Clinical Trials

Date: 2017-12-15

Type of information: Clinical trial authorisation

phase: 2

Announcement: clinical trial authorization

Company: Alnylam Therapeutics (USA - MA), Sanofi (France)

Product: fitusiran (SAR439774 - ALN-AT3)

Action mechanism:

• 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, Alnylam Pharmaceuticals announced that, 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 . This expanded right is in addition to their previously exercised opt-in decision to develop and commercialize fitusiran in their rest of world territories.

Disease: hemophilia A, hemophilia B with or without inhibitors

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country:

Trial details:

Latest news:

• • 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 June 26, 2017, Sanofi Genzyme and Alnylam Pharmaceuticals announced that new results from an ongoing Phase 2 open-label extension (OLE) study with fitusiran, in patients with hemophilia A and B, with or without inhibitors, will be presented in an oral presentation at the International Society of Thrombosis and Haemostasis (ISTH) Congress, being held from July 8 – 13, 2017 in Berlin, Germany. "Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: Interim Results from a Phase 2 Extension Study in Patients with Hemophilia A or B with and without Inhibitors". Presenter: K. John Pasi, Royal London Haemophilia Centre.
• • On December 4, 2016, Alnylam Pharmaceuticals announced new positive results from its ongoing Phase 2 open-label extension (OLE) study with fitusiran in patients with hemophilia A or B without inhibitors. These results were presented  in a poster at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 - 6, 2016 in San Diego, California .
• New clinical data showed that once-monthly subcutaneous administration of fitusiran achieved consistent lowering of AT and increases in thrombin generation, resulting in a median estimated annualized bleeding rate (ABR) of 1.0 in patients with hemophilia A or B without inhibitors. In addition, fitusiran was generally well tolerated, with no thromboembolic events or laboratory evidence of pathologic clot formation through the data cut-off date.The Phase 2 OLE study results as of the data cut-off date of October 6, 2016 included 16 hemophilia A or B patients without inhibitors. All patients were previously enrolled in the fitusiran Phase 1 study, receiving 3 weekly or 3 monthly subcutaneous doses ranging from 45 micrograms per kilogram (mcg/kg) to 1800 mcg/kg. In the Phase 2 OLE study, fitusiran was administered subcutaneously once-monthly at two fixed dose levels, 50 mg (N=8) and 80 mg (N=8), with patients receiving up to 14 months of continuous dosing. Both dose levels achieved mean AT lowering of approximately 80 percent and mean increases in thrombin generation levels approaching the lower end of the range observed in normal healthy individuals in Part A of the Phase 1 study. In an exploratory post hoc analysis of bleed events, fitusiran achieved a median overall ABR of 1.0, over a median observation period of 5.7 months, compared to a median pre-study ABR of 4.0. In the study, 8 out of 16 patients (50 percent) reported zero bleeds and 11 out of 16 patients (69 percent) experienced zero spontaneous bleeds. The data reported from the Phase 2 OLE study also includes the first reported elective surgical procedure in a fitusiran-treated patient. Specifically, a patient with severe hemophilia A receiving 50 mg monthly fitusiran underwent an elective septoplasty procedure. Prior to the surgical procedure, the patient's AT levels were 13 percent relative to baseline. As reported by the investigator via personal communication, the cumulative periprocedural utilization of recombinant factor VIII was approximately 20 percent of that typically used by the investigator for this type of surgery in a severe hemophilia A patient. Based on the International Society of Thrombosis and Haemostasis (ISTH) hemostasis efficacy score, the investigator rated hemostasis control in the intra-operative, 24 hours post-operative, and 7 days post-operative periods as all being "excellent". Fitusiran was generally well tolerated with the longest period of exposure of up to 14 months of continuous treatment. All adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of mild injection site reactions (ISRs) in 4 out of 16 patients (25 percent). Asymptomatic and reversible alanine aminotransferase (ALT) increases greater than 3 times the upper limit of normal (ULN), without concurrent elevations in bilirubin greater than 2 times ULN, were observed in three patients in the OLE study, all of whom have medical history of hepatitis C infection (HCV). All breakthrough bleeding events were successfully managed with replacement factor. There were no drug-related serious adverse events (SAEs), no discontinuations due to AEs in the OLE study, and no thromboembolic events or laboratory evidence of pathologic clot formation through the data cut-off date.

Is general: Yes