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

Fetal Hemoglobin and Total Hemoglobin

HbF and total Hb over time are provided in Table 3 for all patients administered CASGEVY for the treatment of sickle cell disease (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set.

Table 3. Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD:

SD: Standard Deviation.
^* % HbF/Hb data not available for all patients at all timepoints.

The mean (SD) proportion of Hb comprised by HbF was 43.9% (8.6%) at Month 6 and was maintained thereafter. Increases in mean (SD) total Hb levels were observed as early as Month 3 after CASGEVY infusion, continued to increase to 12.5 (1.8) g/dL at Month 6, and was maintained thereafter. Of the 44 patients infused with CASGEVY, three male patients reached total Hb levels of at least 16.5 g/dL at one or more time points after Month 9.

Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 70.1% (13.8%) and continued to increase over time to 94.0% (12.4%) at month 6, with levels remaining stable thereafter, indicating sustained pan-cellular expression of HbF.

Proportion of Alleles with Intended Genetic Modification

The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 4 for all patients administered CASGEVY for the treatment of sickle cell disease.

Table 4. Proportion of alleles with intended genetic modification over time:

^* Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.

Subgroup analyses evaluating the effects of age (adolescent versus adult) and sex (male versus female) showed consistent results on total hemoglobin, fetal hemoglobin and allelic editing.

CASGEVY is an autologous cellular therapy which includes CD34⁺ cells that have been edited ex vivo. The nature of CASGEVY is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY. No studies on the effects of CASGEVY on fertility have been conducted.

Sickle Cell Disease

Trial 1 (NCT03745287) is an ongoing single-arm, multi-center trial evaluating the safety and efficacy of a single dose of CASGEVY in adult and adolescent patients with sickle cell disease. Eligible patients underwent mobilization and apheresis to collect CD34⁺ stem cells for CASGEVY manufacture, followed by myeloablative conditioning and infusion of CASGEVY. Patients were then followed in Trial 1 for 24 months after CASGEVY infusion. Patients who complete or discontinue from Trial 1 are encouraged to enroll in Trial 2 (NCT04208529), an ongoing long-term follow-up trial for additional follow up for a total of 15 years after CASGEVY infusion.

Patients were eligible for the trial if they had a history of at least 2 protocol-defined severe vaso-occlusive crisis (VOC) events during each of the 2 years prior to screening. In this trial severe VOC is defined as an occurrence of at least one of the following events:

• Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions
• Acute chest syndrome
• Priapism lasting >2 hours and requiring a visit to a medical facility
• Splenic sequestration.

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 (TCD), and patients aged 12 to 18 years were excluded if they had any history of abnormal TCD in the middle cerebral artery and the internal carotid artery. Patients with an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor were excluded. Patients with more than 10 unplanned hospitalizations or emergency department visits related to chronic pain rather than SCD-related acute pain crises in the year before screening were excluded.

At the time of the interim analysis, a total of 63 patients enrolled in the trial, of which 58 (92%) patients started mobilization. A total of 44 (76%) patients received CASGEVY infusion and formed the full analysis set (FAS). Thirty-one patients from the FAS (70%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set (PES). The key demographics and baseline characteristics for all patients administered CASGEVY in Trial 1 are shown in Table 5 below. The baseline characteristics and demographics are consistent between the PES and the FAS.

Table 5. Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 1:

^* Interim analysis conducted based on June 2023 data cut-off date.
^† The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to CASGEVY-related adverse events, or continuously received RBC transfusions for more than 10 months after CASGEVY were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in PES.

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 AUC_0-24h 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 AUC_0-6h 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 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 19.3 (0.8, 48.1) months from the time of CASGEVY infusion in FAS. 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.