Concizumab holds promise for patients with haemophilia A or B with inhibitors

In patients with haemophilia A (PwHA) or B (PwHB) with inhibitors, annualized bleeding rate (ABR) was lower with daily subcutaneous (SC) concizumab prophylaxis than with on-demand treatment, findings from the phase IIIa explorer7 trial have shown.

The study enrolled 80 PwHA and 53 PwHB receiving on-demand treatment with bypassing agents. Of these, 19 were randomized to continue to receive on-demand treatment (ie, no prophylaxis) for ≥24 weeks (group 1) while 33 received concizumab prophylaxis for ≥32 weeks (group 2). Eighty-one participants were nonrandomized to receive concizumab prophylaxis for ≥24 weeks (groups 3 and 4). [N Engl J Med 2023;389:783-794]

Following a loading dose of 1.0 mg/kg on day 1, all concizumab recipients started with a QD dosing of 0.2 mg/kg from day 2. After a treatment pause owing to nonfatal thromboembolic events in three concizumab recipients, concizumab was restarted (dose may be adjusted based on concizumab plasma concentration measured at week 4).

The estimated mean annualized rate of treated spontaneous and traumatic bleeding episodes was significantly lower in group 2 vs group 1 (1.7 vs 11.8; ABR ratio, 0.14; p<0.001). “[This] finding confirms the superiority of concizumab prophylaxis over no prophylaxis,” the researchers said.

Group 2 also had lower estimated mean annualized rates of treated spontaneous (1.3 vs 9.4; ABR ratio, 0.14), joint (1.4 vs 9.1; ABR ratio, 0.15), and target joint bleeding episodes (0.1 vs 1.1; ABR ratio, 0.12) relative to group 1, as well as all treated and untreated bleeding episodes (4.4 vs 13.3; ABR ratio, 0.33).

Overall median ABR for concizumab recipients was 0 episodes.

The most common adverse events (AEs) reported with concizumab use were arthralgia (10 percent), injection-site erythema (7 percent), and upper respiratory tract infection (6 percent).

Overall, AEs tied to concizumab use were primarily low-grade, and serious events were rare (18 events in 14 patients in groups 1–4). Before the treatment pause, one serious thromboembolism (renal infarction) occurred, and two patients* had thromboembolism. [Haemophilia 2021;27(Suppl 2):124; Blood 2020;136(Suppl 1):40]

Treatment caveats

The development of inhibitors – which may limit the efficacy of factor-replacement therapies – may increase disease burden in haemophilia. [Haemophilia 2017;23:105-114; Blood 2019;134:317-320]

“These antibody inhibitors prevent exogenous clotting-factor concentrates from achieving haemostasis, which leads to increased morbidity and mortality,” said Dr H Marijke van den Berg from the PedNet Haemophilia Research Foundation, Baarn, the Netherlands and Dr Alok Srivastava from the Christian Medical College Vellore, Ranipet, India, in an editorial. [N Engl J Med 2023;389:853-856]

Moreover, patients with inhibitors may require treatment for breakthrough bleeding with bypassing agents. [J Thromb Haemost 2018;16:2362-2374] Taken together, these factors may negatively impact treatment adherence and outcomes, the researchers stressed.

Guidelines recommend emicizumab prophylaxis over bypassing agents in PwHA and persistent inhibitors who had failed or never had immune tolerance induction. [Haemophilia 2020;26(Suppl 6)1-158] “However, bypassing agents may be needed to treat breakthrough bleeding episodes in [these patients even while on] emicizumab prophylaxis,” the researchers noted.

For PwHB with inhibitors, there are no effective prophylactic therapies or easily administered SC treatments available, success rates are low with immune tolerance induction, and such therapy may have severe consequences, they continued. “[T]hese factors result in poor outcomes for PwHB with inhibitors,” said the researchers.

Furthermore, the IV administration of factor VIII or IX concentrates for treating haemophilia A or B, respectively, may confound treatment because repeated venipuncture is not always feasible (especially in children) and it mostly requires a central venous access device (CVAD), the researchers said. Treatment burden is further amplified by potential complications tied to the CVAD. [Haemophilia 2008;14:931-938; Eur J Haematol 2014;93(Suppl 75):9-18]

Results meet benchmarks of effective haemophilia therapy

SC prophylaxis may cut this treatment burden. The SC delivery of concizumab – a novel, monoclonal antibody to tissue factor pathway inhibitor (TFPI) – despite the required daily administration, offers more convenience than IV infusions, said van den Berg and Srivastava.

In this trial, TFPI was reduced to ~10 percent within 24 hours after the loading dose, there were 0 ABR epi­sodes overall, and about 60 percent of patients had no bleeding episodes. “[These] values meet the current benchmarks of effective haemophilia therapy,” they continued.

“It is reassuring that this first-in-class drug is effective in [this patient setting]. Given its reported efficacy in both types of haemophilia without inhibitors, concizumab is evolving as an attractive therapeutic for all patients with haemophilia,” added van den Berg and Srivastava.