CASGEVY® was studied in patients with transfusion-dependent β-thalassemia1

Trial 2: An ongoing international, multi-center, single-arm, single-dose, Phase 1/2/3, open-label, pivotal study of one-time CASGEVY® (exagamglogene autotemcel) infusion1,2

Trial 2: An ongoing international, multi-center, single-arm, single-dose, Phase 1/2/3, open-label, pivotal study of one-time CASGEVY® (exagamglogene autotemcel) infusion1,2

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Key inclusion criteria1,2

  • Aged 12 to 35 years
  • History of ≥100 mL/kg/year or ≥10 units/year of RBC transfusions in the previous 2 years
  • Eligible for autologous hematopoietic stem-cell transplantation (HSCT)
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Key exclusion criteria1,2

  • Available 10/10 human leukocyte antigen-matched donor
  • Prior HSCT
  • Clinically significant and active bacterial, viral, fungal, or parasitic infection
  • Sickle cell β-thalassemia variant or associated α-thalassemia and >1 alpha deletion or alpha multiplications
  • WBC count <3x109/L or platelet count <50x109/L not related to hypersplenism
  • Severely elevated iron in the heart (ie, patients with cardiac T2* less than 10 msec by MRI or LVEF <45% by echocardiogram) or advanced liver disease*

52 patients received treatment with CASGEVY in the clinical trial1†

Patients were administered CASGEVY with a median (min, max) dose of 7.5 (3.0, 19.7)x106 CD34+ cells/kg as an
intravenous (IV) infusion.‡
All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY.

52 patients received treatment with CASGEVY in the clinical trial1†

Patients were administered CASGEVY with a median (min, max) dose of 7.5 (3.0, 19.7)x106 CD34+ cells/kg as an intravenous (IV) infusion.1†

All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY.

The data presented here are based on an interim analysis as of January 2023. The safety data are for the full analysis set, defined as the 52 patients who received CASGEVY. The efficacy data are for the primary efficacy set (n=35). This set was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set.1

*Advanced liver disease defined as aspartate transaminase (AST) or alanine transaminase (ALT) >3x the upper limit of normal (ULN), or direct bilirubin value >2.5x ULN, or if a liver biopsy demonstrated bridging fibrosis or cirrhosis (liver biopsy was performed if liver iron content was ≥15 mg/g by MRI).1

†At the time of the interim analysis, a total of 59 patients enrolled in the trial, of which 59 (100%) patients started mobilization. A total of 52 (88%) patients received CASGEVY infusion.1

‡All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion.1

      Demographics and baseline characteristics1
        CASGEVY
      Demographics and disease characteristics Full Analysis Set (FAS)§ (N=52) Primary Efficacy Set (PES)§||
      (n=35)
      Sex, n (%)
      Male 27 (51.9) 18 (51.4)
      Female 25 (48.1) 17 (48.6)
      Age, years, median (min, max) 20 (12, 35) 20 (12, 33)
      Adolescents (≥12 and <18 years), n (%) 18 (34.6) 11 (31.4)
      Adults (≥18 and ≤35 years), n (%) 34 (65.4) 24 (68.6)
      Race, n (%)
      Asian 22 (42.3) 13 (37.1)
      White 18 (34.6) 15 (42.9)
      Multiracial 3 (5.8) 3 (8.6)
      Other 2 (3.8) 0
      Genotype, n (%)
      β0/β0-like# 31 (59.6) 20 (57.1)
      Non-β0/β0-like 21 (40.4) 15 (42.9)

      Baseline annualized RBC transfusion volume (mL/kg)

      median (min, max)

      		 201 (48, 331) 205 (115, 331)

      Baseline annualized RBC transfusion episodes

      median (min, max)

      		 17 (5, 35) 17 (11, 35)

      Spleen intact, 
n (%)

      		 36 (69.2) 26 (74.3)

      Baseline liver iron concentration (mg/g)

      median (min, max)

      		 3.5 (1.2, 14.0) 4.0 (1.4, 14.0)

      Baseline cardiac iron T2* (msec)

      median (min, max)

      		 34.0 (12.4, 61.1) 34.8 (19.6, 61.1)

      Baseline serum ferritin (pmol/L)

      median (min, max)

      		 2892 (584, 10837) 2654 (674, 10741)
        CASGEVY
      Demographics and disease characteristics Full Analysis Set (FAS)§ (N=52) Primary Efficacy Set (PES)§||
      (n=35)
      Sex, n (%)
      Male 27 (51.9) 18 (51.4)
      Female 25 (48.1) 17 (48.6)
      Age, years, median (min, max) 20 (12, 35) 20 (12, 33)
      Adolescents (≥12 and <18 years), n (%) 18 (34.6) 11 (31.4)
      Adults (≥18 and ≤35 years), n (%) 34 (65.4) 24 (68.6)
      Race, n (%)
      Asian 22 (42.3) 13 (37.1)
      White 18 (34.6) 15 (42.9)
      Multiracial 3 (5.8) 3 (8.6)
      Other 2 (3.8) 0
      Genotype, n (%)
      β0/β0-like# 31 (59.6) 20 (57.1)
      Non-β0/β0-like 21 (40.4) 15 (42.9)

      Baseline annualized RBC transfusion volume (mL/kg)

      median (min, max)

      		 201
      (48, 331)      		 205
      (115, 331)

      Baseline annualized RBC transfusion episodes

      median (min, max)

      		 17
      (5, 35)      		 17
      (11, 35)

      Spleen intact, 
n (%)

      		 36
      (69.2)      		 26
      (74.3)

      Baseline liver iron concentration (mg/g)

      median (min, max)

      		 3.5
      (1.2, 14.0)      		 4.0
      (1.4, 14.0)

      Baseline cardiac iron T2* (msec)

      median (min, max)

      		 34.0
      (12.4, 61.1)      		 34.8
      (19.6, 61.1)

      Baseline serum ferritin (pmol/L)

      median (min, max)

      		 2892
      (584, 10837)      		 2654
      (674, 10741)

      §Interim analysis conducted based on January 2023 data cut-off date.1

      ||The PES is a subset of the FAS. The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set.1

      Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES.1

      # Low to no endogenous β-globin production (β0/β0, β0/IVS-I-110, and IVS-I-110/IVS-I-110).1

      The baseline characteristics and demographics are consistent between the PES and the FAS.1

      §Interim analysis conducted based on January 2023 data cut-off date.1

      ||The PES is a subset of the FAS. The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set.1

      Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES.1

      #Low to no endogenous β-globin production (β0/β0, β0/IVS-I-110, and IVS-I-110/IVS-I-110).1

      The baseline characteristics and demographics are consistent between the PES and the FAS.1

      Primary efficacy endpoint1

      • Proportion of patients who achieved a maintained weighted average Hb ≥9 g/dL without RBC transfusions for at least 12 consecutive months (TI12) any time within the first 24 months after CASGEVY infusion**
      Evaluation time frame Evaluation time frame

      Select safety endpoints3

      • Time to neutrophil engraftment
      • Time to platelet engraftment
      • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, and vital signs

      Select secondary efficacy endpoints3

      • Duration of transfusion-free period in patients achieving TI12
      • Relative change from baseline in transfusions up to 24 months starting 60 days after CASGEVY infusion
      • Change in Hb concentrations over time
      • Change in HbF concentration over time
      • Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time
      • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time

      **The evaluation starts 60 days after last RBC transfusion for posttransplant support or TDT management. The median (min, max) time to the last RBC transfusion was 30 (11, 91) days following CASGEVY infusion for patients who achieved TI12.1

      ††Postinfusion follow-up includes supportive care, 60-day transfusion-free period after the last supportive RBC transfusion, and the 12 months of the transfusion-free period.1

      Hb=hemoglobin; HbF=fetal hemoglobin; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; RBC=red blood cell; TI12=transfusion independence for 12 consecutive months; TDT=transfusion-dependent β-thalassemia; WBC=white blood cell.

          Trial 3: Long-term study (up to 5 years of follow-up)

          Patients who complete or discontinue Trial 2 are encouraged to enroll in a long-term observational study for up to 15 years post infusion1,4

          Mean duration of follow-up as of March 2024 data cutoff: 32.3 months, ranging from 3.1 to 62.3 months5

          Eligibility criteria4

          Eligibility criteria4

          • Patients who received CASGEVY infusion
            • All patients who received CASGEVY in Trial 2 (or other parent study)
            • All patients who received
              CASGEVY in Trial 2 (or other parent study)
            • Completion of informed consent form and, where applicable, an assent form
            • Completion of informed consent form and, where applicable, an assent form

          Exclusion criteria4

          • There are no exclusion criteria

          Long-term follow-up primary outcomes4

          • New malignancies
          • New or worsening hematologic disorders
          • All-cause mortality
          • Serious AEs occurring up to 15 years post infusion
          • AEs related to CASGEVY

          Secondary outcomes include long-term efficacy outcomes and patient-reported outcomes.4

          Data from this trial are not included in the full Prescribing Information.

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          IMPORTANT SAFETY INFORMATION

          IMPORTANT SAFETY INFORMATION AND INDICATION

          WARNINGS AND PRECAUTIONS

          Neutrophil Engraftment Failure

          There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34+ cells.

          There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34+ cells.

          INDICATION

          CASGEVY is indicated for the treatment of patients aged 12 years and older with:

          • sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs)
          • transfusion-dependent β-thalassemia (TDT)

           

          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.

          Delayed Platelet Engraftment

          Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events 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.

          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.

          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.

          ADVERSE REACTIONS

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

          All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia, and lymphopenia.

          DRUG INTERACTIONS

          No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P450 family of enzymes or drug transporters.

          Use of Granulocyte-Colony Stimulating Factor (G-CSF): G-CSF must not be used for CD34+ HSC mobilization of patients with SCD.

          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.

          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.

          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.

          USE IN SPECIFIC POPULATIONS

          Pregnancy/Lactation: CASGEVY must not be administered during pregnancy and breastfeeding should be discontinued during conditioning because of the risks associated with myeloablative conditioning. Pregnancy and breastfeeding after CASGEVY infusion should be discussed with the treating physician.

          Females and Males of Reproductive Potential: A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and reconfirmed prior to myeloablative conditioning.

          Women of childbearing potential and men capable of fathering a child should use effective methods 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 has been observed with myeloablative conditioning therefore, advise patients of fertility preservation options before treatment, if appropriate.

          INDICATION

          CASGEVY is indicated for the treatment of patients aged 12 years and older with:

          • sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs)
          • transfusion-dependent β-thalassemia (TDT)

          Please see full Prescribing Information for CASGEVY.

          References: 1. CASGEVY [prescribing information]. Vertex Pharmaceuticals Incorporated. Boston, MA; January 2024. 2. A safety and efficacy study evaluating CTX001 in subjects with transfusion-dependent β-thalassemia. ClinicalTrials.gov identifier: NCT03655678. Updated May 13, 2024. Accessed September 12, 2024. https://clinicaltrials.gov/study/NCT03655678 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-16870 (v1.0); 2021. 4. A long-term follow-up study in subjects who received CTX001. ClinicalTrials.gov identifier: NCT04208529. Updated July 3, 2024. Accessed September 12, 2024. https://clinicaltrials.gov/study/NCT04208529 5. Locatelli F, Lang P, Meisel R, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. Presented at: 29th Congress of the European Hematology Association; June 13-16, 2024.

          References: 1. CASGEVY [prescribing information]. Vertex Pharmaceuticals Incorporated. Boston, MA; January 2024. 2. A safety and efficacy study evaluating CTX001 in subjects with severe sickle cell disease. ClinicalTrials.gov identifier: NCT03745287. Updated May 13, 2024. Accessed September 12, 2024. https://clinicaltrials.gov/ct2/show/NCT03745287 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-16870 (v1.0); 2021. 4. A long-term follow-up study in subjects who received CTX001. ClinicalTrials.gov identifier: NCT04208529. Updated July 3, 2024. Accessed September 12, 2024. https://clinicaltrials.gov/ct2/show/NCT04208529 5. Locatelli F, Lang P, Meisel R, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. Presented at: 29th Congress of the European Hematology Association; June 13-16, 2024.