Type of information: Submission of an NDA
Product name: givosiran (ALN-AS1)
Therapeutic area: Rare diseases - Genetic diseases
- 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.
Company: Alnylam Therapeutics (USA - MA)
Disease: acute hepatic porphyria (AHP)
- • On October 15, 2018, Alnylam Pharmaceuticals announced that in consultation with the FDA, the company plans to pursue a full approval based on the complete results 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), rather than filing based on the interim Phase 3 results. The FDA has also agreed to a rolling submission of a New Drug Application (NDA), which will be initiated in 2018 with full clinical sections submitted in mid-2019, assuming positive study results.
- Alnylam previously reported positive topline results from the interim analysis of the ENVISION Phase 3 study of givosiran demonstrating a statistically significant reduction (p less than 0.001) in urinary ALA levels, a surrogate biomarker that is reasonably likely to predict clinical benefit. As previously reported, serious adverse events (SAEs) were reported in 22 percent (5/23) of givosiran patients and 10 percent (2/20) of placebo patients in the interim analysis cohort of 43 patients, with one patient (4 percent) on givosiran discontinuing treatment due to an increase in liver transaminase that resolved. 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. As previously guided, the Company intends to file for marketing authorization in all other markets based on the complete results of the ENVISION Phase 3 study, assuming positive results.
- • On September 7, 2017, Alnylam Pharmaceuticals announced an update on its givosiran investigational RNAi therapeutic program. Based on Phase 1 study results presented , givosiran received PRIME designation by the European Medicines Agency (EMA).
- • On May 31, 2017, Alnylam Pharmaceuticals announced that it has received Breakthrough Therapy designation from the FDA for givosiran (ALN-AS1) for the prophylaxis of attacks in patients with acute hepatic porphyria (AHP). Promising results from the ongoing Phase 1 study of givosiran demonstrating meaningful reductions in the occurrence of porphyria attacks formed the basis of the Breakthrough application.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
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