Exagamglogen autotemcel (1) – Casgevy®

• Clinical trials
  • For the benefit assessment of Exagamglogen autotemcel for the treatment of patients aged 12 years and over with transfusion-dependent beta-thalassaemia who are suitable for haematopoietic stem cell (HSC) and for whom no HLA-compatible related stem cell donor is available, the pharmaceutical manufacturer presents results from the pivotal, single-arm, open-label, multicentre Phase I/II/IIICLIMB-TDT-111 and the extension study CLIMB-CTX001-131.

Patients aged 12 years and over with transfusion-dependent beta-thalassaemia who are suitable for haematopoietic stem cell (HSC) transplantation and for whom no HLA-compatible related stem cell donor is available

• mortality
  • Deaths are recorded as safety events in the CLIMB-TDT-111 study. At the time of the relevant data cut-off, no deaths had occurred.
• Morbidity – Freedom from transfusions
  • Transfusion-dependent beta-thalassaemia is characterised by anaemia caused by a significantly reduced production of functional β-globin, which necessitates frequent and lifelong red blood cell (RBC) transfusions.
  • The long-term or sustained avoidance of transfusions (transfusion-free status) whilst maintaining a defined minimum haemoglobin level is a primary therapeutic objective in this therapeutic indication, enabling the control of anaemia and anaemia-related symptoms whilst avoiding red blood cell transfusions.
  • With regard to the analyses of the various time periods of transfusion-free status, this assessment considers a transfusion-free period of ≥ 24 weeks to be the relevant timeframe for assuming long-term avoidance of transfusions (transfusion-free status).
  • In the context of the study, transfusion-free status was defined as the proportion of patients who received no red blood cell transfusions for at least 12 or 6 consecutive months following the Exagamglogen infusion and who had a weighted average haemoglobin level of ≥ 9 g/dl.
  • In the CLIMB-TDT-111 study, at the time of the current data cut-off, 53 out of 59 (89.8%) patients in the ITT population were found to be transfusion-independent after 12 months.
  • Given the known natural course of the disease, it is unlikely that patients suffering from transfusion-dependent beta-thalassaemia would, in the natural course of their disease, spontaneously achieve clinically relevant higher haemoglobin levels and/or become independent of regular transfusions with red blood cell concentrates.
  • In this regard, the result achieved in the CLIMB-TDT-111 study regarding transfusion independence after 12 months is interpreted as a dramatic effect of the treatment compared with the expected natural course of the disease.
  • Against this background, the results of the presented naive indirect comparison with data from the WebTHAL database on patients with a natural disease course or receiving ‘standard of care’ treatment —despite the aforementioned limitations and taking into account the high effect size—are also used for the present assessment.
  • Overall, there is a significant advantage for treatment with Exagamglogen autotemcel with regard to the endpoint of transfusion independence.
  • However, it is not possible to assess the extent to which the transfusion independence demonstrated in the majority of patients leads to the prevention of complications that may arise from previous regular transfusions with red blood cell concentrates.
  • In particular, it remains unclear to what extent iron chelation therapy remains necessary for patients who have achieved transfusion independence.
• Quality of life – health status using the EQ-5D-VAS
  • The European Quality of Life 5-Dimension Visual Analogue Scale (EQ-5D-VAS) measures patients’ self-assessment of their general health status.
  • Study participants rated their health status on a vertical scale, with scores ranging from 100 (‘best possible health status’) to 0 (‘worst possible health status’).
  • An improvement of 15% was achieved by month 24 in 7 patients in the age group ≥ 18 to ≤ 35 years and in 2 patients in the age group ≥ 12 to < 18 years.
  • 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 measured using the EQ-5D-VAS.
• 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 88.1% of patients.
  • Serious AEs (SAEs) occurred in 44.1% 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.
  • No conclusions can be drawn regarding the long-term adverse reaction profile without long-term data on the safety profile.
  • As no comparative data are available, it is not possible, in summary, to draw any conclusions regarding the extent of the additional benefit from the data on side effects.
• Overall assessment
  • For the benefit assessment of Exagamglogen autotemcel for the treatment of patients aged 12 years and over with transfusion-dependent beta-thalassaemia who are suitable for haematopoietic stem cell (HSC) and for whom no HLA-compatible related stem cell donor is available, data were presented from the pivotal, single-arm, open-label, multicentre Phase I/II/III trial CLIMB-TDT-111, the extension study CLIMB-CTX001-131, as well as a naive indirect comparison with data from the WebTHAL database, were presented for the endpoint of transfusion independence.
  • The data presented provide findings on mortality, morbidity, quality of life and side effects. Apart from the endpoint of transfusion independence, no conclusions regarding the extent of the additional benefit can be drawn for any of the patient-relevant endpoints assessed in the studies, due to a lack of comparative data.
  • In this regard, the result achieved in the CLIMB-TDT-111 study regarding transfusion independence after 12 months is interpreted as a dramatic effect of the treatment compared with the expected natural course of the disease. Against this background, the results of the presented naive indirect comparison with data from the WebTHAL database on patients with a natural disease course or receiving ‘standard of care’ treatment are taken into account for the present assessment, despite the limitations mentioned and in view of the high effect size.

Courtesy translation only, please refer to the German original.