information: Clinical trial authorisation
Announcement: clinical trial authorization
Company: Alnylam Therapeutics (USA - MA), Sanofi (France)
Product: fitusiran (SAR439774 - ALN-AT3)
- RNAi. ALN-AT3 is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand. GalNAc-siRNA conjugates are a proprietary, clinically validated delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Pre-clinical studies have shown that subcutaneous administration of ALN-AT3 can normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model.
- A single subcutaneous dose of ALN-AT3 that resulted in plasma AT reduction of approximately 90% led to normalization of thrombin generation and improvement in hemostasis in hemophilia mice. In wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible silencing of plasma AT. Weekly subcutaneous doses of 0.50 mg/kg resulted in 90% AT knockdown, while an ED50 knockdown was achieved at a dose as low as 0.125 mg/kg. Furthermore, in an NHP “inhibitor” model, in which a hemophilia A (HA) phenotype was induced via administration of a polyclonal anti-factor VIII antibody, ALN-AT3-treated animals showed the expected level of AT knockdown but also showed a statistically significant (p<0.01) dose-dependent increase in thrombin generation, fully restoring this hemostatic parameter back to normal levels.
- • On November 14, 2016, pursuant to the companies' global alliance signed in January 2014 , Sanofi Genzyme elected to opt in to co-develop and co-commercialize fitusiran, for the treatment of hemophilia and rare bleeding disorders, in the United States , Canada and Western Europe .
Disease: hemophilia A and B with or without inhibitors
area: Rare diseases - Genetic diseases - Hematological diseases
- • On December 15, 2017, Sanofi Genzyme and Alnylam Pharmaceuticals announced that the FDA has lifted the hold on clinical studies with fitusiran, including the Phase 2 open-label extension (OLE) study and the ATLAS Phase 3 program.
- Alnylam and the FDA had previously reached alignment on new clinical risk mitigation measures, including protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies. The FDA has now approved the protocol amendments and other updated clinical materials for fitusiran studies.
- • On September 7, 2017, Alnylam Pharmaceuticals provided an update on fitusiran investigational RNAi therapeutic program. Alnylam is reporting a fatal thrombotic event in the Phase 2 open-label extension (OLE) study of fitusiran in development for the treatment of hemophilia A and B with or without inhibitors. This fatal serious adverse event occurred in a patient with hemophilia A. Approximately nine days prior to hospital admission, he developed exercise-induced right hip pain that was treated with a total of three doses of factor VIII concentrate (31-46 IU/kg) on three separate days. Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache. While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and treated with factor VIII concentrate administered two to three times daily. Over a 14-day hospitalization, his medical condition worsened despite the administration of factor and the patient died from subsequent cerebral edema. The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran. For a more complete understanding, the ccompany initiated further investigation of the SAE, including review of the patient's CT scans by three independent neuro-radiologists, who all confirmed on September 1, 2017, that the initiating event was a cerebral venous sinus thrombosis, and not a subarachnoid hemorrhage.
- As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the safety event and development of a risk mitigation strategy. These studies include the ongoing Phase 2 OLE study of hemophilia A and B patients with and without inhibitors and the ATLAS Phase 3 program, which has recently been initiated but in which patient dosing has yet to begin. As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related, and to develop a risk mitigation plan. The company also notified study investigators and global regulatory authorities.
- • On July 7, 2017, Alnylam and Sanofi Genzyme announced the initiation of the ATLAS Phase 3 clinical program for fitusiran. The global, multicenter program is designed to evaluate the safety and efficacy of fitusiran in three separate trials, including patients with hemophilia A and B with or without inhibitors and patients receiving prophylactic therapy.
- The three ATLAS studies are designed to evaluate the safety and efficacy of fitusiran across a spectrum of patients living with hemophilia. They are expected to enroll approximately 250 patients across three separate trials conducted at over 100 clinical centers around the world.
ATLAS-INH is a nine-month, open-label, randomized, active-controlled trial designed to enroll approximately 50 patients with hemophilia A or B with inhibitors receiving prior on-demand therapy. The study's primary endpoint is the annualized bleeding rate (ABR), and key secondary endpoints include the annualized spontaneous bleeding rate, annualized joint bleeding rate, and quality of life as measured by the Haem-A-QOL score.
- Top-line data from the ATLAS trials are expected in mid-to-late 2019.