Alnylam and collaborators publish preclinical results on ALN-AT3 for the treatment of haemophilia

Preclinical results on Alnylam’s ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of haemophilia and rare bleeding disorders (RBD), have been published.

Among the many findings reported, subcutaneous administration of ALN-AT3 led to potent, dose-dependent, and durable knockdown of AT in wild-type mice, haemophilia A mice, and non-human primates (NHPs). In addition, ALN-AT3 treatment improved haemostasis in haemophilia mice and normalised thrombin generation in a non-human primate “inhibitor” model of haemophilia A (HA). Furthermore, long-term ALN-AT3 administration – even at highly exaggerated doses – was shown to be well tolerated in haemophilia mice, supporting a wide therapeutic index in the disease setting.

Once-monthly administration of ALN-AT3 could provide a functional correction of the bleeding phenotype in haemophilia

“We believe that once-monthly subcutaneous administration of ALN-AT3 could provide a functional correction of the bleeding phenotype in haemophilia, representing a significant advance in the field. Our preclinical research findings demonstrate robust efficacy, safety, and durability for ALN-AT3 in mouse and NHP models of haemophilia, and we are pleased to be publishing these peer-reviewed data in Nature Medicine. Amongst other study results, safety data in haemophilia mice suggest that ALN-AT3 administration – even at highly exaggerated doses – should be well tolerated in the disease condition,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam.

“Meanwhile, we are continuing to advance ALN-AT3 in an ongoing Phase 1 clinical trial in subjects with haemophilia. Recent results from this trial presented earlier this year provided clinical evidence for the first time suggesting that AT knockdown with ALN-AT3 has the potential to correct the haemophilia phenotype. While early and based on a limited number of subjects, we believe that these data support further development of ALN-AT3, a potentially promising and innovative strategy for the treatment of haemophilia and rare bleeding disorders as a once-monthly subcutaneous injection. We look forward to the continued data from our Phase 1 study and expect to present additional results in mid-2015 and then again later in the year.”

ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII

Single and multiple subcutaneous doses of ALN-AT3 led to dose-dependent and durable knockdown of serum AT in wild-type and HA mice and in NHPs. In microvessel laser injury and saphenous vein bleeding models in HA mice, subcutaneous administration of ALN-AT3 provided haemostatic 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 haemophilia “inhibitor” model, in which a haemophilia 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 haemostatic parameter back to normal levels. These results demonstrate that ALN-AT3 can normalise 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.

Results of tolerability studies suggest a wide therapeutic index for ALN-AT3 in the haemophilia setting. Alnylam is currently evaluating ALN-AT3 in a Phase 1 clinical trial in subjects with haemophilia.

David Lillicrap, M.D., FRCPC, Department of Pathology and Molecular Medicine at Queen’s University, and Canada Research Chair in Molecular Haemostasis, said, “The clinical advancement of ALN-AT3 is supported by a broad preclinical data package that is now published in Nature Medicine. Of particular interest is the correlation of antithrombin knockdown with thrombin generation, since thrombin generation has been shown to be predictive of disease severity. In addition, I believe that the long-term safety of the drug in the mouse model of haemophilia is an important finding, suggesting that ALN-AT3 may have a wide therapeutic index in people with haemophilia. Finally, I am encouraged by the initial data emerging from Alnylam’s Phase 1 trial and I look forward to seeing further progress in the coming months.”

The research paper is published in Nature Medicine.

For more information about Alnylam, please visit www.alnylam.com.