Alnylam Reports Six-Month Clinical Data from Patisiran Phase 2 Open-Label Extension (OLE) Study in Patients with Familial Amyloidotic Polyneuropathy (FAP)

CAMBRIDGE, Mass.--()--Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today six-month clinical data from its ongoing Phase 2 open-label extension (OLE) study with patisiran (ALN-TTR02), an investigational RNAi therapeutic in development for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP). These data are being presented at the American Neurological Association's 2014 Annual Meeting being held October 12 – 14 in Baltimore. Results showed a mean 0.95 point decrease in modified Neuropathy Impairment Score (mNIS+7) at six months in 19 patients with mNIS+7 data available for the current analysis. This decrease in neuropathy progression compares favorably with the 7 to 10 point increase in mNIS+7 at six months that can be estimated from 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: 26588-67, 2013; Tafamidis European Medicines AgencyAssessment Report, 2011). In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for over nine months, with an up to 89.6% knockdown achieved between doses. Patisiran was found to be generally well tolerated in this study out to one year of therapy, with no drug-related serious adverse events to date, and all 27 patients enrolled in the study continue to receive drug treatment.

Alnylam's ongoing OLE study is treating patients that were previously enrolled in a Phase 2 study of patisiran in ATTR patients with FAP. The OLE study is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration. The two-year study has completed enrollment with 27 patients who receive 0.3 mg/kg of patisiran once every three weeks. This study is also 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 mNIS+7 measurement is the primary endpoint in the company's Phase 3 APOLLO trial of patisiran in FAP patients. A number of additional clinical measures are also being assessed, 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; and nerve fiber density in skin biopsies. Patients with cardiac abnormalities at baseline comprise a cardiac subgroup (N=11) where cardiac biomarkers (NT-proBNP and troponin I) and echocardiographic parameters are measured at baseline and every three to six months. In addition, serum TTR levels are being measured throughout the study."In this open-label study with patisiran, we are very encouraged to see what we believe to be evidence for possible stabilization of neuropathy progression after the first six months of treatment. Indeed, we believe the approximate one point decrease in neuropathy impairment score is an encouraging result in light of multiple historical data sets that would have predicted an increase of 7 to 10 points for untreated patients with similar baseline characteristics. These data will be increasingly meaningful as we monitor neuropathy progression in patisiran-treated patients over time, and we look forward to sharing those results at least once annually hereafter," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "In addition, patisiran treatment showed robust knockdown of serum TTR of up to 90% for over nine months, and was associated with a favorable tolerability profile out to one year of treatment. We believe the potent, rapid, and durable knockdown of TTR achieved by patisiran could be important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit. We will continue to treat patients on our OLE study, and are enrolling FAP patients in our APOLLO Phase 3 study in sites around the world."

The initial results from the ongoing open-label study showed that after six months of treatment with patisiran, neuropathy impairment scores were essentially unchanged from baseline values. As noted above, there was a mean decrease in mNIS+7 of 0.95 points (N=19), which compares favorably to the rapid increase in mNIS+7 of 7 to 10 points estimated at six months from historical data sets in untreated FAP patients with similar baseline characteristics. Similar results were observed for the change in Neuropathy Impairment Score (NIS), where there was a mean increase of 0.22 points at six months (N=20). The stabilization in mNIS+7 was similar in patients with or without concurrent use of TTR tetramer stabilizers. In addition, no significant evidence for disease worsening was observed in measurements of QOL, 10MWT, mBMI, R-ODS, and nerve fiber density, amongst other clinical assessments performed. In the cardiac subgroup, there were no significant changes in cardiac biomarkers (N=5) or in echocardiographic parameters (N=7) after six months of dosing. Finally, repeat dosing of patisiran achieved sustained TTR knockdown at the 80% target level for over nine months, and an up to 89.6% level of TTR knockdown was achieved in post-dose measurements. A similar degree of TTR knockdown was observed in patients with or without concurrent use of TTR tetramer stabilizers.

"These preliminary clinical activity and safety data from Alnylam's OLE study with patisiran are quite encouraging. In particular, the stabilization in neuropathy impairment scores at six months may have important implications for patients suffering from this debilitating, progressive and life-threatening disease," said David Adams, M.D., Ph.D., Head of Department 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 treating patients on the ongoing Phase 2 OLE study and enrolling patients onto the APOLLO Phase 3 study, as there are currently few options for our patients suffering from FAP."

Patisiran administration was found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to one year. As of the time of the data cutoff on September 8, 2014, 282 doses had been administered with a median of 11 doses per patient. Mean treatment duration was seven months and the longest treatment duration was out to one year. There were no drug-related serious adverse events. Infusion-related reactions were infrequent (14.8%), mild in severity, and did not result in any discontinuations. All other reported adverse events were mild to moderate, and there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.

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