Novel Agent Reduces Antithrombin Levels to Treat Hemophilia

Daniel M Keller, PhD

July 14, 2017

BERLIN, GERMANY — An investigational RNA interference (RNAi) agent that reduces levels of circulating antithrombin promotes clotting function in people with hemophilia A or B[1].

By depleting antithrombin, the agent, fitusiran (Alnylam), allows sufficient thrombin generation for effective homeostasis. Because it works downstream in the coagulation cascade from factor VIII, lacking in hemophilia A, or factor IX, lacking in hemophilia B, fitusiran works in either condition.

"This approach can be used for patients with and without inhibitors," Dr John Pasi (Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK) said at a news conference here at the International Society on Thrombosis and Haemostasis 2017 Congress. "The other thing to bear in mind about this approach to treatment is that it can be used for hemophilia A and hemophilia B because it's not dependent on either clotting factor."

The results were also published simultaneously online July 10, 2017 in the New England Journal of Medicine.

In an abstract session at the congress, Pasi reported the full results of a phase 2 open-label extension study in which patients (n=33) with hemophilia A or B with or without inhibitors of coagulation factors received 50 mg or 80 mg of fitusiran monthly by subcutaneous injection. The patients had received the drug previously in a phase 1 trial at various dosages and on various schedules.

"What we can see is that when you get fitusiran at either of the doses, it drives your thrombin generation up, and it gets into the lower part of the normal range. . . . So that's a significant improvement for patients whose thrombin generation is basically extremely low," he said. "Importantly, we don't see very high levels."

RNAi works by targeting specific mRNA and preventing translation into protein, in the case of fitusiran, antithrombin. Fitusiran is a small, chemically synthesized RNA molecule with a ligand to direct it to the liver, which is the site of antithrombin synthesis. It works by the same natural RNAi mechanism that regulates plasma antithrombin levels.

At both doses of fitusiran, antithrombin levels dropped to about 20% to 30% of baseline by 30 days since the first dose. Levels remained within the 20% range or lower out to 360 days.

Thrombin generation crept into the lower level of that seen in healthy volunteers (range 64–210 μM) at 90 days and for both doses hovered around or above 45 μM for the rest of the year.

Most important, bleeding rates were well controlled on fitusiran. Bleed events were evaluated when antithrombin lowering exceeded 75% compared with baseline. On the drug, 48% (16/33) of patients without inhibitors had no bleeds during the study observation period; 67% of patients reported no spontaneous bleeds.

For the entire group of patients without inhibitors, the median annualized bleeding rate (ABR) was 1.7, compared with 2 for those patients on previous prophylaxis and 12 for those with on-demand therapy. For patients with inhibitors, the ABR was 0 during the observation period vs 38 in the prestudy period.

All bleeding events were successfully managed with factor replacement for patients without inhibitors or with activated prothrombin complex concentrates or factor replacement for patients with inhibitors.

The groups of patients getting the 50-mg or 80-mg dose were fairly well matched in terms of age and weight. Twenty-seven patients had hemophilia A, and six had hemophilia B. Thirty had severe disease and three moderate disease. Most (n=27) had a positive history of hepatitis C (HCV).

Patients received fitusiran for up to 20 months (median 11 months) in the extension phase of the trial. Five of the 33 patients discontinued dosing, of which only one was for an adverse event and the others for withdrawal of consent.

Good Safety and Tolerability

Adverse events were reported by 70% of the patients, but most were mild or moderate in severity and were not related to the study drug. Six patients reported severe adverse events, two of which were considered possibly to be related to the drug. One was an elevation in liver enzymes and led to discontinuation in a patient with chronic HCV infection. The other was a seizure in a patient with a history of seizure disorder.

In other patients, some asymptomatic abnormalities in liver-function tests were noted, but they largely resolved on their own.

In patients without hemophilia but with an antithrombin deficiency, thrombosis is a concern, However, in this study, no thromboembolic events occurred, and there was no clinical or laboratory evidence of pathologic clot formation. The researchers did not find any formation of drug-induced antidrug antibodies.

Pasi concluded that the open-label extension phase of the trial provides encouraging data "that demonstrate patient safety in up to 20 months of treatment and that the majority of [adverse events] were mild. And we've got very encouraging results in terms of clinical outcome. We can show that we can reduce antithrombin by approximately 80% with very low interpatient variability, and this treatment can be administered on a once-a-month subcutaneous basis."

Dr Wolfram Ruf (Johannes Gutenberg University, Mainz, Germany) commented to theheart.org | Medscape Cardiology that RNAis are becoming very popular for addressing the coagulation system. "These therapies seem to be quite safe and work well. Inhibiting the inhibitors with this antithrombin III is certainly one way to go about it."

But he cautioned that more study is needed on agents that modulate the coagulation system. "With everything where you rebalance [it] there is the thrombosis risk, and it will be interesting to see how the actual safety data will look in the end. But these are interesting bypassing pathways that one can exploit to reduce the bleeding in factor VIII inhibitor patients in particular."

The study was supported by Alnylam Pharmaceuticals. Dr Pasi receives grant and/or research support from BioMarin, Alnylam Pharmaceuticals, and Bioverativ and honoraria from Pfizer, Sobi, Genzyme, Octapharma, Bayer, Alnylam, BioMarin, Biotest, and Shire. He is a paid instructor for Roche, Novo Nordisk, and Pfizer. Disclosures for the coauthors are listed on the journal website. Dr Ruf had no relevant financial relationships.

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