August 2024 Quick Question Summary: Rebalancing Therapy

Our August 2024 Quick Question, which attracted 18 responses, asked, “Which hemophilia ‘rebalancing’ therapy suppresses antithrombin RNA production?” Here are your answers:

1. Efanesoctocog alfa: 0
2. Concizumab: 3 (17%)
3. Octavian 2 (11%)
4. Hemgenix 3 (17%)
5. Fitusiran 10 (55%)

Rebalancing therapy is the name for using RNA inhibitors (RNAi) that suppress mRNA synthesis, subsequently suppressing selected molecules. In hemophilia, instead of restoring thrombin production with FVIII or FIX concentrates, rebalancing reduces the production of antithrombin (AT) by the RNAi fitusiran, or tissue factor pathway inhibitor (TFPI) by concizumab. Sanofi developed fitusiran and anticipates FDA approval in March 2025. Novo Nordisk submitted concizumab to the FDA, however, in 2023 the FDA requested additional information about the manufacturing process and the company’s system “for monitoring and dosing patients to ensure that the treatment is administered correctly.” Other developers are considering an anti-activated protein C RNAi. Rebalancing therapy bypasses the need for factor concentrates and factor assays, though they may raise the need for AT and TFPI assays.

Efanesoctocog alfa is Sanofi’s generic name for Altuviiio®, an FVIII concentrate that has achieved a half-life 3–4× greater than standard concentrates. The synthetic Fc-fusion FVIII molecule is modified by appending a VWF fragment and applying the “XTEN” function to enhance molecular stability. Efanesoctocog alfa does not bind native VWF and thus eludes the VWF 12-hour half-life, extending the infusion rate to as little as once a week.

Roctavian® is Biomarin’s gene transfer therapy, FDA-approved in 2023, that treats hemophilia A by inducing hepatocytes to produce FVIII. Roctavian therapy theoretically avoids the need for factor concentrates or rebalancing therapy.

Hemgenix® is CSL’s gene transfer therapy, FDA-approved in 2022, that treats hemophilia B by inducing hepatocytes to produce FIX. Pfizer’s Beqvez®, approved in 2024, is a competitor to Hemgenix.

We’ve excluded Hemlibra®, with the scientific name emicizumab, the revolutionary FVIII-bypassing therapeutic, approved in 2018 from this Quick Question, as we first posted a Quick Question about this therapy in 2020.