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Casgevy 4-13 × 10⁶ cells/mL dispersion for infusion

2.1 General description

Casgevy (exagamglogene autotemcel) is a genetically modified autologous CD34⁺ cell enriched population that contains human haematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 at the erythroid-specific enhancer region of the BCL11A gene.

2.2 Qualitative and quantitative composition

Each patient-specific vial of Casgevy contains exagamglogene autotemcel at a batch-dependent concentration of genetically modified autologous CD34⁺ cell enriched population. The medicinal product is packaged in one or more vials which contain a dispersion of 4-13 × 10⁶ cells/mL of viable CD34⁺ enriched cell population suspended in a cryopreservative solution. Each vial contains 1.5 to 20 mL of Casgevy.

The quantitative information of medicinal product, including the number of vials (see section 6) to be administered, is presented in the Lot Information Sheet (LIS) located inside the lid of the liquid nitrogen dry shipper used for transport.

Excipient(s) with known effect

This medicinal product contains 3.5 mg/mL sodium.

For the full list of excipients, see section 6.1.

Dispersion for infusion.

A translucent cell dispersion, which may contain visible particles.

Transfusion-dependent β-thalassemia

Casgevy is indicated for the treatment of transfusion-dependent β-thalassemia in patients 12 years of age and older for whom haematopoietic stem cell transplantation is appropriate and a human leukocyte antigen matched related haematopoietic stem cell donor is not available.

Sickle cell disease

Casgevy is indicated for the treatment of sickle cell disease in patients 12 years of age and older with recurrent vasoocclusive crises who have the β^S/β^S, β^S/β⁺ or β^S/β⁰ genotype, for whom haematopoeitic stem cell transplantation is appropriate and a human leukocyte antigen matched related haematopoietic stem cell donor is not available.

For autologous use only. For one-time, single dose intravenous use only.

Casgevy must be administered in an authorised treatment centre by a physician(s) with experience in both haematopoietic stem cell transplantation and in the treatment of patients with β-haemoglobinopathies.

Posology

The minimum recommended dose of Casgevy is 3 × 10⁶ CD34⁺ cells/kg.

Treatment consists of a single dose for infusion containing a dispersion of viable CD34⁺ cells in one or more vials. See the accompanying lot information sheet for additional information pertaining to dose.

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.

Prior to starting the myeloablative conditioning regimen, confirm availability of the complete set of vials constituting the dose of Casgevy, and unmodified rescue cells. See the lot information sheet provided with the product shipment for confirmation of the number of vials and total dose of Casgevy.

Method of administration

Casgevy is for intravenous use only. For detailed instructions on preparation, administration, accidental exposure and disposal of Casgevy, see section 6.6.

After completion of the myeloablative conditioning regimen, a minimum of 48 hours or the length of time taken for elimination of the conditioning agent (whichever is longer) must elapse before Casgevy infusion. Casgevy must be administered within 7 days of the last dose of myeloablative conditioning.

It is recommended that pre-medication with paracetamol and diphenhydramine, or equivalent medicinal products, be administered per institutional guidelines, before the infusion of Casgevy, to reduce the possibility of a hypersensitivity reaction.

Before thaw and infusion, confirm the patient's identity matches the unique patient information on the Casgevy vial(s). The total number of vials to be administered should also be confirmed with the lot information sheet (see section 4.4).

Casgevy is administered as an intravenous bolus. Casgevy infusion should be completed as soon as possible and no more than 20 minutes after thawing. In the event that more than one vial is provided, all vials must be administered. The entire volume of each vial should be infused.

After Casgevy Administration

Local/national guidelines for patient monitoring and management after autologous haematopoietic stem cell transplantation should be followed after Casgevy infusion.

Special Populations

Elderly

Casgevy has not been studied in patients > 65 years of age. Haematopoietic stem cell transplantation must be appropriate for a patient to be treated with Casgevy.

Renal Impairment

Casgevy has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate < 60 mL/min/1.73 m². Patients should be assessed for renal impairment to ensure haematopoietic stem cell transplantation is appropriate.

Hepatic Impairment

Casgevy has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure haematopoietic stem cell transplantation is appropriate.

Paediatric Population

The safety and efficacy of Casgevy in patients < 12 years of age have not been established.

Contraindications to mobilisation and myeloablative conditioning agents must be considered.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Confirm that haematopoietic stem cell transplantation is appropriate for the patient before mobilisation, apheresis and myeloablative conditioning are initiated.

Refer to local institutional/national guidelines for advice on mobilisation, apheresis and myeloablative conditioning for autologous haematopoietic stem cell transplantation in patients with haemogobinopathies. 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.

Maximise CD34⁺ cell collection to obtain as many CD34⁺ haematopoietic stem and progenitor cells as possible for product manufacturing during each mobilisation and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A back-up collection of at least 2 × 10⁶ CD34⁺ cells/kg is required to be collected for back-up unmodified rescue cells. A third day of cell collection can be used to obtain back up rescue cells, if needed. If the minimum dose of Casgevy is not met after initial medicinal product manufacturing, the patient will need to undergo additional cycles of mobilisation and apheresis. Each mobilisation and apheresis cycle must be separated by a minimum of 14 days.

The back-up collection of ≥ 2 × 10⁶ CD34⁺ cells/kg is required in case of the need for rescue treatment under any one of the following conditions: compromise of Casgevy after initiation of myeloablative conditioning and before Casgevy infusion; neutrophil engraftment failure; or loss of engraftment after infusion with Casgevy. These unmodified cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with Casgevy.

Irradiate any blood products required within the first 3 months after Casgevy infusion.

Warnings and precautions of mobilisation and myeloablative conditioning agents must be considered.

Neutrophil engraftment

Neutrophil engraftment failure may occur after haematopoietic stem cell transplant. Patients should be monitored for absolute neutrophil counts and infections should be managed according to local/national guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with unmodified rescue CD34⁺ stem cells (see section 4.8).

Time to platelet engraftment

There is an increased risk of bleeding until platelet engraftment is achieved. Patients should be monitored for bleeding according to local/national guidelines and medical judgement. Frequent platelet counts should be conducted until platelet engraftment and platelet recovery are achieved. Blood cell count determination and other appropriate testing should be performed whenever clinical symptoms suggestive of bleeding arise (see section 4.8).

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cyropreservative solution. Monitor patients for hypersensitivity reactions during and after infusion.

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years after expiry date of the product.

Autologous use

Casgevy is intended solely for autologous use and must not be administered to anyone other than the donor. Casgevy must not be administered if the information on the product labels and lot information sheet does not match the patient's identity.

Patients seropositive for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)

Casgevy has not been studied in patients with HIV-1, HIV-2, or HCV. Perform screening for HIV-1, HIV-2, HBV, and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. Casgevy should not be used in patients with active HIV-1, HIV-2, HBV, or HCV.

Patients with prior haematopoietic stem cell transplant

Casgevy has not been studied in patients who have received a prior allogeneic or autologous haematopoietic stem cell transplant. Treatment with Casgevy is not recommended in these patients.

Transmission of an infectious agent

Although Casgevy is tested for sterility, mycoplasma and endotoxins, a small risk of transmission of infectious agents exists. Healthcare professionals administering Casgevy should, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Blood, organ, tissue and cell donation

Patients treated with Casgevy must not donate blood, organs, tissues and cells for transplantation.

Long-term follow-up

Patients are expected to enrol and be followed in a registry in order to better understand the long-term safety and efficacy of Casgevy.

Sodium content

This medicinal product contains 5.3 mg to 70 mg sodium per vial, equivalent to 0.3 to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The drug-drug interactions of mobilisation and myeloablative conditioning agents must be considered.

No formal drug interaction studies have been performed. Casgevy is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.

Use of hydroxyurea/hydroxycarbamide should be discontinued at least 8 weeks prior to start of mobilisation and conditioning. There is no experience on the use of hydroxyurea/hydroxycarbamide after Casgevy infusion.

Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilisation and conditioning, as their interaction potential with mobilisation and myeloablative conditioning agents is not known.

Iron chelators should be discontinued at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after Casgevy infusion. Phlebotomy can be used instead of iron chelation, when appropriate.

Live vaccines

The safety of immunisation with live viral vaccines during or following Casgevy treatment has not been studied. Refer to local institutional/national guidance for advice on live vaccines.

The effect of mobilisation and myeloablative conditioning agents on patients with reproductive potential and patients that are pregnant or breast-feeding must be considered.

Women of childbearing potential/Contraception in males and females

A negative serum pregnancy test must be confirmed prior to the start of each mobilisation cycle and re-confirmed prior to myeloablative conditioning. There is insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with Casgevy. Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilisation up to at least 6 months after administration of Casgevy.

Pregnancy

There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause foetal harm when administered to a pregnant woman. It is not known whether exagamglogene autotemcel has the potential to be transferred to the foetus. Casgevy must not be administered during pregnancy because of the risk associated with myeloablative conditioning. Pregnancy after Casgevy infusion should be discussed with the treating physician (see guidance on contraception, above).

Breast-feeding

It is unknown whether exagamglogene autotemcel is excreted in human milk or transferred to the breast-feeding child. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for Casgevy and any potential adverse effects on the breastfed child from Casgevy or from the underlying maternal condition. Breast-feeding after Casgevy infusion should be discussed with the treating physician.

Fertility

There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Infertility has been observed with myeloablative conditioning therefore fertility preservation options should be considered.

Casgevy is not known to have influence on the ability to drive or use machines.

The effect of mobilisation and myeloablative conditioning agents on the ability to drive or use machines must be considered.

Consideration must be given to adverse events that may occur in response to the apheresis procedure and in response to exposure to medicinal products employed (i) to mobilise haematopoietic stem and progenitor cells and (ii) for myeloablative conditioning.

The safety of Casgevy was evaluated in two ongoing open-label, single-arm studies (study 111 and study 121) and one ongoing long-term follow-up study (study 131), in which 97 adolescent and adult patients with transfusion-dependent β-thalassemia or sickle cell disease were treated with Casgevy.

Patients with transfusion-dependent β-thalassemia

Summary of the safety profile

The median (min, max) duration of follow up for 54 patients with transfusion-dependent β-thalassemia after being administered Casgevy was 22.8 (2.1, 51.1) months.

Serious adverse reactions attributed to Casgevy occurred in 2 (3.7%) patients: 1 (1.9%) patient with haemophagocytic lymphohistocytosis, acute respiratory distress syndrome, idiopathic pneumonia syndrome and headache; 1 (1.9%) patient with delayed engraftment and thrombocytopenia.

A life-threatening serious adverse reaction of cerebellar haemorrhage occurred in 1 (1.9%) patient and was attributed to myeloablative conditioning.

There were not any cases of graft versus host disease, graft failure, or graft rejection, and there were not any deaths.

Tabulated list of adverse reactions

Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Tables 1 and 2 list adverse reactions attributed to Casgevy and haematopoietic stem cell transplant complications, respectively, experienced by patients with transfusion-dependent β-thalassemia in clinical studies with Casgevy.

Table 1: Adverse reactions attributed to Casgevy in patients with transfusion-dependent β-thalassemia (N=54)

^* At least one event was also attributed to haematopoietic stem cell transplantation complications.

† Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.

‡ Infusion related reactions includes chills, sinus tachycardia and tachycardia.

Table 2: Adverse reactions attributed to haematopoietic stem cell transplantation complications in patients with transfusion-dependent β-thalassemia (N=54)

^* Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.

† Mucositis included anal inflammation, mucosal inflammation, pharyngeal inflammation and stomatitis.

‡ Abdominal pain included abdominal pain lower, abdominal pain upper, abdominal tenderness and epigastric discomfort.

§ Pigmentation disorder included skin hyperpigmentation.

^# Rash included dermatitis, rash erythematous and rash maculo-papular.

^** Musculoskeletal pain included back pain, bone pain, chest pain and pain in extremity.

Description of selected adverse reactions

Platelet engraftment in patients with transfusion dependent β-thalassemiaPlatelet engraftment is defined as 3 consecutive measurements of platelet counts ≥20 × 10⁹/L in patients with transfusion-dependent β-thalassemia, obtained on 3 different days after Casgevy infusion without administration of platelet transfusions for 7 days.

In study 111, the median (min, max) time to platelet engraftment was 44 (20, 200) days (n=53). Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 46 (27, 200) days in patients with an intact spleen.

Neutrophil engraftment in patients with transfusion-dependent β-thalassemia

Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥500 cells/µL on 3 different days after Casgevy infusion, without use of the unmodified rescue CD34⁺ cells. All patients achieved neutrophil engraftment, and no patients received rescue CD34⁺ cells.

In study 111, the median (min, max) time to neutrophil engraftment was 29 (12, 56) days (n=54).

Patients with sickle cell disease

Summary of the safety profile

The median (min, max) duration of follow-up for the 43 patients with sickle cell disease after administration of Casgevy was 17.5 (1.2, 46.2) months.

There were not any serious adverse reactions attributed to Casgevy. There were not any cases of graft versus host disease, graft failure, or graft rejection.

One (2.3%) patient died due to COVID-19 disease and myeloablative conditioning-related lung toxicity. The event was not related to Casgevy.

Tabulated list of adverse reactions

Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10) and common (≥ 1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Tables 3 and 4 list adverse reactions attributed to Casgevy and haematopoietic stem cell transplant complications, respectively, experienced by patients with sickle cell disease in clinical studies with Casgevy.

Table 3: Adverse reactions attributed to Casgevy in patients with sickle cell disease (N=43)

^* At least one event was also attributed to haematopoietic stem cell transplantation complications.

† Lymphopenia included CD4 lymphocytes decreased.

‡ Rash included dermatitis

Table 4: Adverse reactions attributed to haematopoietic stem cell transplantation complications in patients with sickle cell disease (N=43)

^* Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.

† One patient died due to COVID-19 disease and conditioning-related lung toxicity. The event was considered not related to Casgevy.

‡ Mucositis included anal inflammation, mucosal inflammation, pharyngeal inflammation and stomatitis.

§ Abdominal pain included abdominal discomfort, abdominal pain upper and abdominal tenderness.

^# Pigmentation disorder included nail pigmentation, skin hyperpigmentation and skin hypopigmentation.

^** Rash included dermatitis, rash macular, rash maculo-papular and rash papular.

†† Musculoskeletal pain included back pain and pain in extremity.

Description of selected adverse reactions

Platelet engraftment in patients with sickle cell disease

Platelet engraftment is defined as 3 consecutive measurements of platelet counts ≥50 × 10⁹/L in patients with sickle cell disease, obtained on 3 different days after Casgevy infusion without administration of platelet transfusions for 7 days. In study 121, the median (min, max) time to platelet engraftment was 35 (23, 126) days (n=43).

Neutrophil engraftment in patients with sickle cell disease

Neutrophil engraftment is defined as 3 consecutive measurements of ANC ≥ 500 cells/µL on 3 different days after Casgevy infusion, without use of the unmodified rescue CD34⁺ cells. All patients achieved neutrophil engraftment, and no patients received rescue CD34⁺ cells.

In study 121, the median (min, max) time to neutrophil engraftment was 27 (15, 40) days (n=43).

Paediatric population

The safety profile was generally consistent among adolescent and adult patients. Engraftment times were similar in adolescent and adult patients.

Patients with transfusion-dependent β-thalassemia (study 111)

The safety of Casgevy in study 111 was evaluated in 19 patients with transfusion-dependent β-thalassemia aged 12 to less than 18 years. The median (min, max) time to platelet engraftment was 45 (20, 199) days in adolescent patients and 40 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 31 (19, 56) days in adolescent patients and 29 (12, 40) days in adult patients.

Patients with sickle cell disease (study 121)

The safety of Casgevy in study 121 was evaluated in 12 patients with sickle cell disease aged 12 to less than 18 years. The median (min, max) time to platelet engraftment was 44.5 (23, 81) days in adolescent patients and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in adolescent patients and 26 (15, 38) days in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable in the context of autologous haematopoietic stem cell transplant. The entire patient-specific dose should be administered.

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. No off-target editing has been observed based on in vitro studies with Casgevy manufactured using either healthy donor or patient cells. 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)

* Analysis conducted based on April 2023 data cut

† Low to no endogenous β-globin production (β⁰/β⁰, β⁰/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) × 10⁶ 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)

* 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) × 10⁶ 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.

Casgevy is an autologous gene therapy medicinal product consisting of haematopoietic stem cells that have been genetically modified ex vivo. The nature of Casgevy is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted. No studies on the effects of Casgevy on fertility have been conducted.

The biodistribution and persistence as well as toxicity and tumorigenicity of Casgevy were evaluated in two studies in sub-lethally irradiated, immunodeficient mice. These studies did not identify evidence of aberrant migration, accumulation, or persistence of CD34⁺ human hematopoietic stem and progenitor cells in non-target tissues and results were comparable between edited and unedited CD34⁺ cells. Persistence of edited cells in haematopoietic tissues was confirmed, with comparable overall percent editing of infused CD34⁺ cells throughout the 20-week duration of study. Treatment with edited CD34⁺ cells revealed no evidence of target organ toxicity or tumorigenicity.

In vitro studies with exagamglogene autotemcel manufactured from healthy donors and patients showed no evidence of off target editing. In studies with edited CD34⁺ cells obtained from healthy donors, no translocations were detected by either karyotyping or sequencing methods.

CryoStor CS5 (containing 5% dimethyl sulfoxide [v/v] and dextran 40)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Frozen: 2 years at ≤ -135 °C.

Once thawed: 20 minutes at room temperature (20 °C – 25 °C).

Casgevy must be stored in the vapour phase of liquid nitrogen at ≤ -135 °C and must remain frozen until the patient is ready for treatment to ensure viable cells are available for patient administration.

Thaw one vial at a time. Do not thaw until ready to infuse. Do not re-freeze after thawing.

For storage conditions after thawing of the medicinal product, see section 6.3.

Casgevy is supplied in cryopreservation vials made of cyclic olefin copolymer. Each vial contains 1.5 ml to 20 ml of Casgevy.

Vials are packed in paperboard carton(s). One carton may contain up to 9 vials.

Casgevy is shipped from the manufacturing facility to the treatment centre storage facility in a liquid nitrogen dry shipper. One shipper may contain multiple cartons, which may contain multiple vials, all intended for a single patient.

Precautions to be taken before handling or administering the medicinal product

Do not sample, alter, or irradiate the medicinal product. Irradiation could lead to inactivation of the product.

This medicinal product contains human blood cells. Healthcare professionals handling Casgevy should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.

Receipt and storage of Casgevy

• Casgevy is shipped to the treatment centre frozen in the vapour phase of liquid nitrogen.

• Confirm patient identifiers on the product label(s) and lot information sheet.

• If there are any concerns about the product or packaging upon receipt, contact Vertex at 0800-028-2616.

• Store in the vapour phase of liquid nitrogen at ≤ -135 °C until ready for thaw and administration.

Preparation prior to administration

Preparation for the infusion

• Coordinate the timing of Casgevy thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that Casgevy is available for infusion when the patient is ready, as Casgevy must be administered within 20 minutes of thawing the vial. Thaw and infuse one vial at a time.

• Before thaw, confirm the patient's identity matches the patient information on the Casgevy vial(s). Do not remove the Casgevy vials from cryo-storage if the information on the patient-specific label does not match the intended patient.

• A dose of Casgevy may be contained in one or more cryopreserved patient-specific vial(s). Account for all vials and confirm each vial is within the expiry date using the accompanying lot information sheet.

• Inspect the vial(s) for any breaks or cracks prior to thawing. If a vial is compromised, do not infuse the contents. Call Vertex at 0800-028-2616.

• Assemble supplies needed to thaw and withdraw the product from the vial(s). With the exception of the water bath, these supplies are single use. Assemble sufficient supplies for each vial to be administered:

Thawing the Casgevy vials

• When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing a vial, remaining vials must remain in cryo-storage at ≤ -135 °C.

• Thaw each vial at 37 °C using a water bath. Ensure water bath temperature does not exceed 40 °C.

• Thaw each vial holding the vial neck, gently agitating clockwise and counterclockwise. This can take between 10 to 15 minutes.

• Do not leave vial unattended during thaw.

• Thawing is complete when ice crystals are no longer visible in the vial.

• Remove vial from water bath immediately once thawed.

• The thawed product should appear as a translucent cell dispersion, which may contain visible particles.

• Infuse within 20 minutes of thaw.

Administration of Casgevy

Casgevy is for autologous use only. The patient's identity must match the patient identifiers on the Casgevy vial(s). Do not infuse Casgevy if the information on the patient-specific label does not match the intended patient.

A patient's dose may consist of multiple vials. All vials must be administered. The entire volume of each vial provided should be infused. If more than one vial is provided, administer each vial completely before proceeding to thaw and infuse the next vial.

Attaching the vial adapter and filter

• Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab.

• Remove the cap on the adapter spike.

• With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until you hear a single pop.

• Pull up on the adapter until you feel it lock.

• Attach the filter to the vial adapter.

Withdrawing Casgevy from the vial

• Attach an empty 30 mL syringe to the filter.

• Withdraw the entire vial product volume.

• Remove the product-filled syringe from the filter and set aside.

• Draw 5 to 10 mL of saline into the empty 10 mL syringe.

• Attach the saline-filled syringe to the filter.

• Inject the saline into the Casgevy vial and remove the empty syringe from the filter. Discard the empty syringe.

• Attach the product-filled syringe to the filter.

• Withdraw the contents of the vial into the product syringe, then remove the syringe from the filter.

• The optional product/patient identifier label can be peeled from the lot information sheet and affixed to the syringe.

Administration of Casgevy through a central venous catheter

• Casgevy must be administered within 20 minutes of product thaw.

• Perform a two-person confirmation and verification of patient's identification at the bedside prior to the infusion of each vial(s).

• Casgevy is administered as an intravenous bolus.

• The total volume of Casgevy administered within one hour must not exceed 2.6 mL/kg.

• Do not use an inline filter when infusing Casgevy.

• After administration of each vial of Casgevy, flush the primary line with 0.9% sodium chloride solution.

Repeat the steps listed above for each remaining vial.

After administration of Casgevy

• Monitor vital signs every 30 minutes from when the first vial of Casgevy is infused until 2 hours after the last vial of Casgevy is infused.

• Standard procedures for patient management after haematopoeitic stem cell transplantation should be followed after Casgevy infusion.

• Irradiate any blood products required within the first 3 months after Casgevy infusion.

• Patients should not donate blood, organs, tissues, or cells at any time in the future.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Casgevy (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling human-derived material.

Accidental exposure

In case of accidental exposure local guidelines on handling of human-derived material should be followed. Work surfaces and materials which have potentially been in contact with Casgevy must be decontaminated with appropriate disinfectant.

Vertex Pharmaceuticals (Europe) Limited

2 Kingdom Street

London, W2 6BD

United Kingdom

PLGB 22352/0019

15/11/2023

15/11/2023