This article is part 2 in a series on haemophilia diagnostics and therapeutics. The first article, which can be viewed here, provides an overview of its clinical presentation, diagnosis and treatment.

As researchers develop innovative new treatments for haemophilia, clinical lab professionals should be aware of these developments and their potential impact on diagnostic workflows. This article will explore some emerging treatment modalities and their implications for laboratory medicine.

What are some emerging therapies for haemophilia?

Treatment for haemophilia today focuses on replacement therapy, a process that involves using clotting factor concentrates to replenish a patient’s blood. These treatments can cause complications, such as the development of neutralising antibodies (inhibitors) that attack the clotting factor in blood and lead to higher morbidity rates from haemophilia [1].

To address these issues and others, healthcare professionals are exploring a variety of new approaches to haemophilia therapy, including extended half-life (EHL) clotting factors; monoclonal antibodies that target the tissue factor pathway inhibitor (TFPI); bispecific antibodies that work as non-factor replacement therapies; and gene therapies that hold promise to cure the condition.

EHL clotting factors

Since the 2010s, recombinant technology has been introduced to engineer the factors to extend their time in the circulation, reducing the dosing frequency [2]. Currently,  EHL FVIII and FXI products are available. The pharmacokinetics and efficacy of the various EHL products are well demonstrated, particularly in the prevention and treatment of bleeds.

Monoclonal antibodies that target the tissue factor pathway inhibitor (TFPI)

Multiple studies are underway of monoclonal antibodies that target TFPI inhibitors and promise enhanced haemostatic activity, more stable clot formation and a subsequent reduction of bleeding events. One example is concizumab, a human monoclonal antibody that is being evaluated in phase 2 clinical trials in patients with haemophilia A and B.  Regulatory approval for concizumab in haemophilia A or B is anticipated in the EU, UK and US in 2023/4.   Recruitment is also ongoing for a phase 1 clinical trial of BAY1093884, another monoclonal antibody similar to concizumab.

Bispecific antibodies that work as non-factor replacement therapies

Other emerging therapies include non-factor replacement products. These are generally bispecific antibodies like emicizumab that mimic the clotting factors, effectively bridging FXIa and FX.  Emicizumab is indicated for routine prophylaxis in adult and paediatric patients with FVIII inhibitors. It was granted a breakthrough therapy designation for haemophilia A in April 2018[3].

Gene therapies that hold promise to cure the condition

In addition, gene therapy is being researched as a potential for a cure for haemophilia. On 24 May 2022, FDA accepted the priority review request for etranacogene dezaparvovec for a haemophilia B gene therapy [4]. On 24 June 2022, The European Medicines Agency had recommended granting a conditional approval to valoctocogene roxaparvovec to treat patients with severe haemophilia A who do not have factor VIII inhibitors. It is now pending for the approval decision by the European Commission [5].

What does this mean for laboratory diagnostics?

Clinical lab diagnostics play an important role to monitor the effectiveness of the different haemophilia therapies. When replacement therapy is administered, for example, the choice of factor concentrate is crucial as it influences the choice of assays used for the measurement.

With the introduction of non-factor therapeutics such as emicizumab, laboratories would first need to understand the therapeutic mode of action and the biochemical impact for the different types of assays. After that, they can select the most appropriate assays for monitoring:

Regardless of the choice of therapy, the possibility of developing inhibitors remains. Clinical labs need to monitor the development of inhibitors as they impact the effectiveness of therapy. The following are some points to note for inhibitor testing.

Although replacement therapy in the form of both plasma-derived and recombinant factor products remains the leading treatment for haemophilia today, promising research is clearly underway for the discovery of novel agents. These agents use different molecular drug targets, genes and proteins involved in the process of a clotting cascade. The results have generated reasonable optimism that a pathway toward a cure for haemophilia may exist in the near future [6].

References:

[1] Centres for Disease Control and Prevention, Haemophilia Homepage-Inhibitors and Haemophilia https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html

[2] Mannucci, P., 2020. Hemophilia therapy: the future has begun. Haematologica, 105(3), pp.545-553.

[3] FDA approves emicizumab-kxwh for prevention and reduction of bleeding in patients with hemophilia A with factor VIII inhibitors. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-emicizumab-kxwh-prevention-and-reduction-bleeding-patients-hemophilia-factor-viii

[4] CSL Behring gene therapy makes comeback after hold for FDA priority review. https://www.fiercebiotech.com/biotech/2020-trial-pause-isnt-holding-csl-behring-back-fda-oks-priority-review-application

[5] BioMarin’s haemophilia gene therapy Roctavian wins conditional EU backing amid FDA delay. https://www.fiercepharma.com/pharma/biomarins-hemophilia-gene-therapy-roctavian-wins-conditional-eu-backing-fda-plan-delayed

[6] World Federation of Haemophilia Guidelines for the Management of Haemophilia. https://www1.wfh.org/publications/files/pdf-1863.pdf

[7] National Haemophilia Foundation for all bleeding disorders-current treatments. https://www.hemophilia.org/bleeding-disorders-a-z/treatment/current-treatments

[8] World Federation of Haemophilia Guidelines for the Management of Haemophilia. https://www1.wfh.org/publications/files/pdf-1863.pdf