CASGEVY Suspension for infusion Ref.[107241] Active ingredients: Exagamglogene autotemcel

5.1 Potential Neutrophil Engraftment Failure

Neutrophil engraftment failure is a potential risk in HSC transplant, defined as not achieving neutrophil engraftment after CASGEVY infusion and requiring use of unmodified rescue CD34 cells. In the clinical trial, all treated patients achieved neutrophil engraftment and no patients received rescue CD34 cells.

Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34⁺ cells [see Adverse Reactions (6.1)].

5.2 Prolonged Time to Platelet Engraftment

Longer median platelet engraftment times were observed with CASGEVY treatment compared to allogeneic HSC transplant. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trial, there was no association observed between incidence of serious bleeding and time to platelet engraftment.

Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise [see Adverse Reactions (6.1)].

5.3 Hypersensitivity Reactions

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.

5.4 Off-Target Genome Editing Risk

Although off-target genome editing was not observed in the edited CD34 cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual’s CD34 cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown.

The most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥25%) were mucositis, febrile neutropenia, and decreased appetite.

The most common Grade 3 or 4 laboratory abnormalities (occurring in ≥50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Potential Neutrophil Engraftment Failure [see Warnings and Precautions (5.1)]
• Prolonged Time to Platelet Engraftment [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of CASGEVY in patients with SCD was evaluated in an open-label, single-arm trial (Trial 1) and a long-term follow-up trial (Trial 2), in which 44 adolescent and adult patients with SCD were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.

The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months.

Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY.

Table 1 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1. Table 2 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD.

Table 1. Grade 3 or 4 non-laboratory adverse reactions in ≥10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion*:

^* Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.
^† Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis.
^‡ Encompasses preferred terms that belong to other system organ class.
^¶ Abdominal pain includes abdominal pain and abdominal pain upper.
^‡ Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity.

Other clinically important adverse reactions that occurred in less than 10% of patients with SCD or were Grade 1 or Grade 2 include the following:

Hepatobiliary disorders: Veno-occlusive liver disease (1 [2%] patient).

Infusion-related reactions: 6 (14%) patients, including preferred terms of abdominal pain in 3 (7%) patients; and infusion-related reaction, nausea, non-cardiac chest pain, pruritus, sinus tachycardia, and vomiting in 1 (2%) patient each.

Table 2. Grade 3 or 4 laboratory abnormalities in ≥10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion*:

^* Table includes laboratory abnormalities associated with busulfan myeloablative
conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant.
^† The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis.

Platelet engraftment

Platelet engraftment in patients with SCD is defined as 3 consecutive measurements of platelet counts ≥50 × 10⁹/L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. In Trial 1, the median (min, max) time to platelet engraftment was 35 (23, 126) days (n=43). There was no association observed between bleeding events and time to platelet engraftment.

Neutrophil engraftment

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. In Trial 1, the median (min, max) time to neutrophil engraftment was 27 (15, 40) days (n=44). There was no association observed between infections and time to neutrophil engraftment. There was no use of rescue CD34 cells in any patient.

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.

7.1 Use of Granulocyte-Colony Stimulating Factor (G-CSF)

Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34⁺ HSC mobilization of patients with sickle cell disease.

7.2 Use of Hydroxyurea

Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion.

7.3 Use of Voxelotor and Crizanlizumab

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

7.4 Use of Iron Chelators

Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, 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.

7.5 Live Vaccines

The safety of immunization with live viral vaccines during or following CASGEVY treatment has not been studied.

Risk Summary

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 fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

There are no data on the presence of exagamglogene autotemcel in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breastfeeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding 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. Breastfeeding after CASGEVY infusion should be discussed with the treating physician.

Pregnancy Testing

A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and re-confirmed prior to myeloablative conditioning.

Contraception

There are 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 mobilization through at least 6 months after administration of CASGEVY.

Infertility

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, advise patients of fertility preservation options before treatment, if appropriate.

The safety and efficacy of CASGEVY has been established in pediatric patients with SCD aged 12 years and older. Use of CASGEVY is supported by data in 12 patients aged 12 to less than 18 years in Trial 1. The efficacy and safety profile was generally consistent among pediatric patients aged 12 years and older and adult patients. [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients aged 12 years and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients aged 12 years and older and 26 (15, 38) days in adult patients.

The safety and efficacy of CASGEVY in pediatric patients aged less than 12 years has not been established.

CASGEVY has not been studied in patients >65 years of age. HSC transplantation must be appropriate for a patient to be treated with CASGEVY.

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 HSC transplantation is appropriate.

CASGEVY has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

Consider the risks of mobilization and myeloablative conditioning agents in patients with reproductive potential and patients that are pregnant or breast-feeding.

8.8 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, HBV 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.

8.9 Patients with Prior HSC Transplant

CASGEVY has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with CASGEVY is not recommended in these patients.