Betibeglogene Autotemcel (1) – Zynteglo®

• Clinical trials
  • The HGB-204 study is a completed, open-label, single-arm, Phase I/II dose-finding study in which patients with transfusion-dependent β-thalassaemia (regardless of genotype) aged between 12 and 35 years were investigated.
  • The HGB-205 study is a completed open-label, single-arm Phase I/II dose-finding study in which 7 patients with β-haemoglobinopathies (severe sickle cell anaemia and transfusion-dependent β-thalassaemia, regardless of genotype) aged between 5 and 35 years were studied.
  • The HGB-207 study is an ongoing open-label, single-arm, Phase III trial investigating the efficacy and safety of betibeglogene autotemcel in patients aged ≤ 50 years with transfusion-dependent β-thalassaemia who do not carry a β or IVS-I-110 mutation on both HBB alleles.
  • The HGB-212 study is an ongoing open-label, single-arm study (Phase III) in which patients aged up to and including 50 years with transfusion-dependent β-thalassaemia were enrolled.
  • The LTF-303 study is a long-term safety and efficacy follow-up study for patients with haemoglobinopathies who have completed the follow-up phase of the original studies.

Patients aged 12 years and over with transfusion-dependent β-thalassaemia (TDT) who do not have the β⁰/β⁰genotype and who are suitable for haematopoietic stem cell transplantation (HSCT), but for whom no human leukocyte antigen (HLA)-compatible, related HSC donor is available

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification
• On balance, there remains a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • Deaths were recorded as safety events. No deaths occurred during the studies.
• Morbidity – transfusion independence
  • The endpoint ‘transfusion independence’ (TI) is defined as a continuous period of at least 12 months without receiving red blood cell concentrate transfusions and with a weighted mean haemoglobin (Hb) level of ≥ 9 g/dl at any time following infusion with betibeglogene autotemcel.
  • Treatment with betibeglogene autotemcel resulted in transfusion independence in 8 out of 10 (80%) patients in the HGB-204 study and in 3 out of 4 (75%) patients in the HGB-205 study.
  • In the HGB-207 study, at the time of the latest data cut-off, 13 out of 15 (86.7%) patients (of whom 14 had reached the required follow-up period); in the HGB-212 study, this applies to 1 in 4 (25.0%) patients, of whom 2 have already reached the required follow-up period.
  • Consequently, for the majority (on average approximately 80 %) of patients in the HGB-204, HGB-205 and HGB-207 studies, transfusion independence was observed following treatment with betibeglogene autotemcel.
  • The data on transfusion independence therefore indicate a very clear advantage of treatment with betibeglogene autotemcel compared with the expected natural course of the disease in terms of the primary treatment objective in this therapeutic indication, namely the prevention of anaemia.
  • It remains unclear, however, to what extent the transfusion independence observed in the majority of patients contributes to the prevention of complications that may arise from previous regular transfusions with red blood cell concentrates, and to what extent iron chelation therapy remains necessary for patients who have achieved transfusion independence.
  • According to the information provided by the pharmaceutical manufacturer in the dossier, only 13 out of 32 patients (40.6%) in studies HGB-204, HGB-205, HGB-207 and HGB-212 had been able to discontinue chelation therapy by the data cut-off date of 12 June 2019 (defined as discontinuation of chelation therapy for at least six months).
• Morbidity – VAS of the EQ-5D(-Y)
  • General health status was assessed in the HGB-207 study using the VAS of the EuroQol 5-Dimensional Questionnaire (EQ-5D-3L).
  • On average, the EQ-5D VAS score increased by 7.29 (SD: 10.44) points to a mean of 91.29 points; for the EQ-5D(-Y), the score increased by 24.5 (SD: 20.8) points after 6 months to a mean of 93.3 points.
  • As no comparative data are available, no conclusions regarding the extent of the additional benefit can be drawn from the results of the EQ-5D(-Y) endpoint.
• Quality of life – PedsQL
  • The PedsQL measures general health-related quality of life in children and adolescents and was used in the HGB-207 study for participants aged 12 years or older.
  • On average, the PedsQL total score increased by 9.96 (SD: 24.30) points after 6 months compared with baseline, reaching a mean of 80.98 points.
  • Without comparative data, it is not possible to draw any conclusions about changes in quality of life as measured by the PedsQL.
• Side effects
  • In the studies presented, no study discontinuations due to adverse events were observed.
  • Adverse events (AEs) occurred in almost all patients in the studies. Severe AEs of grade ≥ 3 occurred in 93.8% of participants in study HGB-207 and in 100% and 91% of participants in studies HGB-205 and HGB-204, respectively.
  • Serious AEs (SAEs) occurred in 56.3% of patients in the HGB-207 study and in 75% and 54.5% of patients in the HGB-205 and HGB-204 studies, respectively.
  • A definitive assessment of the adverse reaction profile of betibeglogene autotemcel is not possible due to the limited data on long-term safety and the lack of comparative data.
  • Statements regarding the long-term adverse reaction profile, particularly regarding a possible risk of insertion mutagenesis, which could potentially lead to the development of malignancy, cannot be made without long-term data on the safety profile, which are to be collected, amongst other things, in the LTF-303 follow-up study.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.
• Overall assessment
  • For the benefit assessment of betibeglogene autotemcel for the treatment of patients aged 12 years and over with transfusion-dependent β-thalassaemia (TDT) who do not have the β0/β0 genotype, data were used from the open-label, uncontrolled, ongoing Phase IIIstudy HGB-207 and the open-label, uncontrolled, completed Phase I/II dose-finding studies HGB-205 and HGB-204, as well as data on the endpoint of transfusion independence from the open-label, uncontrolled, ongoing Phase III study HGB-212 and, in addition, data from the ongoing follow-up study LTF-303.
  • Apart from the endpoint of transfusion independence, no conclusions regarding the extent of the additional benefit can be drawn for any patient-relevant endpoint assessed in the studies, due to a lack of comparative data.
  • With regard to transfusion independence, a very clear advantage of treatment with betibeglogene autotemcel compared with the expected natural course of the disease is inferred at the endpoint level in relation to the primary therapeutic objective in this therapeutic indication, namely the prevention of anaemia.
  • However, it is not possible to assess the extent to which the transfusion independence observed in the majority of patients leads to the prevention of complications that may arise from the regular transfusions of red blood cell concentrates that have already taken place.
  • Overall, a non-quantifiable additional benefit is identified for betibeglogene autotemcel, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.