Date: 2018-09-27
Type of
information: Interim results
phase: 3
Announcement: interim results
Company: Alnylam Therapeutics (USA - MA)
Product: givosiran (ALN-AS1)
Action
mechanism:
- RNAi. Givosiran (ALN-AS1) is a subcutaneously administered, investigational RNAi therapeutic that utilizes Alnylam's proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. This RNAi is targeting aminolevulinic acid synthase 1 (ALAS1). ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. In pre-clinical studies, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED50 of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of ALA and PBG, the toxic heme intermediates in AIP. Pre-clinical studies with RNAi therapeutics targeting ALAS1 have been published by Alnylam and collaborators previously (Yasuda et al., Proc Natl Acad Sci USA 2014;111(21):7777-7782).
- 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, including ALN-AS1, in the rest of the world.
Disease: acute hepatic porphyria
Therapeutic
area: Rare diseases - Metabolic diseases
Country: Australia,Belgium,Bulgaria,Canada, Denmark, Finland, France, Germany, Italy, Japan, Republic of Korea, Mexico, The Netherlands, Poland, Spain, Sweden, Switzerland,Taiwan, UK, USA
Trial
details:
- The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of AHPs. Patients were randomized on a 1:1 basis to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly, over a 6-month treatment period. The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over the 6-month treatment period. The planned interim analysis will evaluate reduction of a urinary biomarker – ALA – in approximately 30 patients after three months of dosing, as a surrogate endpoint reasonably likely to predict clinical benefit. Key secondary and exploratory endpoints will evaluate reductions in the hallmark symptoms of AHPs, such as pain, nausea, and fatigue, as well as impact on quality of life.
- All patients completing the 6-month treatment period are eligible to continue on an open-label extension (OLE) study in which they will receive treatment with givosiran for up to 30 months. (NCT03338816)
Latest
news:
- • On September 27, 2018, Alnylam Pharmaceuticals announced topline results from the interim analysis of the ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP). The pre-specified interim analysis was based on lowering of urinary ALA levels as a surrogate biomarker that is reasonably likely to predict clinical benefit.
- Results of the interim analysis showed that givosiran treatment was associated with a statistically significant reduction in urinary ALA levels in acute intermittent porphyria (AIP) patients, relative to placebo (p less than 0.001). The company plans to discuss these data and the regulatory path forward with the FDA, and, pending the outcome of those discussions, intends to file a New Drug Application (NDA) at or around year-end 2018 in support of a potential Accelerated Approval.
- The interim analysis had a data cut-off date of August 22, 2018 and included 43 patients with AHPs (41 patients with AIP, one with variegate porphyria [VP], and one with hereditary coproporphyria [HCP]) who were on study for at least three months. As of the data cut-off date, there were no deaths, and serious adverse events (SAEs) were reported in 22 percent (5/23) of givosiran patients and 10 percent (2/20) of placebo patients. One patient (4 percent) on givosiran discontinued treatment due to an increase in liver transaminase – which resolved – that was greater than eight times the upper limit of normal (ULN), a protocol-defined stopping rule. There were no treatment discontinuations in the placebo group.
- Alnylam continues to dose patients in the ongoing ENVISION study, where enrollment was completed ahead of schedule with 94 AHP patients. The company expects to report topline full study results of the primary endpoint – the annualized attack rate after six months of treatment – in early 2019.
- • On August 21, 2018, Alnylam Pharmaceuticals announced that it has achieved full patient accrual in its ENVISION Phase 3 study of givosiran for the treatment of acute hepatic porphyrias (AHPs). Enrollment was completed with 94 AHP patients randomized across 36 sites in 18 countries, surpassing the initial target of approximately 75 patients due to high patient demand. The company reiterated its previous guidance that it expects to report topline results of the interim analysis by the end of September in support of a potential accelerated approval, and topline results on the primary endpoint of annualized attack rate after six months of treatment in early 2019. The interim analysis is based on lowering of urinary aminolevulinic acid (ALA) levels from approximately 30 patients at three months of treatment as a surrogate biomarker that is reasonably likely to predict clinical benefit.
- • On November 7, 2017, Alnylam Pharmaceuticals announced the initiation of the ENVISION Phase 3 clinical study with givosiran for the treatment of acute hepatic porphyrias (AHPs). Alnylam has also reached alignment on the ENVISION Phase 3 study design with the European Medicines Agency (EMA).
Is
general: Yes
