Participants with a History of Stroke in Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials

Introduction: Overt ischemic stroke is a devastating complication for patients with sickle cell disease (SCD) and is considered an indication for allogeneic transplantation. Lovo-cel is a one-time gene addition therapy for patients ≥12 y with SCD and a history of vaso-occlusive events (VOEs). Lovo-cel uses autologous transplantation of hematopoietic stem and progenitor cells transduced with a functional β-globin gene. Here, we provide a post hoc analysis of participants with histories of overt or silent stroke enrolled in the phase 1/2 HGB-206 (NCT02140554) and phase 3 HGB-210 (NCT04293185) clinical trials of lovo-cel in SCD.

Methods: Study designs have been previously described (Kanter, et al. Am J Hematol. 2023;98:11-22; Kanter, et al. N Engl J Med. 2022;386:617-628). This analysis included participants from HGB-206 (Groups A, B, or C) and HGB-210 with a history of overt or silent stroke. Prior to Jul 30, 2018, HGB-206 protocols allowed enrollment of participants with history of overt stroke (without moyamoya); HGB-210 excluded such participants. Overt stroke was defined as a sudden neurological change lasting >24 hr accompanied by cerebral MRI changes. Silent stroke was defined as abnormal brain MRI in the setting of normal neurologic examination without history of findings associated with overt stroke. For participants with history of overt stroke, the following were evaluated: globin response, VOEs (evaluated 6-18 mo post lovo-cel infusion), stroke recurrence, and transfusion independence post lovo-cel infusion. For participants with history of silent stroke, stroke recurrence post lovo-cel infusion was evaluated. Outcomes are reported through Feb 2024 (inclusive of the ongoing LTF-307 extension [NCT04628585]).

Results: As of Feb 2024, 67 participants had received lovo-cel in HGB-206 or HGB-210. Six participants (HGB-206 Group A, n=2; HGB-206 Group C, n=4) had a history of overt stroke (age range at informed consent, 19-34 y). Age at first stroke ranged from 4-15 y; time range between first stroke and informed consent was 4-15 y. Follow-up (range) was 54.2-95.9 mo. Both participants with overt stroke history from Group A (ie, initial manufacturing process) had improvements in total hemoglobin (Hb) and some expression of HbA^T87Q which remained stable, but neither achieved globin response. One Group A participant experienced 1 VOE during the evaluation period. Both participants remain stable without recurrent stroke or VOEs up to 95.5 and 95.9 mo. The 4 participants with overt stroke history from Group C (ie, current manufacturing process) were receiving chronic red cell transfusions at informed consent. All 4 achieved globin response post lovo-cel infusion; % HbA^T87Q and % HbS of total Hb at 6 mo post infusion ranged from 39.7%-62.0% and 35.8%-53.0%, respectively. Single-cell western blots from Group C participants showed 78.6%-91.6% of red blood cells contained HbA^T87Q between 6 mo and last follow-up. None of these participants experienced a VOE during the evaluation period; 1 participant experienced a single VOE at >36 mo. There were no reports of stroke post lovo-cel infusion. All Group C participants with overt stroke history remained transfusion independent without recurrent stroke up to 70.1 mo. Nontransfused Hb at last visit post infusion ranged from 10.4-14.4 g/dL. There were no new safety findings in participants with overt stroke history.

Among all treated participants, 40 had MRI data available at screening; retrospective review identified evidence of silent stroke in 21 (52.5%). There were no reports of recurrent overt or silent stroke in any participant with a history of silent stroke (follow-up range, 0.9-77.0 mo). Among all treated participants, 41 had MRIs available 12 or 24 mo post infusion; no new overt or silent strokes were observed.

Conclusion: These data show hematologic response to lovo-cel in participants from Group C with a history of stroke was generally consistent with the overall Group C population (Kanter, et al. Am J Hematol. 2023;98:11-22; Kanter, et al. Blood. 2023;142(Suppl 1):abs 1051). No recurrent stroke or new safety findings have been reported, suggesting continued therapeutic benefit of lovo-cel treatment. Longer follow-up will be required to understand the impact on neurovasculature and risk of stroke recurrence. These data will help inform real-world lovo-cel treatment recommendations and decisions for those with SCD and their care providers.

Jaroscak:Just Worldwide: Other: Market Research; Bioline Rx: Other: Advisory Board; Pfizer: Other: Advisory Board. Kanter:Bausch: Consultancy; Beam Tx: Consultancy, Research Funding; Bioline Rx: Consultancy; Optum United Health: Consultancy; Novo Nordisk: Consultancy, Research Funding; Fulcrum: Consultancy; Guidepoint Global: Consultancy; EcoR1: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GLG Pharma: Consultancy; Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Emerging Therapy Solutions: Honoraria; Novartis: Consultancy; Health Resources and Services Administration: Other: Federal Funding; Sanofi: Consultancy; Affimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; NIH/NHLBI: Other: Federal Funding; CDC: Other: Federal Funding; bluebird bio: Consultancy, Research Funding; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Watkins, Lourie, Roll & Chance: Consultancy. Chawla:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Kinney:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Lodaya:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Pan:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Sheldon-Waniga:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Pierciey:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson:Editas: Consultancy, Research Funding; Beam Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; Global Blood Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; CRISPR/Vertex: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding.