4.1. Therapeutic indications

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 vaso-occlusive crises who have the βS/βS, βS/β+ or βS/β0 genotype, for whom haematopoietic stem cell transplantation is appropriate and a human leukocyte antigen matched related haematopoietic stem cell donor is not available.

4.2. Posology and method of administration

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.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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 haemoglobinopathies. 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 cryopreservative 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 lymphohistiocytosis, 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)

System organ class

Very common (≥10%)

Common (≥1% - <10%)

Blood and lymphatic system disorders

Lymphopenia *, †

Thrombocytopenia *, Neutropenia *, Anaemia *, Leukopenia *

Immune system disorders

Haemophagocytic lymphohistiocytosis

Metabolism and nutrition disorders

Hypocalcaemia *

Nervous system disorders

Headache *, Paraesthesia

Cardiac disorders

Tachycardia *

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome, Idiopathic pneumonia syndrome *, Epistaxis *

Skin and subcutaneous tissue disorders

Petechiae *

General disorders and administration site conditions

Chills *, Pyrexia *

Injury, poisoning and procedural complications

Delayed engraftment *, Infusion related reactions ‡

* 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)

System organ class

Very common (≥10%)

Common (≥1% - <10%)

Infections and infestations

Pneumonia, Klebsiella sepsis, Sepsis

Blood and lymphatic system disorders

Thrombocytopenia, Febrile neutropenia, Neutropenia, Anaemia, Lymphopenia *, Leukopenia

Splenomegaly

Metabolism and nutrition disorders

Decreased appetite, Hypokalaemia, Fluid retention, Hypophosphataemia

Hypoalbuminaemia, Hypomagnesaemia, Hypocalcaemia

Nervous system disorders

Headache

Cerebellar haemorrhage, Hydrocephalus, Neuralgia

Eye disorders

Vision blurred

Cardiac disorders

Tachycardia

Vascular disorders

Hypotension

Respiratory, thoracic and mediastinal disorders

Epistaxis

Idiopathic pneumonia syndrome, Oropharyngeal pain, Cough, Dyspnoea

Gastrointestinal disorders

Mucositis †, Nausea, Abdominal pain ‡, Vomiting, Diarrhoea, Constipation

Colitis, Gastritis, Gingival bleeding, Dyspepsia, Dysphagia, Gastrointestinal inflammation, Haematochezia, Mouth ulceration

Hepatobiliary disorders

Veno-occlusive liver disease, Alanine aminotransferase increased

Hepatomegaly, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Alopecia, Petechiae, Pigmentation disorder §

Rash #, Dry skin, Pruritus, Erythema

Musculoskeletal and connective tissue disorders

Musculoskeletal pain **

Arthralgia

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Amenorrhoea, Premature menopause

General disorders and administration site conditions

Pyrexia, Fatigue

Investigations

C-reactive protein increased, International normalised ratio increased, Weight increased

Injury, poisoning and procedural complications

Delayed engraftment, Subcutaneous haematoma

* 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)

System organ class

Very common (≥10%)

Common (≥1% - <10%)

Blood and lymphatic system disorders

Lymphopenia *, †

Thrombocytopenia *, Neutropenia *

Skin and subcutaneous tissue disorders

Rash *, ‡

* 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)

System organ class

Very common (≥10%)

Common (≥1% - <10%)

Infections and infestations

Pneumonia, Sepsis, Oral candidiasis, Folliculitis

Blood and lymphatic system disorders

Febrile neutropenia, Thrombocytopenia, Neutropenia, Anaemia, Lymphopenia *, Leukopenia

Pancytopenia, Reticulocytopenia

Metabolism and nutrition disorders

Decreased appetite, Hypokalaemia, Hyperphosphataemia, Hypomagnesaemia

Hypophosphataemia

Nervous system disorders

Headache

Peripheral sensory neuropathy, Dysgeusia, Neuropathy peripheral

Eye disorders

Dry eye

Cardiac disorders

Tachycardia

Vascular disorders

Hot flush

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain, Epistaxis

Respiratory failure †, Hypoxia

Gastrointestinal disorders

Mucositis ‡, Nausea, Vomiting, Abdominal pain §, Diarrhoea, Constipation, Gastritis

Dyspepsia, Gastrooesophageal reflux disease, Haematemesis, Oesophagitis

Hepatobiliary disorders

Hyperbilirubinaemia, Alanine aminotransferase increased

Aspartate aminotransferase increased

Skin and subcutaneous tissue disorders

Pigmentation disorder #, Skin exfoliation, Alopecia, Dry skin, Rash **

Pruritus

Musculoskeletal and connective tissue disorders

Musculoskeletal pain ††

Renal and urinary disorders

Dysuria

Reproductive system and breast disorders

Amenorrhoea, Intermenstrual bleeding, Vulvovaginal pain, Dysmenorrhoea, Menstruation irregular

General disorders and administration site conditions

Pyrexia, Fatigue

Pain

Investigations

Weight decreased

International normalised ratio increased

Injury, poisoning and procedural complications

Skin abrasion, Skin laceration

* 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.

4.9. Overdose

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