Exagamglogen autotemcel (2) – Casgevy®

• Clinical trials
  • For the benefit assessment of Exagamglogen autotemcel for the treatment of patients aged 12 years and over with severe sickle cell disease and recurrent vaso-occlusive crises, who are suitable for haematopoietic stem cell (HSC) transplantation and for whom no related, HLA-identical stem cell donor is available, the pharmaceutical manufacturer presents results from the pivotal Phase I/II/III trial CLIMB-SCD-121 and the extension trial CTX001-131.
  • The CLIMB-SCD-121 study is a single-arm, open-label, multicentre study in which 63 patients aged 12 to 35 years inclusive with sickle cell disease and a documented β/β, β/β or β/β+-SCD genotype and at least two vaso-occlusive crises (VOCs) per year in the two-year period prior to screening.

Patients aged 12 years and over with severe sickle cell disease and recurrent vaso-occlusive crises who are eligible for haematopoietic stem cell (HSC) transplantation and for whom no related, HLA-identical stem cell donor is available

• Consequently, it is concluded that there is a hint of a non-quantifiable additional benefit for Exagamglogen autotemcel, as the scientific evidence does not permit quantification.
• mortality
  • Deaths are recorded throughout the entire duration of the CLIMB-SCD-121 and CLIMB-CTX001-131 studies.
  • As of the 5th data cut-off on 2 January 2025, one death had occurred, which was assessed as transplant-related.
• Morbidity – Severe vaso-occlusive crises
  • Vaso-occlusive pain crises associated with sickle cell disease and other vaso-occlusive complications perceptible to patients are considered patient-relevant events.
  • In the CLIMB-SCD-121 study, a vaso-occlusive pain crisis was defined as: – Acute pain requiring admission to a medical facility and the administration of analgesics (opioids or intravenous non-steroidal anti-inflammatory drugs (NSAIDs)) or blood transfusions, the occurrence of an acute chest syndrome, characterised by the appearance of a new pulmonary infiltrate in conjunction with pneumonia-like symptoms, pain or fever; the occurrence of priapism lasting longer than 2 hours and requiring admission to a medical facility; or the occurrence of splenic sequestration, defined by an enlarged spleen, pain in the left upper quadrant and an acute drop in haemoglobin (Hb) concentration of ≥ 2 g/dl.
  • The median duration of freedom from severe VOCs for those who achieved freedom from severe VOCs is 33.4 months (min: 12.7; max: 64.5). If a subject has achieved multiple periods qualifying for VF12, the longest VF12 duration is used for the analysis.
  • In an analysis conducted from the time of infusion without further restriction of the analysis population (FAS, N = 46), 11 patients experienced a severe VOC following the Exagamglogen autotemcel infusion.
  • As no comparative data are available, no conclusions regarding the extent of the additional benefit of exagamglogen autotemcel can be drawn from these results.
  • No data suitable for benefit assessment are available for the annualised rates of severe VOCs.
• Quality of life – Quality of life as measured by the ASCQ-Me
  • The ASCQ-Me is a disease-specific, multidimensional questionnaire for the self-assessment of quality of life in adults with sickle cell disease.
  • In 10 to 28 patients aged between ≥ 18 and ≤ 35 years, a 15% improvement was achieved by month 24 in the respective individual domains: Emotional distress 11, impairment due to pain 11, impairment due to pain crises (frequency) 28, impairment due to pain crises (severity) 7, sleep disturbance 10, impairment of social life and impairment due to stiffness 11.
  • As no comparative data are available, no conclusions regarding the extent of the additional benefit can be drawn from the results of the ‘health status’ endpoint as measured by the ASCQ-Me.
• Quality of life – PedsQL
  • The PedsQL measures general health-related quality of life in children and adolescents and was used in the CLIMB-SCD-121 study among participants aged 12 years or older.
  • Among 6 patients in the age group ≥ 12 to < 18 years, an improvement of 15 % was achieved by month 24 in the total score, in the ‘Health’ subdomain in 7 patients and in the ‘Psychosocial Health’ subdomain in 6.
  • As no comparative data are available, no conclusions regarding the extent of the additional benefit can be drawn from the results of the health status endpoint using the PedsQL.
• Quality of life – PedsQL-SCD
  • The specific ‘PedsQL Sickle Cell Disease Module’ (PedsQL-SCD) comprises 9 scales: pain and injury, impact of pain, pain management and control, worry I, worry II, emotions, treatment, communication I and communication II.
  • In 6 patients aged ≥ 12 to < 18 years, a 15% improvement in the total score was achieved by month 24.
  • As no comparative data are available, no conclusions can be drawn from the results of the health status endpoint using the PedsQL-SCD regarding the extent of the additional benefit.
• Quality of life – FACT-BMT
  • The ‘Functional Assessment of Cancer Therapy – Bone Marrow Transplantation’ (FACT-BMT) is a self-assessment questionnaire on health-related quality of life for people who have undergone a bone marrow transplant.
  • There are uncertainties regarding the transferability of the questionnaire’s validity to the therapeutic indication for sickle cell disease.
  • In the FACT-BMT Total Core, 8 patients showed a 15% improvement by month 24; in the FACT-G Total Score, 12 patients showed a 15% improvement; and in the BMTS, 8 patients showed a 15% improvement.
• Side effects
  • No study withdrawals due to adverse events were observed in the studies presented.
  • Adverse events (AEs) occurred in almost all patients in the studies. Severe AEs of grade ≥ 3 occurred in 91.4% of patients.
  • Serious AEs (SAEs) occurred in 65.5% of patients.
  • A definitive assessment of the adverse reaction profile of exagamglogen autotemcel is not possible due to the limited data on long-term safety and the lack of comparative data.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.
• Overall assessment
  • The basis for the benefit assessment is the results of the single-arm, open-label CLIMB-SCD-121 study and the CLIMB-CTX001-131 extension study, which provide data on mortality, morbidity, health-related quality of life and side effects. As these are single-arm studies, a comparative assessment – and thus a quantification of the extent of the additional benefit – is not possible on the basis of these data.
  • The adjusted and naive indirect comparisons submitted by the pharmaceutical manufacturer are, on the whole, unsuitable for the benefit assessment for the reasons stated above.
  • Overall, a non-quantifiable additional benefit is inferred for Exagamglogen autotemcel, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.