Current and emerging biologics for the treatment of hemophilia

ABSTRACT

Introduction: The development of new biologic agents able to restore thrombin generation has become the focus of innovation in hemophilia management. There is growing interest in the proposal of novel, non-replacement therapy with alternative mechanisms of action and route of administration, hoping to solve still unmet needs in treatment of hemophilic patients with or without inhibitors.

Areas covered: The review describes the new molecules, in particular the bi-specific antibody mimicking the coagulation function of FVIII and/or those which work by inhibiting the natural anticoagulants, their mechanism of action and the results of ongoing clinical trials.

Expert opinion: Exciting results in enhancing the protection against bleeding and improving quality of life are emerging from clinical trials. However, these molecules with their mechanisms of action also open new problems. Treatment of bleeding and management of surgery in subjects with a rebalanced hemostasis may be difficult, especially for the lack of laboratory tests perfectly reflecting the in vivo coagulation status. A careful surveillance is required to evaluate the risk of thrombotic complication in patients with rebalanced hemostasis, in addition to understand whether these new products offer the same protection on joints as regular prophylaxis with the missing clotting factors.

Trial registration: ClinicalTrials.gov identifier: NCT03361137.

KEYWORDS:

• Anti-TFPI
• antithrombin suppression
• bi-specific antibody
• bleeding
• hemophilia
• inhibitors
• prophylaxis
• rebalanced hemostasis

Article highlights

• Despite significant recent improvements, replacement therapy for hemophilia treatment still has some drawbacks as frequency and route of administration, breakthrough bleeding in prophylaxis, inability to implement a long-term prophylaxis in patients with inhibitors

• Recent researches have led to the development of nonfactor replacement products such as bi-specific antibody mimicking FVIII (Emicizumab) or molecules which work by inhibiting the natural anticoagulants in order to rebalance the hemostatic system such as TFPI (Concizumab), AT (Fitusiran) and APC.

• Emicizumab will offer the opportunity to implement a suitable prophylactic regimen in patients with hemophilia A with and without inhibitors. The selection of patients will be an important task in the real life. The management of bleeding and surgery will represent a challenge and specific guidelines will be needed.

• Better knowledge on efficacy and safety of Concizumab and Fitusiran will be implemented by clinical trials. Their use in treatment of bleeding and in management of surgery may be difficult, especially for the lack of laboratory tests perfectly reflecting the in vivo coagulation status.

• The search for laboratory tests useful for monitoring these therapies is an important upcoming task.

• These new biologic agents would likely improve access to regular prophylaxis because they are administered subcutaneously, they have a long half-life and they can be used in patients with hemophilia A and B, with or without inhibitors.

Declaration of interest

G Castaman has participated on Advisory Boards and or as a speaker for Novo Nordisk, Roche, CSL Behring, Sobi, Kedrion, Shire and Bayer. S Linari has participated on Advisory Boards for Shire, Kedrion, Novo Nordisk, CSL Behring, Roche and Sobi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.