Taking aim at AT

CAMBRIDGE, Mass.—RNAi therapeutics company Alnylam Pharmaceuticals Inc. has released updated results for its ongoing Phase 1 study of ALN-AT3 as a potential treatment for hemophilia and rare bleeding disorders. The compound is a subcutaneously administered, investigational RNAi therapeutic that targets antithrombin (AT). AT, which is also known as antithrombin III and SERPINC1, is a liver-expressed plasma protein and a member of the “serpin” protein family that acts as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. The protein plays a significant role in normal hemostasis.

The data revealed that subcutaneous administration of ALN-AT3 in the study's second dose cohort in hemophilia subjects resulted in an up to 70-percent knockdown of AT, and new results have offered initial evidence for possible correction of the hemophilia phenotype linked to ALN-AT3 administration and AT knockdown. ALN-AT3 administration generated an increase in thrombin generation of up to 334 percent and a noticeable improvement in whole blood clotting. The most advanced severe hemophilia A subject in the cohort had been bleed-free for 47 days without replacement factor prophylaxis at the time of the announcement. Patients receiving ALN-AT3 saw marked improvements in clotting time and clot formation time, both of which are significantly impaired in hemophiliacs.

The second dose cohort of hemophilia subjects received ALN-AT3 subcutaneously once a week for three weeks at 45 mcg/kg. Based on the most advanced subject in that cohort, the nadir effects seem to occur at roughly day 28. Based on the essentially complete time course for AT knockdown from the first dose cohort receiving 15 mcg/kg, ALN-AT3's effects were found to be highly durable, lasting approximately 60 days.

Alnylam is continuing to enroll hemophilia subjects in additional dose cohorts for the Phase 1 study, including a possible once-monthly subcutaneous dose regimen following a protocol amendment. The company expects to begin a Phase 2 study of ALN-AT3 late this year.

“We believe that these new results from our ongoing Phase 1 study with ALN-AT3 provide initial evidence for potential disease-modifying effects in hemophilia. Specifically, data from the study’s second dose cohort provide clinical evidence for the first time suggesting that AT knockdown with ALN-AT3 has the potential to correct the hemophilia phenotype. In particular, we’ve observed clear increases in thrombin generation and marked improvements in whole blood clotting, as if the severe hemophilia A disease phenotype has been modified to a milder form. Further, we are encouraged to see that the most advanced subject has remained free from bleeding for a significant period without need for replacement factor prophylaxis,” commented Dr. Akshay Vaishnaw, executive vice president and chief medical officer of Alnylam, adding that the treatment continues to be well tolerated, with no serious adverse events or study discontinuations.

“While early and based on a limited number of subjects, we believe that these new data support human proof of concept for ALN-AT3, a promising and innovative strategy for the treatment of hemophilia and rare bleeding disorders,” said Vaishnaw. “Indeed, we believe that once-monthly subcutaneous administration of ALN-AT3 could provide a functional correction of the hemophilia phenotype, representing an attractive disease-modifying therapy. We look forward to the continued data from this Phase 1 study and expect to present additional results in mid-2015 and then later in the year.”

Alnylam noted that thrombin generation is a known biomarker for bleeding frequency and severity in hemophilia patients, and that “the results achieved following ALN-AT3 administration are consistent with thrombin generation levels measured in mild hemophilia.” Additionally, “the observed maximal increase in thrombin generation in the hemophilia subjects remained at the low end of the range for peak thrombin levels in the healthy volunteers enrolled in Part A of the study. These data show that AT knockdown of up to 70 percent in hemophilia subjects should not lead to an excessive increase in thrombin generation beyond normal.”

Hemophilias and rare bleeding disorders result from genetic deficiencies of various blood clotting factors. Standard-of-care treatment for hemophilia consists of replacing the missing clotting factor either as prophylaxis or on-demand therapy; unfortunately, as many as one-third of patients with severe hemophilia A will develop an antibody against their replacement factor, which speaks to a significant need for new hemophilia treatment options.

In other recent news, Alnylam announced on Jan. 21 the pricing of an underwritten registered public offering of 4,736,842 shares of common stock at $95 per share. The offering was expected to close on or about Jan. 26, subject to customary closing conditions, and Alnylam granted the underwriters a 30-day option to purchase up to 710,526 additional shares. The company plans to use the net proceeds for general corporate purposes in hopes of achieving its Alnylam 2020 goal of three marketed products and 10 RNAi therapeutic clinical programs, including four in late-stage development, by the end of 2020. These products and programs will be focused on three therapeutic areas: genetic medicines, cardio-metabolic disease and hepatic infectious disease.