Positive Interim Clinical Results from Ongoing Phase 1 Trial of ALN-AT3 for the Treatment of Hemophilia and Rare Bleeding Disorders

We presented positive interim clinical data from our ongoing Phase 1 study for ALN-AT3, a subcutaneously administered, investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Data were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress held June 20 – 25, 2015. New clinical results from 12 subjects with severe hemophilia show that subcutaneous administration of ALN-AT3 achieved potent and dose-dependent knockdown of AT of up to 86%. AT knockdown was highly durable, with effects lasting over two months after the last dose, supporting further evaluation of a once-monthly subcutaneous dose regimen. In addition, AT knockdown was associated with statistically significant increases in thrombin generation with a mean increase of up to 350% and marked improvements in whole blood clotting; these results demonstrate a re-balancing of hemostasis in severe hemophilia subjects. Furthermore, in an exploratory post-hoc analysis, a reduced frequency of bleeding was observed at higher AT knockdown levels with a maximum bleed-free interval of 114 days. Very importantly, ALN-AT3 continues to be generally well tolerated.

With the potential for infrequent subcutaneous dose administration and possible correction of disease phenotype, we believe that ALN-AT3 represents an innovative investigational medicine for the treatment of hemophilia and rare bleeding disorders and we now intend to advance ALN-AT3 into pivotal Phase 3 studies in mid-2016.

Alnylam scientists and collaborators also are presenting new pre-clinical data on ALN-AT3 at the ISTH meeting. In an oral presentation, ex vivo AT depletion was demonstrated to result in increased thrombin generation in plasma from donors with deficiencies in factors V, VII, and XI. These new pre-clinical data support the evaluation of ALN-AT3 in these rare bleeding disorders.

In a separate poster presentation, the effects of AT depletion on thrombin generation were analyzed in hemophilia plasma. Pre-clinical study results showed that when AT levels are decreased, substantially lower levels of replacement factor or bypass agent addition could potentially be used to achieve a similar level of hemostatic effect.

Finally, we presented pre-clinical toxicology data demonstrating that chronic administration of ALN-AT3 was well tolerated in non-human primates, a relevant pre-clinical model. Further, chronic dosing at exaggerated dose levels in hemophilia A mice was also well tolerated and resulted in a survival benefit relative to saline-treated controls.