Casgevy

Pharmacotherapeutic group: Other haematological agents, ATC code: B06AX05 Mechanism of action Casgevy is a cellular therapy consisting of autologous CD34 + human haematopoietic stem and progenitor cells edited by CRISPR/Cas9-technology.‍‍‍‍‍‍​​​‍​​​​​​ The guide RNA enables CRISPR/Cas9 to make a precise DNA double-strand break at the critical transcription factor binding site (GATA1) in the erythroid-specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is irreversibly disrupted and BCL11A expression reduced. Reduced BCL11A expression results in an increase in γ-globin expression and foetal haemoglobin protein production in erythroid cells, addressing the absent globin in transfusion-dependent β-thalassemia and the aberrant globin in sickle cell disease, which are the underlying causes of disease. In patients with transfusion-dependent β-thalassemia, γ-globin production corrects the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and haemolysis and increasing total haemoglobin levels, eliminating the dependence on regular red blood cell transfusions. In patients with severe sickle cell disease, foetal haemoglobin expression reduces intracellular haemoglobin S concentration, preventing the red blood cells from sickling, thereby eliminating vaso-occlusive crises. Following successful engraftment, the effects of Casgevy are expected to be life-long. Pharmacodynamic effects Transfusion-dependent β-thalassemia Allelic editing in the peripheral blood was detectable within 1 month after Casgevy infusion. At month 3 the mean (SD) proportion of alleles with intended genetic modification in peripheral blood was 65.6% (11.5%; n=41) and remained stable up to month 24. The mean (SD) proportion of alleles with intended genetic modification in CD34 + cells of the bone marrow was 77.4% (11.8%; n=38) at month 6 (the first evaluation) and thereafter remained stable up to month 24. Sickle cell disease Allelic editing in the peripheral blood was detectable within 1 month after Casgevy infusion. At month 3 the mean (SD) proportion of alleles with intended genetic modification in peripheral blood was 71.5% (10.4%; n=29) and remained stable up to month 24. The mean (SD) proportion of alleles with intended genetic modification in CD34 + cells of the bone marrow was 85.9% (8.3%; n=28) at month 6 (the first evaluation) and thereafter remained stable up to month 24. Clinical efficacy and safety The efficacy of Casgevy was evaluated in adolescent and adult patients with transfusion-dependent β-thalassemia or sickle cell disease in two on-going open-label, single-arm studies (study 111 and study 121) and one long-term follow-up study (study 131). Refer to the UK Public Assessment Report on the MHRA website for details of cell mobilisation, apheresis, and myeloablative conditioning used in the clinical studies for Casgevy. Transfusion-dependent β-thalassemia Study 111 is an ongoing open-label, multicentre, single-arm study to evaluate the safety and efficacy of Casgevy in adult and adolescent patients with transfusion-dependent β-thalassemia. After completion of 24 months of follow-up in study 111, patients were invited to enrol in study 131, an ongoing long-term safety and efficacy study. Patients were eligible for the study if they had a history of requiring at least 100 mL/kg/year or 10 units/year of red blood cell transfusions in the 2 years prior to enrolment. Patients were also required to have a Lansky or Karnofsky performance score of ≥ 80%. Patients who had severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI]) or advanced liver disease were excluded from the study. MRI of the liver was performed on all patients. Patients with MRI results demonstrating liver iron content ≥ 15 mg/g underwent liver biopsy for further evaluation. Patients with a liver biopsy demonstrating bridging fibrosis or cirrhosis were excluded. The key demographics and baseline characteristics for patients eligible for the primary efficacy analysis in study 111 are shown in Table 5, below. Table 5: Study 111 demographics and baseline characteristics (primary efficacy set) Demographics and disease characteristics Casgevy Interim Analysis * (N=42) Age (years), n (%) Adults (≥ 18 and ≤ 35 years) Adolescents (≥ 12 and < 18 years) 29 (69.0%) 13 (31.0%) All ages (≥ 12 and ≤ 35 years) Median (min, max) 20 (12, 35) Sex, n (%) Female 21 (50.0%) Male 21 (50.0%) Race, n (%) Asian 16 (38.1%) White 17 (40.5%) Multiracial 3 (7.1%) Other 1 (2.4%) Not collected 5 (11.9%) Genotype, n (%) β 0 /β 0 -like † 25 (59.5%) Non-β 0 /β 0 -like 17 (40.5%) Baseline annualised Red Blood Cell transfusion volume (mL/kg) Median (min, max) 201.0 (115.2, 330.9) Baseline annualised Red Blood Cell transfusion episodes (number/year) Median (min, max) 16.5 (10.5, 34.5) Spleen intact, n (%) 30 (71.4%) Baseline liver iron concentration (mg/g) Median (min, max) 3.8 (1.2, 14.0) Baseline cardiac iron T2* (msec) Median (min, max) 34.8 (12.4, 61.1) Baseline serum ferritin (pmol/L) Median (min, max) 3157.0 (584.2, 10837.3) * Analysis conducted based on April 2023 data cut † Low to no endogenous β-globin production (β 0 /β 0 , β 0 /IVS-I-110 and IVS-I-110/IVS-I-110) To maintain a total haemoglobin concentration ≥ 11 g/dL patients underwent red blood cell transfusions prior to mobilisation and apheresis. If transfusions were not continued to maintain haemoglobin at ≥ 11 g/dL after apheresis, they were reinitiated at least 60 days prior to the start of myeloablative conditioning to achieve the same target total haemoglobin levels. Iron chelation therapy was discontinued at least seven days prior to initiation of myeloablative conditioning. Casgevy administration Patients were administered Casgevy with a median (min, max) dose of 8.0 (3.0, 19.7) × 10 6 CD34 + cells/kg as an IV infusion. Efficacy results – β-thalassemia At the time of the interim analysis 54 patients had been administered Casgevy. Forty-two patients were eligible for the primary efficacy analysis. Twenty-three patients have completed study 111 and enrolled into a long-term follow-up study. The median (min, max) total duration of follow-up was 22.8 (2.1, 51.1) months from the time of Casgevy infusion. 39 of 42 patients achieved the primary outcome by maintaining an average Hb ≥9 g/dL without red blood cell transfusions for at least 12 consecutive months any time after Casgevy infusion. Three patients did not achieve the primary outcome. These patients had reductions in annualised red blood cell transfusion frequency requirements of 73.4%, 82.4% and 96.0%, respectively, compared to baseline requirements. Refer to the UK Public Assessment Report on the MHRA website for results of additional outcome measures. Sickle Cell Disease Study 121 is an ongoing open-label, multicentre, single-arm study to evaluate the safety and efficacy of Casgevy in adult and adolescent patients with sickle cell disease. After completion of 24 months of follow-up in study 121, patients were invited to enrol in study 131, an ongoing long-term safety and efficacy study. Patients were eligible for the study if they had a history of at least 2 severe vaso-occlusive crisis events per year in the 2 years prior to screening, which were defined as: • Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous non-steroidal anti-inflammatory drugs) or red blood cell transfusions • Acute chest syndrome • Priapism lasting > 2 hours and requiring a visit to a medical facility • Splenic sequestration. Patients with Hb S/S , Hb S/β0 and Hb S/β+ genotypes were eligible for inclusion. Patients were also required to have a Lansky or Karnofsky performance score of ≥ 80%. Patients were excluded if they had advanced liver disease, history of untreated Moyamoya disease or presence of Moyamoya disease that in the opinion of the investigator put the patient at risk of bleeding. Patients aged 12 to 16 years were required to have normal transcranial doppler and patients aged 12 to 18 years were excluded if they had any history of abnormal transcranial doppler in the middle cerebral artery and the internal carotid artery. The key demographics and baseline characteristics for patients eligible for the primary efficacy analysis in study 121 are shown in Table 6, below. Table 6: Study 121 demographics and baseline characteristics (primary efficacy set) Demographics and disease characteristics Casgevy Interim Analysis * (N=29) Age (years), n (%) Adults (≥ 18 and ≤ 35 years) 23 (79.3%) Adolescents (≥ 12 and < 18 years) 6 (20.7%) All ages (≥ 12 and ≤ 35 years) Median (min, max) 21 (12, 34) Sex, n (%) Male 16 (55.2%) Female 13 (44.8%) Race, n (%) Black or African American 26 (89.7%) White 1 (3.4%) Other 2 (6.9%) Genotype, n (%) β S /β S 28 (96.6%) β S /β 0 1 (3.4%) β S /β + 0 (0%) Annualised rate of severe vaso-occlusive crises in the 2 years prior to enrolment (events/year) Median (min, max) 3.0 (2.0, 9.5) Annualised rate of hospitalisations due to severe vaso-occlusive crises in the 2 years prior to enrolment (events/year) Median (min, max) 2.0 (0.5, 8.5) Annualised duration of hospitalisation due to severe vaso-occlusive crises in the 2 years prior to enrolment (days/year) Median (min, max) 12.5 (2.0, 64.6) Annualised units of Red Blood Cells transfused for Sickle Cell Disease-related indications in the 2 years prior to enrolment (units/year) Median (min, max) 3.5 (0.0, 75.5) * Analysis conducted based on April 2023 data cut Patients underwent red blood cell exchange or simple transfusions to achieve a target haemoglobin S < 30% of total haemoglobin, while keeping total haemoglobin concentration ≤ 11 g/dL, for a minimum of eight weeks before the planned start of mobilisation. If exchange or simple transfusions were paused after apheresis, they were reinstated at least eight weeks prior to the start of myeloablative conditioning to achieve the same target total haemoglobin and Haemoglobin S (%) levels. At initiation of red blood cell exchange or simple transfusions, disease modifying therapies were discontinued. Iron chelation therapy was discontinued at least seven days prior to myeloablative conditioning. Casgevy administration Patients were administered Casgevy with a median (min, max) dose of 4.0 (2.9, 14.4) × 10 6 CD34 + cells/kg as an IV infusion. Efficacy results – Sickle Cell Disease At the time of the interim analysis 43 patients had been administered Casgevy. Twenty-nine patients were eligible for the primary efficacy analysis. Thirteen patients had completed study 121 and enrolled into a long-term follow-up study. The median (min, max) total duration of follow-up was 17.5 (1.2, 46.2) months from the time of Casgevy infusion. 28 of 29 patients achieved the primary outcome by not experiencing any severe vaso-occlusive crisis for at least 12 consecutive months after Casgevy infusion. Refer to the UK Public Assessment Report on the MHRA website for results of additional outcome measures. Paediatric population The MHRA has deferred the obligation to submit the results of studies with Casgevy in one or more subsets of the paediatric population in β-thalassemia and sickle cell disease (see section 4.2 for information on paediatric use). Conditional approval This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this Summary of Product Characteristics will be updated as necessary.