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Alnylam and Collaborators Present New Clinical Data for Patisiran, an RNAi Therapeutic Targeting Transthyretin TTR in Development for the Treatment...

May 14, 2014

Alnylam and Collaborators Present New Clinical Data for Patisiran, an RNAi Therapeutic Targeting Transthyretin TTR in Development for the Treatment of TTR-Mediated Amyloidosis ATTR

By a News Reporter-Staff News Editor at Biotech Week -- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, and collaborators announced new clinical data for patisiran (ALN-TTR02), an RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR). These data are being presented at the International Symposium on Amyloidosis (ISA) held April 27 - May 1, 2014 in Indianapolis, Indiana. First, the company presented updated Phase 2 results in patients with Familial Amyloidotic Polyneuropathy (FAP) confirming robust TTR knockdown of up to 96% with a mean TTR knockdown of approximately 80%. Further, Alnylam presented preliminary results from the open-label extension (OLE) study with patisiran in patients that were enrolled in the Phase 2 study. Preliminary results from the OLE study showed that multiple doses of patisiran achieved sustained knockdown of serum TTR protein levels at the 80% target level through 168 days. Moreover, OLE results showed a favorable tolerability profile with up to eight doses administered. Finally, the company presented results of a natural history, cross-sectional analysis study of 283 FAP patients aimed at measuring the rate of neuropathy progression and its correlation with disease severity. These results provide support for Alnylam's Phase 3 APOLLO trial where patisiran is being evaluated for its potential efficacy and safety in the FAP indication (see also Pharmaceutical Companies).

"We continue to make strong progress in our patisiran development program, which is focused on making a difference in the lives of ATTR patients with polyneuropathy. Several highlights from our efforts are being presented at ISA, including updated Phase 2 study results, initial data from our Phase 2 OLE study, and results from a natural history study of neuropathy progression in FAP. Notably, our initial results from the Phase 2 OLE confirm a sustained TTR knockdown at the 80% target level through up to 168 days. Further, we are very encouraged by the tolerability data, especially the significant reduction in infusion reactions due to the use of our proprietary micro-dosing regimen. With this early update on the OLE study, we still expect to present clinical endpoint data results later this year consistent with our external guidance," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "Another notable highlight is the presentation of FAP natural history study results. This cross-sectional analysis evaluated the neuropathy progression rate in a multinational population of patients with FAP, and demonstrates a rapid progression in NIS and a high correlation of this measurement with disease severity. Moreover, these results give us confidence that our APOLLO Phase 3 trial of patisiran in FAP patients is robustly powered to show the potential impact of TTR lowering on the mNIS+7 endpoint used in that study."

Alnylam presented updated results from its Phase 2 study of patisiran, which was conducted in 29 patients with FAP where patients received two doses of drug administered as an intravenous infusion. As previously reported at the International Society of Familial Amyloidotic Polyneuropathy (ISFAP) meeting in November 2013, patisiran demonstrated a rapid, dose-dependent, and durable knockdown of serum TTR of up to 96% and an average TTR knockdown of approximately 80%. The updated data included results from an additional patient dosed in the study and follow up TTR knockdown data from other patients.

The company also presented initial results from its Phase 2 OLE study with patisiran. The OLE study is enrolling patients that were treated in the Phase 2 study and is designed to evaluate the long-term safety and tolerability of patisiran administration. The OLE study is also measuring a number of clinical endpoints every six months, including the modified composite Neuropathy Impairment Score, termed "mNIS+7"; this score is also the primary endpoint of the Phase 3 APOLLO trial of patisiran in FAP. Further, serum TTR levels are being measured following the first dose and then pre-dose every six to twelve weeks; since TTR levels are measured pre-dose, the results are a conservative estimate of TTR knockdown achieved over time with repeat dosing. Of the 29 patients eligible for enrollment, 25 have been enrolled to date and an additional two patients are expected to be enrolled by the end of May; the results from 23 patients are currently evaluable for analysis based on a data cut-off as of April 3, 2014.

Preliminary results showed that the TTR knockdown observed following the first dose in the OLE study closely matched TTR knockdown shown in the Phase 2 study, with essentially superimposable pharmacodynamic effects. Moreover, repeat dosing of patisiran led to a sustained TTR knockdown of approximately 80% through up to day 168, equivalent to up to eight doses of drug, as measured in pre-dose blood samples. These data provide the first clinical evidence of sustained, RNAi-mediated TTR knockdown in FAP patients beyond two doses of patisiran. Repeat dosing of patisiran was found to be well tolerated, with minimal adverse events. Importantly, the incidence of infusion-related reactions (IRR) was found to be significantly reduced to 2% in patients from the Phase 2 and Phase 2 OLE studies receiving study drug with a proprietary micro-dosing regimen, as compared with an incidence of 15% in patients receiving a standard infusion (p=0.03). All other reported adverse events were mild to moderate, and there were no changes in liver function tests, renal function, or hematological parameters. Consistent with earlier guidance, Alnylam continues to plan on reporting initial clinical endpoint data from the OLE study in late 2014. Specifically, the company expects to have 6-month mNIS+7 data from approximately 20 patients at that time. The company intends to provide recurrent updates from the OLE study at least annually thereafter.

"These preliminary clinical activity and safety data from the OLE study with patisiran are promising. In particular, the potent, rapid, and durable knockdown of TTR achieved by patisiran, which is now confirmed to be sustained with multi-dosing, is important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit. It is also encouraging to see the favorable tolerability profile for multiple dose administration of patisiran, including the clear reduction in the occurrence of infusion reactions with micro-dosing," said David Adams, Head of Department of Neurology and Coordinator of the French Reference Center for FAP (NNERF)/APHP/CHU Bicetre/France. "I very much look forward to participating in the continued clinical advancement of this RNAi therapeutic, including the ongoing Phase 2 OLE and APOLLO Phase 3 studies, as there are currently few options for our FAP patients suffering from this debilitating, progressive, and life-threatening disease."

Keywords for this news article include: Alnylam Pharmaceuticals Inc., Pharmaceutical Companies, Therapy, Nephrology, Amyloidosis, Metabolic Diseases, Adverse Drug Reaction, Biotechnology Companies, Proteostasis Deficiencies, Clinical Trials and Studies.

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Source: Biotech Week

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