Health-Related Quality-of-Life Improvements after Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia

Background: Transfusion-dependent β-thalassemia (TDT), an inherited hematological disorder requiring life-long, chronic red blood cell (RBC) transfusion and iron chelation therapy, has a negative impact on health-related qualify of life (HRQoL). Exagamglogene autotemcel (exa-cel), a one-time, ex vivo, CRISPR/Cas9 gene-edited, autologous cell therapy shown to eliminate the need for RBC transfusions and achieve transfusion independence, is approved for the treatment of TDT in patients ≥12 years of age. We report long-term HRQoL measures for participants with TDT after exa-cel infusion in the ongoing phase 3 CLIMB THAL-111 and CLIMB-131 studies.

Methods: CLIMB THAL-111 is a 2-year, pivotal phase 3 study of a single dose of exa-cel in participants (12-35 years) with TDT who have a history of ≥100 mL/kg/year or ≥10 U/year of packed RBC transfusions for 2 years before screening. After completing CLIMB THAL-111, participants may enroll in the 13-year, long-term extension study, CLIMB-131. In both studies, changes from baseline over time for patient-reported outcomes (PROs) were assessed as a secondary endpoint. PROs for adults included EuroQol Scale 5 dimensions 5 levels of severity (EQ-5D-5L, includes descriptive system and visual analog scale [VAS]) and Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, includes FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]). PROs for adolescents included EuroQol Scale 5 dimensions youth (EQ-5D-Y) and Pediatric Quality of Life Inventory (PedsQL). Minimal clinically important difference (MCID) thresholds and population norms are provided, where applicable, to contextualize clinical meaningfulness of HRQoL scores. Data are presented for participants who were followed for ≥16 months and were included in the efficacy evaluable population.

Results: As of May 2024, a total of 34 adults (mean: 25.1 years; range: 18, 35) and 18 adolescents (mean: 14.6 years; range: 12, 17) in the efficacy evaluable population were followed for up to 5.3 years (median: 3.0 years, range: 1.5, 5.3) after exa-cel infusion. Clinically meaningful improvements in HRQoL measures were observed across all measures and exceeded MCID thresholds, when applicable. The mean (SD) EQ-5D-5L US index score at baseline (n=34; 0.88 [0.16]) was similar to scores for the general US population norm (80.4 [15.6]) and those previously reported for adults with TDT. By Month 48, mean EQ-5D-5L health utility US index scores and mean EQ VAS scores showed substantial improvements exceeding population norms and MCID (n=5; 0.22 [0.3], MCID: 0.078; 14.2 [10.9], MCID: 7 to 10). The mean FACT-G total score improved from baseline by Month 6 and was maintained through Month 48 (n=5; 16.8 [15.7], MCID: 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, functional well-being). Mean BMTS improved by Month 6 and was maintained through Month 48 (n=5; 7.5 [3.6], MCID: 2 to 3). For adolescents, mean EQ VAS scores improved through Month 24 (n=14; 7.3 [16.4]). The mean PedsQL total score, which includes psychosocial functioning and physical health scores, improved by Month 6 and were maintained through Month 24 (n=13; 12.2 [11.8], MCID: 4.36). Improvement in psychosocial functioning score was observed in all 3 subscales (social, emotional, school functioning).

Conclusion: These results demonstrate that exa-cel provides substantial and durable clinical benefit to adults and adolescents with TDT with improvements exceeding MCID across applicable outcomes for HRQoL including physical, social/family, emotional, functional well-being, and overall health status.

de la Fuente:MAAT Pharma: Membership on an entity's Board of Directors or advisory committees; Sangamo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Meisel:Vertex: Consultancy. Wall:Editas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals Incorporated: Membership on an entity's Board of Directors or advisory committees, Other: Steering committee. Corbacioglu:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Li:Novartis Pharmaceuticals Canada: Membership on an entity's Board of Directors or advisory committees. Shah:Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Mapara:Bluebirdbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ossiumhealth: Consultancy. Merkeley:Novartis: Other: Educational Grants, Clinical Trials; Vertex Pharmaceuticals: Other: Clinical Trials; Novo-Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trials, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medison: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kuo:Alexion Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Biossil: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy, Research Funding; Vertex Pharmaceuticals: Consultancy, Honoraria; Sangamo: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Consultancy; Agios Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kohli:Vertex Pharmaceuticals Incorporated: Current Employment. Li:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Rubin:Vertex Pharmaceuticals: Current Employment. Zhang:Vertex Pharmaceuticals: Current Employment. Liu:Vertex Pharmaceuticals: Current Employment. Hobbs:Vertex Pharmaceuticals Incorporated: Current Employment. Frangoul:Vertex Pharmaceuticals: Consultancy; Editas Medicine: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; BioLineRx: Consultancy; Rocket Pharma: Consultancy.