Health-Related Quality-of-Life Improvements after Exagamglogene Autotemcel in Patients with Severe Sickle Cell Disease

Background: Severe sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs), which negatively impact health-related quality of life (HRQoL). Exagamglogene autotemcel (exa-cel), a one-time, ex vivo, CRISPR/Cas9 gene-edited, autologous cell therapy shown to eliminate VOCs is approved for the treatment of severe SCD in patients ≥12 years of age. We report long-term HRQoL measures for participants with SCD in the ongoing phase 3 CLIMB SCD-121 and CLIMB-131 studies.

Methods: CLIMB SCD-121 is a 2-year, pivotal phase 3 study of a single dose of exa-cel in participants (12-35 years) with SCD and a history of ≥2 VOCs/year in each of the 2 years before screening. Participants who completed CLIMB SCD-121 may enroll in the 13-year, long-term extension study, CLIMB-131. Changes from baseline over time for patient-reported outcomes were assessed as a secondary endpoint in both studies: EuroQol Scale 5 dimensions 5 levels of severity (EQ-5D-5L; includes descriptive system and visual analog scale [VAS]), Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT; includes FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]), Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), 11-point pain Numerical Rating Scale (NRS) for adults; EuroQol Scale 5 dimensions youth (EQ-5D-Y), Pediatric Quality of Life Inventory (PedsQL), and 11-point pain NRS for adolescents. Minimal clinically important difference (MCID) thresholds and population norms are provided to contextualize clinical meaningfulness of HRQoL change scores, as applicable. 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 29 adults (mean: 23.6 years; range: 18, 34) and 11 adolescents (mean: 14.5 years; range: 12, 17) in the efficacy evaluable population were followed for up to 4.9 years (median 2.6 years, range: 1.4, 4.9) after exa-cel infusion. Clinically meaningful improvements were observed in all HRQoL instruments and met or exceeded MCID thresholds, where applicable. For adults, baseline EQ-5D-5L US index (mean [SD]: 0.77 [0.26]) and EQ VAS (mean [SD]: 70.3 [22.4]) scores were lower than that of the general US population norm (EQ-5D-5L US index mean [SD]: 0.85 [0.21]; EQ VAS mean [SD]: 80.4 [15.6]) and similar to baseline scores for adults with recurrent VOCs. By Month 6, substantial improvements that were maintained through Month 36 were observed in EQ-5D-5L health utility US index (n=14; mean [SD]: 0.12 [0.16]; MCID: 0.078) and EQ VAS (n=14; mean [SD]: 26.8 [22.0]; MCID: 7-10). Mean FACT-G total scores improved from baseline at Month 36 (n=14; 24.3 [23.4], MCID: 3 to 7) with improvements seen in all 4 subscales (physical, social/family, emotional, functional well-being). Mean BMTS scores improved by Month 6 and were maintained through Month 36 (n=14; 5.1 [6.4], MCID: 2 to 3). All subscales of the ASCQ-Me except stiffness (emotional impact, pain impact, social functioning impact, sleep impact, pain episode frequency, pain episode severity) showed clinically meaningful improvements from baseline through month 36 exceeding MCID; for the pain-related subscales, the largest numerical improvement was pain episode frequency (n=14; mean [SD]: -21.1 [6.4], MCID: -5). Improvements in pain NRS were observed by Month 6 and maintained through Month 36 (n=14; mean [SD]: -1.9 [2.2], MCID: -1). For adolescents, improvements in the EQ-5D-Y VAS were observed by Month 12 and maintained through Month 24 (n=6; mean [SD]: 11.2 [26.6]). Mean PedsQL total score improved by Month 3 and was maintained through Month 24 (n=5; 27.4 [16.8], MCID: 4.36), with consistent improvements in domains and sub-domains, including physical functioning and psychosocial health (social, emotional, school functioning). For adolescents, improvements in pain NRS were maintained through Month 24 (n=7; mean [SD]: -0.9 [0.7], MCID: -1).

Conclusion: These results demonstrate that exa-cel provides substantial and durable clinical benefit to adults and adolescents with SCD in HRQoL including physical, social/family, emotional, functional well-being, pain experience, and overall health status.

Sharma:Sangamo Therapeutics: Consultancy; Vertex Pharmaceuticals: Consultancy, Other: Clinical Trial site-PI; Editas Medicine: Consultancy; Medexus Inc.: Consultancy; Beam Therapeutics: Other: Clinical Trial site-PI; Novartis: Other: Clinical Trial site-PI; CRISPR Therapeutics: Other: Clinical Trial site-PI, Research Funding. Frangoul:Editas Medicine: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; Vertex Pharmaceuticals: Consultancy; Rocket Pharma: Consultancy; BioLineRx: Consultancy. Kuo:Alexion Pharmaceuticals: Consultancy, Honoraria; Forma Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biossil: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Vertex Pharmaceuticals: Consultancy, Honoraria; Sangamo: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mapara:Ossiumhealth: Consultancy; Incyte Corporation: 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; Bluebirdbio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Eckrich:Vertex Pharmaceuticals: Consultancy. Imren:Vertex Pharmaceuticals: Ended employment in the past 24 months. 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. Grupp:Jazz: Consultancy, Research Funding; Servier: Research Funding; Kite: Research Funding; Adaptimmune: Consultancy; Cellectis: Research Funding; Vertex: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cabaletta: Consultancy.