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Presentation Details
| Insights into effective immune tolerance induction in hemophilia A patients with inhibitors:New findings from the interim analysis of the MOTIVATE study Robert F.Sidonio, Jr.1, Carmen Escuriola Ettingshausen2. 1Associate Professor of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, USA.2HZRM Hämophilie Zentrum Rhein Main, Frankfurt, Germany |
Abstract
Background: Inhibitor development is a serious complication in patients with hemophilia A (HA) receiving factor VIII (FVIII) replacement therapy, rendering it ineffective. Emicizumab can prevent bleeding episodes (BEs) in patients with inhibitors, but cannot eradicate them. Immune tolerance induction (ITI) remains the only clinically proven method to tolerize patients to FVIII. Objectives: MOTIVATE (NCT04023019) is an investigator-initiated, international, prospective study of real-life management of patients with HA and inhibitors, and is documenting real-world ITI approaches. Here, we report updated findings of a pre-planned interim analysis evaluating the efficacy of ITI with or without emicizumab prophylaxis. Methods: Males with HA and FVIII inhibitors, with or without prior ITI, were included. Patients were grouped by therapy: standard ITI (Group 1), ITI and emicizumab prophylaxis (Group 2), or emicizumab prophylaxis (Group 3). Treatment regimens were at the discretion of the physician and patients could change groups during the study. The primary outcome for Groups 1 and 2 was ITI success (inhibitor titer <0.6 BU/mL, FVIII recovery ≥66% of normal, FVIII half-life ≥6 h). Secondary outcomes included BEs and time to achieve ITI outcomes. Results: As of August 2025, 52 patients were eligible for analysis (Table 1). Of this cohort, 7/7 patients (Group 1) and 13/27 patients (Group 2) achieved negative inhibitors after a median (range) of 7.9 (1.2–21.2) and 19.8 (1.0–49.1) months, respectively. Median ITI dose was 350 IU/kg/week (range 149.6–625.0) in Group 1 and 222 IU/kg/week (range 56.9–811.6) in Group 2. Seven patients in Group 2 failed ITI, with five subsequently switching to Group 3. At the time of the analysis, 7 patients in Group 2 were ongoing. Of high-responding patients (titer ≥5 BU/mL) on primary ITI, 5/5 patients (Group 1) and 8/19 patients (Group 2) achieved negative inhibitors after a median (range) of 7.9 (2.0–21.2) and 9.9 (1.0–49.1) months, respectively. BEs occurred in all groups, with a total of 134 BEs occurring in 38/52 patients, including 28 moderate joint BEs (Figure 1). Of these joint BEs, 82% (23/28) occurred in 5 patients from Group 3. One mild adverse drug reaction (ADR) related to emicizumab (rash with red papules) was recorded, with no drug discontinuation. No serious ADRs or thrombotic complications were reported. Conclusions: Group 1 (standard ITI) reached negative inhibitors faster than Group 2 (ITI with emicizumab) for all patients and for high-responders on primary ITI. This was likely due to higher and more frequent FVIII dosing in Group 1. BEs were low and occurred in all groups, with most joint BEs occurring in Group 3. No serious ADRs or thrombotic complications were reported.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.