Strategies for Immune Tolerance Induction in Hemophilia a Patients with Inhibitors: The First Prespecified Interim Analysis from the Motivate Study

Field: Medicine (Health Sciences)

Introduction: Inhibitor development is a serious treatment-related complication in patients with hemophilia A treated with factor VIII (FVIII) replacement therapy which renders FVIII therapy ineffective. Emicizumab is currently approved to prevent bleeding in patients with and without inhibitors but does not eradicate inhibitors. Immune tolerance induction (ITI) therapy involves the intensive and repeated administration of FVIII and is the only clinically proven strategy to eliminate inhibitors. Aim: MOTIVATE aims to investigate the real-life management of patients with hemophilia A who have developed inhibitors to FVIII. The study will evaluate the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis. Methods: MOTIVATE is an investigator-initiated, international, multicenter, prospective study (ClinicalTrials.gov NCT04023019; EudraCT 2019-003427-38). Male patients of any age with hemophilia A and FVIII inhibitors, with or without previous unsuccessful ITI attempts, were included following consent. All treatment was at the discretion of the investigator and according to routine clinical practice. Patients were assigned to 1 of 3 groups based on the initial management approach: Group 1 - ITI (FVIII only); Group 2 - ITI and emicizumab prophylaxis; Group 3 - routine prophylaxis with emicizumab without ITI. For all groups, activated prothrombin complex concentrates/recombinant FVIIa could be administered as needed to treat bleeding episodes (BEs) or to cover surgical prophylaxis. Patients were not randomized to a treatment group and could change treatment groups during the study. The primary outcome measure for Groups 1 and 2 was a comparison of ITI outcomes as determined by the proportion of participants achieving: FVIII inhibitor titer &lt; 0.6 Bethesda Unit (BU)/mL; FVIII recovery ≥ 66% of normal; FVIII half-life ≥ 6 hours. The primary outcome measure for Group 3 was the annualized bleeding rate (ABR) compared to the ABR in Groups 1 and 2. Secondary outcome measures included time to achieve ITI outcomes and frequency and severity of BEs. The safety of all treatments was assessed based on the incidence of adverse drug reactions. Results: An interim analysis was performed per protocol once 20 patients were documented for at least one year in Groups 1 and 2. As of June 2024, 56 patients had enrolled from 25 sites across 11 countries. Forty-six patients were eligible for analysis: 7 in Group 1, 22 in Group 2, and 17 in Group 3. Age at study entry (median years [range]) was 4 [1-14], 4.5 [1-29] and 7 [3-66] in Groups 1, 2 and 3, respectively. Total treatment duration (median years [range]) for each group respectively was 2.8 [1.5-5.0], 2.0 [0.7-5.0] and 3.5 [0.3-5.1]. Nineteen patients received recombinant FVIII and 10 patients received plasma-derived FVIII/von Willebrand factor concentrate for ITI. At the time of the interim analysis, 6 patients in Group 1 and 10 patients in Group 2 had achieved a negative inhibitor titer. In Group 2, 2 patients had failed ITI and switched to Group 3. Time to reach negative inhibitors (median months [range]) in Group 1 and 2 respectively was 8.0 [3.6-50.4] and 18.6 [4.8-44.4] with a FVIII dose at ITI initiation (median [range]) of 394.1 [149.6-700.0] and 225.9 [89.6-811.6] IU/kg/week. Overall, there were 151 BEs in 35/45 patients. Six major BEs were recorded in Group 2 (n=3) and 1 in Group 3 (n=1). There were 4 moderate BEs reported in Group 1 (n=4), 13 in Group 2 (n=7) and 35 in Group 3 (n=9). Half of the moderate BEs were joint bleeds (26/52) and 22/26 (85%) occurred in Group 3 patients. Thirty-one minor BEs were reported in Group 1 (n=4), 18 in Group 2 (n=11) and 43 (n=10) in Group 3. One mild adverse drug reaction related to emicizumab was recorded with no discontinuation of drug. No thrombotic events or thrombotic microangiopathy events were reported. Conclusion: The MOTIVATE study is collecting real-world data on the management of patients with hemophilia A and inhibitors. In patients on ITI, time to reach a negative inhibitor titer was shorter in patients receiving ITI without emicizumab (Group 1) compared to patients receiving ITI with emicizumab (Group 2), likely the result of a higher and more frequent FVIII dosing in Group 1. At the time of the interim analysis, minor and moderate bleeds occurred in all groups, while no major bleeds occurred in Group 1. No serious adverse drug reactions and no thrombotic complications were reported.