued evidence for possible halting of neuropathy progression after the first 12 months of treatment. Indeed, we believe the 2.5-point mean decrease in the modified neuropathy impairment score is a promising result in light of analysis of multiple historical data sets that would have predicted an increase of 13 to 18 points for untreated FAP patients with similar baseline characteristics. It will be of great interest to see how these data mature going forward, and we now look forward to sharing 18-month clinical results in late 2015," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President, R&D and Chief Medical Officer of Alnylam. "In addition, patisiran treatment showed robust mean knockdown of serum TTR of up to 88%, and was associated with a favorable tolerability profile out to 17 months of drug administration. In aggregate, we believe that these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. We continue to treat patients in our OLE study, and are actively enrolling FAP patients around the world in our APOLLO Phase 3 study, where we aim to obtain definitive evidence for patisiran efficacy and safety in FAP."

Alnylam's ongoing 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. New results - presented at the AAN meeting for patients (N=20) who reached the 12-month endpoint as of a data cut off of March 13, 2015 - showed that neuropathy impairment scores were essentially unchanged from baseline values after 12 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 2.5 points, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics (Adams et al., International Symposium on Amyloidosis, April 2014; Berk et al., JAMA 310: 2658-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.4 points at 12 months (N=20), which compares favorably to an estimated 10 to 14 point increase in NIS at 12 months derived from historical data sets in untreated FAP patients with similar baseline characteristics. The effects on mNIS+7 and NIS were similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, complete 6-month results were presented for all 27 patients, and showed mean decreases of 1.4 and 0.7 points in mNIS+7 and NIS endpoints, respectively; these data are consistent with previously reported data for patients that reached the 6 month endpoint (N=19), as reported at the American Neurological Association meeting in October, 2014.

A summary of mNIS+7 and NIS results (mean ± standard error of the mean (SEM)) at 6 and 12 months is provided in the table below.

6 months (N=27) 12 months (N=20)
Mean (SEM)
Change in mNIS+7
-1.4 ± 2.1 -2.5 ± 2.9
Mean (SEM)
Change in NIS
-0.7 ± 1.3 0.4 ± 1.2

A number of additional exploratory clinical measures are also being assessed in the OLE study, including: quality of life (QOL); timed 10-meter walk test (10MWT) to evaluate mobility; hand grip strength test; modified body mass index (mBMI) as a measure of nutritional status; level of disability by R-ODS; autonomic neuropathy symptoms by COMPASS-31; and nerve fiber density in skin biopsies. New results presented at the AAN meeting showed that these clinical measures were largely unchanged over the 12-month evaluation period. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) in the study, where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three or six months, respectively. Results in the cardiac subgroup showed no clinically significant changes in cardiac biomarkers (N=7-8) or in echocardiographic parameters (N=6-7) after 12 months of dosing. Finally, serum TTR levels are being measured throughout the OLE study. New results showed that repeat dosing with patisiran achieved sustained mean TTR knockdown at the 80% target level for approximately 16 months, and an up to 88% mean level of TTR knockdown was achieved in between doses. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.

Patisiran administration was also found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to 17 months. As of the time of the current data cutoff on March 13, 2015, 511 doses had been administered with a median of 19 doses per patient. Mean treatment duration was 13 months and the longest treatment duration was out to 17 months. There were no drug-related serious adverse events. The most common drug-related or possibly drug-related adverse events were flushing (22.2%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations. Additional reported drug-related adverse events seen in > 5% of patients were mild to moderate in severity and included diarrhea (7.4%) and peripheral edema (7.4%). There were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.

"I view these new clinical activity and safety data from Alnylam's ongoing patisiran OLE study as very encouraging. In particular, the possibility of halting neuropathic progression over 12 months of treatment is promising in light of the rapid increase in neuropathy impairment scores observed in analysis of other historical data sets. If these results are replicated in a randomized, double-blind, placebo-controlled study, I believe that patisiran could emerge as an important treatment option for patients suffering from this debilitating, progressive and life-threatening disease," said David Adams, M.D., Ph.D., Head ofDepartment of Neurology and Coordinator of the French Reference Center for FAP (NNERF)/APHP/CHU Bicêtre/France. "I very much look forward to continuing to participate in the clinical advancement of this investigational RNAi therapeutic, including enrolling patients onto the APOLLO Phase 3 study, as there are currently few options for our patients suffering from FAP."

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