Casgevy Prescribing Information

Sickle Cell Disease

Prior to apheresis it is recommended that patients be transfused with a goal to maintain hemoglobin S (HbS) levels < 30% of total hemoglobin (Hb) while keeping total Hb concentration ≤ 11 g/dL.

Transfusion-dependent β-thalassemia

Prior to apheresis procedure it is recommended that patients be transfused with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL.

Mobilization and Apheresis

Patients are required to undergo CD34+ HSC mobilization followed by apheresis to isolate the CD34+ cells needed for CASGEVY manufacturing.

Plerixafor and Granulocyte-Colony Stimulating Factor (G-CSF) were used for mobilization in patients with TDT.

Single agent plerixafor was used for mobilization in patients with SCD. G-CSF should not be administered for mobilization in patients with SCD.

Refer to the prescribing information for the mobilization agent(s) prior to treatment. See Clinical Studies (14) for description of the mobilization regimen used in the clinical trials.

Maximize CD34+ cell collection to obtain as many CD34+ cells as possible for product manufacturing during each mobilization and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 106 CD34+ cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. In addition, 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 (3 × 106 CD34+ cells/kg) is not met after initial product manufacturing, the patient will need to undergo additional cycles of mobilization and apheresis. Each mobilization and apheresis cycle must be separated by a minimum of 14 days.

The back-up collection of ≥ 2 × 106 CD34+ cells/kg of unmodified rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with CASGEVY. The unmodified back-up cells may be needed for rescue treatment under any one of the following conditions: (1) compromise of CASGEVY after initiation of myeloablative conditioning and before CASGEVY infusion; (2) neutrophil engraftment failure; or (3) loss of engraftment after infusion with CASGEVY [see Warnings and Precautions (5.1)].

Myeloablative Conditioning

In patients with SCD it is recommended that patients be transfused at least 8 weeks prior to the initiation of myeloablative conditioning, with a goal of maintaining hemoglobin S (HbS) levels of < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. At initiation of red blood cell exchange or simple transfusions, discontinue disease modifying therapies for sickle cell disease (e.g., hydroxyurea, crizanlizumab, voxelotor).

In patients with TDT it is recommended that patients be transfused to maintain hemoglobin (Hb) ≥ 11 g/dL for 60 days prior to myeloablative conditioning.

Stop iron chelation therapy at least 7 days prior to myeloablative conditioning.

Do not begin myeloablative conditioning until the complete set of vial(s) comprising the total dose of CASGEVY has been received and stored at the treatment center and the availability of the back-up collection of unmodified rescue cells is confirmed. See the Lot Information Sheet provided with the product shipment for confirmation of the total dose of CASGEVY.

Administer full myeloablative conditioning prior to treatment with CASGEVY 1. Refer to the prescribing information for the myeloablative conditioning agent prior to treatment. See Clinical Studies (14) for the conditioning regimen used in the clinical trials.

Consider administration of anti-seizure prophylaxis. Use agents other than phenytoin prior to initiating busulfan conditioning. Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome prior to initiating busulfan conditioning.

CASGEVY must be administered between 48 hours and 7 days after the last dose of the myeloablative conditioning.

Receipt and Storage of CASGEVY

• CASGEVY is shipped to the treatment center frozen in a vapor phase of liquid nitrogen shipper.
• 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 +1-877-634-8789.
• Transfer CASGEVY from the vapor phase of nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -135 °C (≤ -211 °F).

Preparing for CASGEVY Administration

CASGEVY contains human cells. Follow universal precautions (wearing gloves, protective clothing, and eye protection) and local biosafety guidelines applicable for handling and disposal of such products to avoid potential transmission of infectious diseases. 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 biosafety guidelines.

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 and healthcare providers are ready. Thaw and infuse one vial at a time.

Premedication: Administer an antipyretic (e.g., acetaminophen) and an antihistamine (e.g., diphenhydramine hydrochloride) prior to administering CASGEVY.

Before thaw, confirm CASGEVY is printed on the vial label and the patient's identity matches the unique patient information located on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label on any of the vials does not match the intended patient, and contact Vertex at +1-877-634-8789.

A dose of CASGEVY may be contained in one or more cryopreserved patient-specific vial(s). Ensure that the correct number of vials are present. Use the accompanying Lot Information Sheet to confirm the total number of vials to be administered and confirm that each vial is within the expiration date prior to preparation of CASGEVY for infusion.

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 +1-877-634-8789.

When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing and administering a vial, remaining vials must remain in cryostorage at ≤ -135 °C (≤ -211 °F).

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:

• Water bath
• Alcohol swabs
• Vial adapter (to allow for needleless extraction)
• 18-micron stainless steel filter
• 30 mL luer-lock syringe
• 0.9% sodium chloride (saline, 5 to 10 mL needed for each vial)
• 10 mL luer-lock syringe for saline rinse

After CASGEVY Administration

Follow standard procedures for patient management after HSC transplantation after CASGEVY infusion.

• Irradiate any blood products required within the first 3 months after CASGEVY infusion.
• Patients treated with CASGEVY should not donate blood, organs, tissues, or cells at any time in the future.
• Restarting iron chelation after CASGEVY infusion may be necessary and should be based on clinical practice. 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 in lieu of iron chelation, when appropriate [see Drug Interactions (7.4)].

Sickle Cell Disease

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 3), 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.

Other clinically important adverse reactions that occurred in less than 10% of patients 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.

Transfusion-dependent β-thalassemia

The safety of CASGEVY in patients with TDT was evaluated in an open-label, single-arm trial (Trial 2) and a long-term follow-up trial (Trial 3), in which 52 adolescent and adult patients with TDT 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 52 patients with TDT after being administered CASGEVY was 20.4 (2.1, 48.1) months.

Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reactions (≥ 2 patients) were veno-occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection.

Table 3 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 2. Table 4 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT.

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

Immune system disorders: Hemophagocytic lymphohistiocytosis (1 [2%] patient).

Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (1 [2%] patient).

Infusion-related reactions: 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each.

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 should use effective method of contraception from start of mobilization through at least 6 months after administration of CASGEVY. Advise patients of the risks associated with conditioning agents.

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.

Patients with SCD

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.

Patients with TDT

The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients.

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

Sickle Cell Disease

Transfusion-dependent β-thalassemia

Mobilization and Apheresis

Patients underwent RBC exchange or simple transfusions for a minimum of 8 weeks before the planned start of mobilization and continued receiving transfusions or RBC exchanges until the initiation of myeloablative conditioning. Hemoglobin S (HbS) levels were maintained at < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL.

To mobilize stem cells for apheresis, patients in Trial 1 were administered plerixafor at a planned dose of 0.24 mg/kg via subcutaneous injection approximately 2 to 3 hours prior to each planned apheresis. Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34+ cells.

The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for the manufacture of CASGEVY and for the back-up collection of rescue CD34+ cells were 2.3 (1.41) and 2 (1, 6), respectively. Six (10%) patients were unable to receive CASGEVY therapy due to not achieving the minimum dose.

Pre-treatment Conditioning

All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range.

For the once daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC0-6h of 1125 µM*min (range: 900 to 1350 µM*min).

All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan.

Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines.

CASGEVY Administration

Patients were administered CASGEVY with a median (min, max) dose of 4.0 (2.9, 14.4) × 106 CD34+ cells/kg as an IV infusion.

All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion.

After CASGEVY Administration

G-CSF was not recommended within the first 21 days after CASGEVY infusion.

As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning.

Efficacy Results

An interim analysis (IA) was conducted with 31 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 26.0 (17.8, 48.1) months from the time of CASGEVY infusion in PES. There were no cases of graft failure or graft rejection.

The primary efficacy outcome was the proportion of VF12 responders, defined as patients who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after CASGEVY infusion in Trial 1. The proportion of patients who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period (HF12) was also assessed. The evaluation of VF12 and HF12 began 60 days after the last RBC transfusion for post-transplant support or SCD management. The median (min, max) time to the last RBC transfusion was 19 (11, 52) days following CASGEVY infusion for patients in the primary efficacy set.

The interim analysis occurred at the time when the alpha spending was approximately 0.02 for a one-sided test, when 31 patients were evaluable for VF12 responder status. The VF12 response rate was 29/31 (93.5%, 98% one-sided CI: 77.9%, 100.0%). The 29 VF12 responders did not experience protocol-defined severe VOCs during the evaluation period with a median duration of 22.2 months at the time of the interim analysis. One VF12 responder, after initially achieving a VF12 response, experienced an acute pain episode meeting the definition of a severe VOC at Month 22.8 requiring a 5-day hospitalization; this patient was reported to have a parvovirus B19 infection at the time. Of the 31 patients evaluable for VF12 response, one patient was not evaluable for HF12 response; the remaining 30 patients (100%, 98% one-sided CI: 87.8%, 100.0%) achieved the endpoint of HF12.

Mobilization and Apheresis

To maintain a total Hb concentration ≥ 11 g/dL, patients underwent RBC transfusions prior to mobilization and apheresis and continued receiving transfusions until the initiation of myeloablative conditioning.

To mobilize stem cells for apheresis, patients in Trial 2 were administered G-CSF and plerixafor. Patients with a spleen were administered a planned dose of 5 µg/kg G-CSF approximately every 12 hours via intravenous or subcutaneous injection for 5 to 6 days. Splenectomized patients were administered a planned dose of 5 µg/kg G-CSF once daily for 5 to 6 days. The dose was increased to every 12 hours in splenectomized patients if there was no increase in white blood cell (WBC) or peripheral blood CD34+ counts. After 4 days of G-CSF administration, all patients received plerixafor at a planned dose of 0.24 mg/kg administered via subcutaneous injection approximately 4 to 6 hours prior to each planned apheresis.

Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34+ cells.

The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for manufacture CASGEVY and for the back-up collection of rescue CD34+ cells were 1.3 (0.7) and 1 (1, 4), respectively.

Pre-treatment Conditioning

All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range.

For the once-daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC0-6h of 1125 µM*min (range: 900 to 1350 µM*min).

All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan.

Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines.

CASGEVY Administration

Patients were administered CASGEVY with a median (min, max) dose of 7.5 (3.0, 19.7) × 106 CD34+ cells/kg as an IV infusion.

All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion.

After CASGEVY Administration

G-CSF was not recommended within the first 21 days after CASGEVY infusion.

As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning.

Efficacy Results

An interim analysis (IA) was conducted with 35 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 23.8 (16.1, 48.1) months from the time of CASGEVY infusion in the PES. There were no cases of graft failure or graft rejection.

The primary outcome was the proportion of patients achieving transfusion independence for 12 consecutive months (TI12), defined as maintaining weighted average Hb ≥9 g/dL without RBC transfusions for at least 12 consecutive months any time within the first 24 months after CASGEVY infusion in Trial 2, evaluated starting 60 days after the last RBC transfusion for post-transplant support or TDT disease management.

The interim analysis occurred at the time when the alpha spending was approximately 0.017 for a one-sided test, when 35 patients were evaluable for TI12 responder status. The TI12 responder rate was 32/35 (91.4%, 98.3% one-sided CI: 75.7%, 100%). All patients who achieved TI12 remained transfusion-independent, with a median (min, max) duration of transfusion-independence of 20.8 (13.3, 45.1) months and normal mean weighted average total Hb levels (mean [SD] 13.1 [1.4] g/dL). The median (min, max) time to last RBC transfusion for patients who achieved TI12 was 30 (11, 91) days following CASGEVY infusion. Three patients did not achieve TI12. These patients had reductions in annualized RBC transfusion volume requirements of 79.8%, 83.9% and 97.9%, and reductions in annualized transfusion frequency of 78.6%, 67.4% and 94.6%, respectively, compared to baseline requirements.