Sanofi Revises Fitusiran Dosing Regimen to Mitigate Risk

Source: Joint statement from the European Hemophilia Consortium, the World Federation of Hemophilia, and the National Hemophilia Foundation

Fitusiran update following EAHAD 2021 Congress

Fitusiran is an RNA drug that can prevent antithrombin protein from being made in the liver. Antithrombin is an important brake for the coagulation system. Insufficient amounts of circulating antithrombin in normal adults lead to thrombosis. In persons with hemophilia (PWH) A or B, who don’t have sufficient clotting, lowering antithrombin with fitusiran has been shown to increase coagulation and protect PWH from bleeding. It is presently in Phase 3 clinical trials.

On October 30, 2020, in response to reports of non-fatal vascular thrombotic events within the fitusiran clinical program for patients with hemophilia A/B with and without inhibitors for adult and adolescents, the sponsor voluntarily paused dosing in all patients in the ongoing clinical studies. See the joint statement of the WFHEHC and NHF.

In total, there have been 5 events. The first 2 events were previously reported.  The first was a cerebral sinus venous thrombosis initially diagnosed as a cerebral bleed resulting in a large amount of concomitant factor concentrate being used, and resulted in a fatal outcome. The second was an atrial thrombosis after concomitant use with a bypassing agent (rFVIIa). These events were associated with the use of doses of clotting factor concentrates or bypassing agent that exceeded current breakthrough bleed management guidelines.

The 3 more recent events, which resulted in the October 2020 voluntary dosing pause, include a cerebral infarct, a cerebrovascular accident and a spinal vascular disorder (suspected thrombosis involving a spinal injury) despite adherence to breakthrough bleed management guidelines. Evaluation of all 5 of these events has suggested the risk of vascular thrombotic events may be greater with antithrombin (AT) levels that have been reduced below 10% of normal levels. As a result, the study will now target AT levels between 15% and 35%, seeking to maintain a favorable benefit-risk balance for patients.

In January 2021, a revised dosing plan came under review by global health authorities and has been approved by the US Food and Drug Administration (FDA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).  Following review by health authorities, international review boards (IRB) and patient re-consent, fitusiran dosing will resume on a country-by-country basis. During the Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) in early February 2021, Sanofi presented its revised fitusiran dosing regimen proposed to mitigate the risk of vascular thrombosis.

There is no change to the bleed management guidelines during fitusiran prophylaxis.

We are reporting this information, available in the public domain, and will continue to keep our patient communities informed of further relevant developments.

Fitusiran is one of the rebalancing agents in clinical development. These agents, which include anti-TFPI antibodies and an inhibitor of activated protein C, aim to make the clotting system more procoagulant, to compensate for defective coagulation in hemophilia A/B. In some anti-TFPI clinical trials, thrombotic events have also occurred in a small number of participants. Thus, careful dose selection and careful use of clotting factor concentrates during breakthrough bleeds is extremely important.

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