Concizumab could be a safe and effective subcutaneous prophylactic treatment option for patients with hemophilia A or B with or without inhibitors, according to results from two studies presented at the 2019 Congress of the International Society on Thrombosis and Haemostasis.
“Clinical proof-of-concept for once-daily subcutaneous prophylaxis with concizumab was established in these phase II trials, as evidenced by both the decrease in annual bleeding rates and the normalization of thrombin generation potential for these patients,” lead study author Jan Astermark, MD, PhD, from Skåne University Hospital in Lund, Sweden, told ASH Clinical News.
He added that concizumab – a humanized monoclonal antibody that enhances thrombin generation potential by inhibiting tissue factor pathway inhibitor – could offer patients a minimally invasive treatment option, as it has “a very small volume of administration, a small needle, and a simple, portable injection device.”
Dr. Astermark presented the results of two separate phase II trials, explorer 4 and explorer 5. The studies enrolled 36 patients with hemophilia A, nine with hemophilia A with inhibitors (HAwI), and eight with hemophilia B with inhibitors (HBwI). Participants received concizumab 0.15 mg/kg, with potential dose escalation to 0.20 or 0.25 mg/kg using a stepwise dose-escalation protocol.
Treatment continued for 24 weeks. Explorer 4 evaluated concizumab in both the main phase and extension phase, with recombinant FVIIa administered as needed during bleeding episodes; explorer 5 evaluated daily administration of concizumab for both on-demand treatment and bleeding prophylaxis. Also, in explorer 4, patients received a loading dose of concizumab 0.5 mg/kg as the first dose before beginning treatment at the 0.15 mg/kg dose.
After 24 weeks of treatment, concizumab prophylaxis reduced the annualized bleeding rates (ABR) across all participants. For example, in patients with HAwI/HBwI who received recombinant FVIIa on demand, the estimated ABR dropped from 20.4 in the year prior to study treatment to 4.5 at 24 weeks after treatment (p values not reported). Patients with hemophilia without inhibitors also experienced a reduction in ABR with concizumab, with an estimated ABR of 7.0.
This finding confirmed the clinical proof-of-concept reported previously, according to the study authors.
During the 24-week follow-up, the researchers observed no thromboembolic events, no adverse event (AE)–related withdrawals, and no safety concerns with breakthrough-bleed treatment. “Importantly there were no withdrawals due to AEs and all patients who completed the main phases [of explorer 4 and explorer 5] chose to continue into the ongoing extension phases,” added Dr. Astermark.
Although these findings are limited by a short duration of follow-up, Dr. Astermark noted that the results and positive safety profile bode well for the next phase of the studies.
“The phase III program is now recruiting for a non-interventional trial establishing a solid set of baseline data for the patients that will continue later this year into the pivotal trials,” he explained. “The pivotal studies consist of a trial for patients with inhibitors and without inhibitors (explorer 7 and 8), both aimed at establishing the efficacy and safety of once-daily subcutaneous prophylaxis with concizumab.”
The authors report relationships with Novo Nordisk, which sponsored both trials.
Astermark J, Angchaisuksiri P, Benson G, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 Trial Results. Abstract LB 01.1. Presented at the International Society of Thrombosis and Haemostasis 2019 Congress, July 9, 2019; Melbourne, Australia.