Correction of ineffective erythropoiesis and durable clinical benefit with exagamglogene autotemcel for transfusion-dependent β-thalassemia

Abstract Background: Transfusion-dependent β-thalassemia (TDT) patients have tissue iron overload (IO) from chronic red blood cell (RBC) transfusion and ineffective erythropoiesis (IE) resulting in the need for life-long transfusion support and iron removal therapy (IRT); nevertheless, despite IRT, IO can lead to organ damage, failure, and premature death. Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo CRISPR/Cas9 gene-edited, autologous cell therapy approved for TDT patients ≥12 years (y) old. We report long-term efficacy and safety in TDT participants (pts) from the CLIMB THAL-111 and the CLIMB-131 follow-up trials, including measures of IO and IE before and after cessation of IRT. Methods: CLIMB-111 is an ongoing 2-y, Phase 3 trial of exa-cel in TDT pts aged 12-35 y. The primary endpoint is transfusion independence defined as proportion of pts maintaining a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 consecutive months (m; TI12). Following completion of CLIMB-111, pts enroll in CLIMB-131 for up to 15 y of follow-up after exa-cel. Duration and modality of IRT (chelation and/or phlebotomy) was captured in both trials. Measures of tissue IO (e.g., serum ferritin, liver iron concentration [LIC], and T2* cardiac iron content [CIC]) and measures of iron homeostasis (e.g., erythroferrone and hepcidin), were assessed after exa-cel and subsequent cessation of IRT. Results: As of 10 April 2025, 56 pts (mean age: 21.2 [range: 12, 35] y; 55.4% male) received exa-cel in the CLIMB-111 trial and had median follow-up of 38.1 (range: 7.9, 67.1) m. 35/56 pts (62.5%) had severe genotypes (β0/β0 or β0/β0-like). At baseline, median serum ferritin was 1280.5 (range: 260.0, 4823.0) mcg/L, LIC was 3.6 (range: 1.2, 14.8) mg/g, and CIC was 34.0 (range: 12.4, 61.1) msec. After exa-cel, 98.2% (55/56) achieved TI12 in CLIMB-111 and CLIMB-131 combined with a 41.4-m mean duration of transfusion independence (TI; range: 13, 72.3 m); 53/56 (94.6%) achieved TI12 within 2 y in CLIMB-111. Mean total Hb was maintained at normal/near normal levels of ≥12 g/dL and mean HbF was ≥11 g/dL from Month 5 onward. Allelic editing in bone marrow and blood remains stable over time. Exa-cel safety was consistent with myeloablative conditioning and autologous transplant. Consistent with that, there were 7 cases (7/56; 12.5%) of hepatic veno-occlusive disease; none resulted in end-organ dysfunction, all were related to busulfan and all resolved after defibrotide treatment. There were no deaths or malignancies. All 56 pts received IRT after exa-cel infusion, with chelation alone (30.4%), phlebotomy alone (33.9%), or both (35.7%). Median time after exa-cel to restart iron-chelation and phlebotomy was 6.6 (range: 2.0, 30.1) m and 9.4 (range: 2.9, 37.0) m, respectively. Following expected initial increases associated with stem cell transplantation preparation and management, median serum ferritin and LIC progressively decreased to 451.0 (range: 77.3, 2720.0) mcg/L and 3.4 (range: 0.7, 29.2) mg/g at Month 48, respectively. Mean CIC remained stable at >25 msec. 38/56 (67.9%) pts discontinued IRT for ≥6 m, with median duration off IRT of 19.4 (range: 8.2, 64.7) m. After IRT cessation, serum ferritin, LIC, and CIC were generally stable without progressive increase over time. Erythroferrone, a measure of IE and iron regulation that suppresses hepcidin, was elevated at baseline consistent with TDT disease status and ongoing IE and then decreased to normal or near-normal after exa-cel. Hepcidin, which regulates iron absorption and storage, was normal at baseline, transiently increased after transplantation, and normalized by Month 12. Mean erythroferrone and hepcidin levels remained stable after IRT cessation consistent with normalization of iron homeostasis and correction of IE after exa-cel. Conclusion: Exa-cel demonstrated durable clinical benefit for up to 6 y in adults and adolescents with TDT. After exa-cel, iron was successfully removed by IRT with no evidence of iron reaccumulation after IRT cessation. This suggests that in addition to durable TI in 98% of subjects, exa-cel potentially prevents tissue iron deposition by restoring iron homeostasis via correction of underlying IE. Normalized iron homeostasis eliminates the need for chronic IRT after exa-cel and may thus preserve end-organ function by preventing tissue iron deposition. These data continue to support exa-cel as a one-time functional cure for TDT.

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