Clinical Trials

Date: 2017-06-26

Type of information: Presentation of results at a congress

phase: preclinical

Announcement: presentation of results at the International Society of Thrombosis and Haemostasis (ISTH) Congress

Company: Alnylam Pharmaceuticals (USA - MA)

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

Therapeutic area: Hematological diseases - Genetic diseases - Rare diseases

Country:

Trial details:

Latest news:

• • On June 26, 2017, Sanofi Genzyme and Alnylam Pharmaceuticals announced that preclinical data further elucidating fitusiran’s novel mechanism of action will be presented at the International Society of Thrombosis and Haemostasis (ISTH) Congress. “The data being presented at ISTH demonstrate the growing body of clinical and nonclinical evidence that support fitusiran as a potential treatment approach for patients with hemophilia A and B, with and without inhibitors,” said Akin Akinc, Ph.D., Alnylam’s Vice President and General Manager, Fitusiran. The abstract is entitled: Development of a Pharmacokinetic-Pharmacodynamic (PK-PD) Model of Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia in Patients with and without Inhibitors. Presenter: Husain Attarwala (Alnylam Pharmaceuticals).
• • On April 13, 2015, Alnylam Pharmaceuticals announced  the publication in Nature Medicine of pre-clinical results with ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). The paper, titled "An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia" (Sehgal et al., Nat Med), documents a broad set of pre-clinical data supporting the clinical advancement of ALN-AT3. Among the many findings reported, subcutaneous administration of ALN-AT3 led to potent, dose-dependent, and durable knockdown of AT in wild-type mice, hemophilia A mice, and non-human primates (NHPs).  In microvessel laser injury and saphenous vein bleeding models in HA mice, subcutaneous administration of ALN-AT3 provided hemostatic protection that was comparable to or better than that achieved with intravenously administered factor VIII replacement therapy. Furthermore, in wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible knockdown of plasma AT. Studies were also performed in an NHP hemophilia "inhibitor" model, in which a hemophilia phenotype was induced via administration of a polyclonal anti-factor VIII antibody. ALN-AT3 treated animals showed robust AT knockdown as well as dose-dependent increases in thrombin generation, restoring this hemostatic parameter back to normal levels. These results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key pre-clinical proof of concept for the program.
• In addition, the new paper documents the results of tolerability studies that suggest a wide therapeutic index for ALN-AT3 in the hemophilia setting. Specifically, highly exaggerated doses of ALN-AT3 resulting in essentially complete ablation of AT were evaluated in wild-type and hemophilia mice. Weekly administration of ALN-AT3 in HA mice for 7 weeks at 10, 30, or 100 mg/kg was well tolerated across all dose levels, with no toxicologically significant findings in clinical or anatomic pathology exams, including the absence of any evidence for thrombosis. Finally, a 26-week toxicity study was performed in HA mice to evaluate long-term safety. As in the 7-week study, ALN-AT3 was well tolerated across all dose levels, with no adverse clinical signs. Further, compared to placebo treatment, ALN-AT3 administration was shown to confer a statistically significant survival benefit (p < 0.0001; log-rank, Mantel-Cox test), consistent with the hypothesis that a reduction in AT levels leads to disease modification. In aggregate, these results suggest a wide therapeutic index for AT knockdown in the hemophilia setting.
• Alnylam is continuing to advance ALN-AT3 in an ongoing Phase 1 clinical trial in subjects with hemophilia. The ongoing study is being conducted in Bulgaria, Switzerland and the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A - which is complete - was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3:placebo) in healthy volunteer subjects. This part of the study was completed after the first dose cohort that received a single subcutaneous dose of ALN-AT3 at 30 micrograms/kilogram (mcg/kg). Part B of the study - which is ongoing - is an open-label, multi-dose, dose-escalation study enrolling up to 18 subjects with moderate or severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. In addition, the study is recording potential effects of ALN-AT3 on the incidence of bleeding.
• At the Goring Coagulation Conference , held January 11 - 12, 2015, Alnylam presented initial positive results from the ongoing Phase 1 trial. Specifically, in the study's second dose cohort in hemophilia subjects (n=3), subcutaneous administration of ALN-AT3 at a dose of 45 mcg/kg administered once weekly for 3 weeks resulted in an up to 70% knockdown of AT. Furthermore, ALN-AT3 administration resulted in a statistically significant increase in thrombin generation of up to 334% and a marked improvement in whole blood clotting. In addition, the most advanced severe hemophilia A subject in the cohort was shown to be bleed-free for 47 days without replacement factor prophylaxis as of the data cut-off date of January 6, 2015 . Finally, ALN-AT3 administration was generally well tolerated. Alnylam believes that, collectively, these results provide initial evidence for potential correction of the hemophilia phenotype associated with ALN-AT3 administration and AT knockdown. The company intends to provide additional results from the ongoing Phase 1 study in mid-2015 and then again in late 2015.

Is general: Yes