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Alnylam Releases Preliminary Phase I Data on Hemophilia Drug

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NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals this week released early Phase I data on its subcutaneously administered hemophilia therapy ALN-AT3, which showed the drug could durably suppress its target by as much as 57 percent at low microgram per kilogram doses.

Notably, ALN-AT3 is Alnylam's first clinical candidate to feature an optimized version of the company's GalNAc conjugate delivery technology, dubbed enhanced stabilization chemistry, which is expected to replace standard GalNAc conjugates in future Alnylam programs.

ALN-AT3 comprises siRNAs targeting antithrombin (AT), an endogenous inhibitor of thrombin generation. Earlier this year, Alnylam presented top-line data from the first part of the ongoing Phase I trial, showing that single, sub-pharmacologic doses of ALN-AT3 could silence AT by up to 28 to 32 percent in healthy volunteers. This arm of the study included a dose-escalation stopping rule to prevent AT knockdown from exceeding 40 percent.

On these data, the company initiated the second arm of the study, which is testing multiple, escalating pharmacologic doses of ALN-AT3 in patients with moderate to severe hemophilia A or B.

As with the first portion of the trial, the primary objective of this part is to evaluate safety and tolerability, but it does not include a stopping rule and is also assessing clinical activity by measuring knockdown of circulating AT levels and increases in the generation of thrombin, a known biomarker for bleeding frequency and severity in hemophiliacs.

According to the newly released data from the second part of the study, three patients in the lowest dose cohort received three weekly 15 mcg/kg doses of ALN-AT3, which resulted in an up to 52 percent reduction in AT in the most advanced subject, Alnylam said. Nadir was achieved on day 35.

In the second dose cohort, one patient received three weekly doses of the drug at 45 mcg/kg and experienced at 57 percent knockdown of AT at day 14. Knockdown in this patient has not yet reached expected nadir levels, Alnylam noted.

None of the subjects in the Phase I trial are so-called inhibitor patients, a term used to describe individuals who have developed antibodies against replacements for the missing clotting factors that cause their disease.

The Phase I trial is continuing to enroll hemophilia subjects in the 45 mcg/kg dose cohort, and additional multi-dose cohorts are planned. Complete results from the study are expected for mid-2015.

During a conference call held to discuss the preliminary data, Alnylam CEO John Maraganore cautioned that the findings are from the earliest stages of the trial, and limited to just a few patients.

"That said, we're already seeing what we believe to be very interesting results related to antithrombin knockdown," he said. Further, "these results provide solid support … that we are achieving very potent and durable clinical activity and an encouraging tolerability profile for investigational RNAi therapeutics that use our enhanced stabilization chemistry … GalNAc delivery platform."

He also reiterated Alnylam's expectation that, while the Phase I trial is testing weekly doses of ALN-AT3, the company anticipates the drug will ultimately be dosed once a month — something that could give it an edge over existing hemophilia treatments.

Also contributing to ALN-AT3's market potential is its expected efficacy in multiple bleeding disorders, Maraganore said. "It has a broader potential [than replacement therapies and] we think the profile we are creating is going to make it very competitive."

Although Alnylam has not provided formal guidance on future clinical trials of ALN-AT3, CMO Akshay Vaishnaw said in a statement that a once-a-month dosing regimen is expected for upcoming studies. Maraganore had previously disclosed that the firm anticipates multiple Phase II and Phase III trials to test the drug in different patient populations.

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