Summary Basis of Decision for Casgevy

Clinical Pharmacology

Casgevy (exagamglogene autotemcel) is a therapy consisting of an autologous cellular product composed of a patient’s own CD34-positive (CD34+) hematopoietic stem/progenitor cells (HSPCs), obtained by apheresis. Following collection, these cells undergo ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) (CRISPR/Cas9)-mediated gene editing of the erythroid lineage specific enhancer region of the B-cell lymphoma/leukemia 11A (BCL11A) gene. A specific guide ribonucleic acid (RNA) enables CRISPR/Cas9 to make a precise deoxyribonucleic acid (DNA) double-strand break, which disrupts the critical transcription factor (GATA1) binding site in the erythroid specific enhancer region of the BCL11A gene. As a result of this permanent editing, GATA1 binding is disrupted and BCL11A expression is reduced. Reduced BCL11A expression results in increased gamma-globin expression and fetal hemoglobin (HbF) protein production in erythroid cells, addressing the underlying causes of disease.

After ex vivo editing of the patient’s cells, the patient receives myeloablative conditioning chemotherapy and the edited cells are infused back into the patient. The goal of therapy, which is analogous to a hematopoietic stem cell transplant (HSCT) procedure, is to reconstitute the bone marrow with hematopoietic stem cells (HSCs) capable of differentiating into erythrocytes that express sufficient HbF to overcome the hemoglobin (Hb) defects that are characteristic of sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). In patients with severe SCD, HbF expression is expected to reduce the concentration of intracellular hemoglobin S, thereby preventing the red blood cells (RBCs) from sickling. In patients with TDT, gamma-globin production corrects the alpha-globin to non-alpha-globin imbalance, thereby reducing ineffective erythropoiesis and hemolysis and increasing total Hb levels, primarily in the form of HbF, thereby eliminating the dependence on regular RBC transfusions.

The clinical pharmacology program for Casgevy was limited due to the nature of the product. Pharmacodynamic endpoints were assessed as part of the pivotal studies (studies 121 and 111, discussed in the Clinical Efficacy section below) and a long-term follow-up study (Study 131). Key pharmacodynamic endpoints included HbF levels and total Hb levels over time. The proportion of edited alleles in the administered dose, in the peripheral blood, and in the CD34+ cells of the bone marrow were also evaluated as was persistence of the edited cells. Patients with TDT have very little to no beta-globin expression. In these patients, HbF constituted the majority of total Hb (more than 80%) by month six following Casgevy treatment. In patients with SCD, HbF was increased to approximately 44% of total Hb after Casgevy treatment (by month six), which is sufficient to improve the negative effects of sickle Hb. For both diseases, HbF concentrations remained stable during follow-up. The intended genetic modification was present in a high proportion of alleles in the drug product and in the bone marrow samples examined at month six. The percent allelic editing remained stable at the level of the individual over time.

Busulfan myeloablation was successful, resulting in profound neutropenia (as expected) and the engraftment of edited cells in both SCD and TDT patients. No covariate effects on the pharmacokinetics of busulfan were detected; however, it is acknowledged that the study populations were limited in size. The effects on neutrophil count, engraftment, and editing were consistent for patients across the range of busulfan exposures, which is supportive of the busulfan regimens administered in the study. The Casgevy Product Monograph instructs healthcare professionals to consult the Product Monograph for busulfan prior to treatment.

The clinical pharmacology data support the use of Casgevy for the recommended indication. For further details, please refer to the Casgevy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Casgevy was evaluated using data from two pivotal studies; one in patients with severe sickle cell disease (SCD), and one in patients with transfusion-dependent beta thalassemia (TDT).

Severe Sickle Cell Disease

The efficacy and safety of a single-dose of Casgevy were evaluated in the pivotal Study 121, a single-arm, open-label, multicentre study in patients with severe SCD. At the time of authorization of Casgevy, this study was ongoing.

Patients were eligible for the study if they had severe SCD, were between the ages of 12 to 35 years (inclusive), and were eligible for allogeneic stem cell transplant, but did not have an available 10/10 human leukocyte antigen (HLA)-matched hematopoietic stem cell (HSC) related donor. Severe SCD was defined by the occurrence of at least two severe vaso-occlusive crises (VOCs) per year over the two years preceding enrolment. Severe VOCs, adjudicated by an endpoint adjudication committee, were defined as any of the following: acute pain events requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] nonsteroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions; acute chest syndrome; priapism lasting at least 2 hours requiring a visit to a medical facility; or splenic sequestration defined by an enlarged spleen, left upper quadrant pain, and an acute decrease in Hb concentration (20 g/L or more).

As of the data cut-off, 63 patients met the eligibility criteria and were enrolled in the study. Patients (total number [n] = 58) received mobilization treatment with plerixafor to allow for adequate collection of CD34+ human hematopoietic stem/progenitor cells (hHSPCs) via apheresis. This treatment stimulates the migration of CD34+ hHSPCs from the bone marrow into the peripheral blood. Following apheresis, the CD34+ hHSPCs were transferred to a central manufacturing facility where they underwent CRISPR/Cas9 gene editing. Once the cells were ready for use, in preparation for treatment with Casgevy, patients were required to receive myeloablative conditioning chemotherapy (i.e., busulfan). After myeloablative conditioning, 44 patients received a single IV infusion of Casgevy with a minimum dose of 3 x 10⁶ cells/kg. These patients formed the full analysis set. Patients received RBC transfusions during the recovery and engraftment period. After this period, efficacy was evaluated. Of the 44 patients in the full analysis set, 30 were followed for a sufficient length of time (16 months after Casgevy infusion and 14 months after completion of RBC transfusions for post-transplant support or SCD management) to be included in the analyses of primary and key secondary outcomes. These 30 patients comprised the primary efficacy set (PES), of which 80.0% of patients were adults (18 to 35 years of age, inclusive) and 20.0% were adolescents (12 years to less than 18 years of age). In addition, 53.3% were male, 46.7% were female, 86.7% were Black or African American, 3.3% were White, and 10.0% were classified as other.

The primary efficacy endpoint of Study 121 was the proportion of patients in the PES who did not experience any severe VOC for a period of at least 12 consecutive months (VF12) within the first 24 months after the treatment with Casgevy. A key secondary efficacy endpoint was the proportion of patients who did not require hospitalization for severe VOCs over a period of at least 12 consecutive months (HF12) after treatment with Casgevy. The evaluations of VF12 and HF12 began 60 days after the last RBC transfusion for post-transplant support or SCD management. After Casgevy infusion, patients in the PES had a median time to last RBC transfusion of 19.0 days (range: 11 to 52 days). The study was to be considered a success if a statistically significant improvement in VF12 compared to a VF12 of 50% was demonstrated. This was acceptable given that no available pharmacotherapy is expected to provide results of this magnitude, and only HLA-matched allogenic HSCT provides a potential cure; however, allogenic HSCT is unavailable to most patients and carries with it significant risks such as graft-versus-host disease.

As of the clinical cut-off date corresponding to the interim analysis, the VF12 in the primary efficacy set was 96.7% (95% Confidence Interval [CI]: 82.8%, 99.9%), with 29 of 30 patients achieving the primary endpoint. This far exceeded the target rate of 50%. For the key secondary endpoint, all 30 patients (100%; 95% CI: 88.4%, 100%) achieved HF12.

The one patient who did not achieve VF12 experienced VOCs throughout the follow-up of the study. However, the investigator’s assessments indicated that the patient did well after treatment with Casgevy, which was corroborated by a high HbF level (49%) recorded at Month 24 in addition to a normal Hb level. Furthermore, the patient achieved HF12 despite a historical average of 28.5 days of hospitalization for severe VOC per year based on the 2 years prior to baseline. Although this patient was not a VF12 responder, they appeared to have benefited from Casgevy treatment.

Overall, the efficacy of Casgevy observed in Study 121 substantially exceeded that afforded by available treatments with the possible exception of an HLA-matched allogeneic HSCT.

Transfusion-Dependent Beta-Thalassemia

The efficacy and safety of a single-dose of Casgevy in adult and adolescent patients aged 12 to 35 years with TDT was evaluated in the pivotal Study 111, a single-arm, open-label, multicentre Phase I/II/III study. Patients were eligible for the study if they had a history of requiring at least 100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrolment and did not have a 10/10 HLA‑matched related HSC donor. Patients were excluded from the study if they had elevated iron in the heart, advanced liver disease, renal impairment, or were positive for human immunodeficiency virus 1 (HIV 1) or HIV 2, hepatitis B virus, syphilis or hepatitis C virus. A total of 54 patients were enrolled with 42 patients comprising the primary efficacy set (PES), defined as all patients who had been followed for at least 16 months after Casgevy infusion. Of the 42 patients in the PES, 69.0% were adults (18 to 35 years of age) and 31.0% were adolescents (12 years to less than 18 years of age, inclusive). In addition, 50.0% were male, 50.0% were female, 38.1% were Asian, 40.5% were White, 7.1% were multiracial, 2.4% were classified as other, and 11.9% did not have their race/ethnicity collected.

Prior to collecting CD34+ cells by apheresis, patients underwent a mobilization step of treatment with granulocyte-colony stimulating factor (G-CSF) followed by plerixafor. Subsequently, patients received full myeloablative conditioning with busulfan for 4 consecutive days followed by IV infusion of Casgevy between 48 hours and 7 days after the last dose of the myeloablative conditioning agent.

The primary efficacy endpoint was the proportion of patients achieving TI12, defined as maintaining a weighted average of 9 g/dL Hb or more without RBC transfusions for at least 12 consecutive months any time after Casgevy infusion. The evaluations of TI12 began 60 days after the last RBC transfusion for post-transplant support or TDT disease management. According to the statistical analysis plan, the study was considered a success if the TI12 was statistically significantly improved against a 50% response rate. This was considered acceptable given that a 50% TI12 would be a meaningful benefit as no current therapies offer the potential for cure outside of an allogeneic HLA-matched HSCT.

At the time of the interim analysis, 42 patients were evaluable for TI12. Of these patients, 39 out of 42 (92.9%; 95% CI: 80.5%, 98.5%) achieved TI12. The three patients who did not achieve TI12 had reductions in annualized RBC transfusion volume requirements of 83.4%, 86.9% and 98.5%, and reductions in annualized transfusion frequency of 82.4%, 73.4% and 96.0%, respectively, compared to baseline requirements. Transfusion independence corresponded to observed increases in mean total Hb and HbF by Month 3 after treatment with Casgevy where a mean greater than 100 g/L for total Hb and HbF was reported at Month 6. After Month 6, levels of total Hb and HbF were maintained thereafter, of which 88% or more of the total Hb detected was present as HbF. Outside of an HLA-matched HSCT, this level of efficacy has not been observed previously for other therapies to treat TDT. Therefore, Casgevy has the potential to be a curative treatment for most patients, acknowledging that long-term follow-up is still required to ensure that erythroid-specific downregulation of the BCL11A gene is maintained with concomitant upregulation of HbF.

Indication

The New Drug Submission for Casgevy was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Casgevy (exagamglogene autotemcel) is an autologous genome edited hematopoietic stem cell-based therapy indicated for the treatment of patients 12 years of age and older with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) or transfusion dependent beta-thalassemia (TDT).

Overall Analysis of Efficacy

Casgevy may provide life-changing therapy for many patients with severe SCD and TDT by offering a potential for long-term disease control where patients can carry out normal daily activities without pain and hospitalization due to vaso-occlusive crises or the requirement for RBC transfusions and the downstream toxicities resulting from iron overload. Patients who took part in the pivotal studies are enrolled in the long-term follow-up Study 131 in which the persistence of efficacy and long-term safety will be further evaluated.

It was reported that a small number of SCD patients intended to be treated with Casgevy were not able to mobilize sufficient numbers of CD34+ cells in clinical studies, therefore it is anticipated Casgevy will not be a viable treatment option for all SCD patients who initiate mobilization. All TDT patients had sufficient CD34+ cells following mobilization, which is likely reflective of the addition of G-CSF to the mobilization regimen for these patients. Granulocyte-colony stimulating factor is contraindicated in patients with SCD due to safety concerns.

For more information, refer to the Casgevy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Casgevy was evaluated in the two pivotal studies (Study 121 and Study 111) described above in which 98 adolescent and adult patients with severe SCD or TDT were treated with Casgevy after undergoing myeloablative conditioning with busulfan. After completion of the pivotal study, patients could enroll in the long-term follow-up Study 131.

The risks of Casgevy therapy are mainly related to the standard myeloablative regimen busulfan. Long-term follow-up will provide further data informing the possibility of rare effects of this gene therapy that could arise if editing occurs at a critical off-target site within the CD34+ cells (i.e., such as hematologic oncogenesis). At the time of authorization of Casgevy, such risks are considered theoretical.

In Study 121, the median duration of follow-up for the 44 patients with severe SCD was 19.3 months (range: 0.8 to 48.1 months) following the administration of Casgevy. Serious adverse reactions after myeloablative conditioning and Casgevy infusion were observed in 45% of these patients, with the most common (observed in two or more patients) being cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, upper abdominal pain, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis.

In Study 111, the median duration of follow-up for the 54 patients with TDT was 22.8 months (range: 2.1 to 51.1 months) following administration of Casgevy. Serious adverse reactions after myeloablative conditioning and Casgevy infusion were observed in 35% of patients with TDT, with the most (observed in two or more patients) being veno-occlusive liver disease, pneumonia, coronavirus disease 2019 (COVID-19), hypoxia, thrombocytopenia, and upper respiratory tract infection.

In both pivotal studies, the most common adverse events (due to treatment with busulfan as part of the overall therapy) were febrile neutropenia, headaches, and stomatitis. One serious adverse event (Grade 4) of hemophagocytic lymphohistiocytosis occurred in a patient with TDT. This event was considered as possibly related to Casgevy and not related to busulfan, and was likely related to a severe engraftment syndrome event. In the group of patients with SCD, one death occurred due to coronavirus disease 2019 (COVID-19) and subsequent respiratory failure. This event was not considered related to treatment with Casgevy.

The safety profile and engraftment times was generally consistent among adolescent and adult patients.

There is a greater risk of poor mobilization of HSPCs in SCD patients due to the fact that they cannot receive G-CSF as part of the mobilization treatment and must rely on single-agent plerixafor. In Study 121, 6 of 58 patients who initiated mobilization had inadequate cell collections to proceed with manufacturing. Therefore, it is anticipated that up to 10% of SCD patients may not be eligible for treatment with Casgevy.

Appropriate warnings and precautions are in place in the approved Casgevy Product Monograph to address the identified safety concerns.

For more information, refer to the Casgevy Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non-clinical studies provided in support of Casgevy (exagamglogene autotemcel) were non-traditional given the unique mechanism of action and single administration of the product.

The non-clinical programme involved guide ribonucleic acid (gRNA) screening (to identify a suitable gRNA sequence), characterization of the selected gRNA including genotype/phenotype characterization, in vitro proof-of-concept studies, in vivo toxicology studies, and in vitro off-target analyses. The selected gRNA was referred to as SPY101. Additional studies confirmed that donor CD34+ hHSPCs edited with CRISPR/Cas9 SPY101 gRNA had increased gamma-globin expression. As well, biodistribution studies evaluated HSC maintenance and function as well as the persistence of editing in Casgevy that engrafted in NOD/SCID/IL2Rγnull (NSG) immunocompromised mice. In vivo toxicology studies were limited to a single-dose study evaluating engraftment, toxicity, and tumorigenicity. Finally, extensive on and off-target analyses were conducted to qualify the specificity of the SPY101 gRNA to the target site within the BCL11A enhancer region.

Overall, the non-clinical studies are considered adequate to support the authorization of Casgevy. The studies definitively demonstrated that SPY101 gRNA directed editing of CD34+ HSPCs results in increased expression of gamma-globin and a rise in the levels of HbF. On target editing was efficient, resulting in indels that were under 30 bp in the vast majority of cases. While the initial rate of growth of edited cells was slowed compared to unedited cells, longer term growth kinetics were similar between the two. In the New Drug Submission, no off-target editing was reported in studies that investigated numerous potential alternative editing sites, which were identified using several orthogonal methods. However, as discussed above in the clinical safety section, this does not exclude the possibility that off-target editing may occur with Casgevy and this will be monitored for in long-term follow-up of patients treated with this gene-editing therapy.

Karyotyping analysis did not identify any exagamglogene autotemcel induced chromosomal aberrations. An in vivo toxicity and carcinogenicity study, conducted in NSG mice, did not identify any exagamglogene autotemcel-related toxicities or tumorigenicity. Biodistribution in the same species was limited to hematopoietic tissue except for minimal detection in highly perfused tissues (e.g., lung), which is likely due to blood within the sample. In vitro studies did not find evidence of an immune reaction after donor cells were edited with CRISPR/Cas9 using the SPY101 gRNA.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Casgevy Product Monograph. In view of the intended use of Casgevy, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Casgevy Product Monograph, approved by Health Canada and available through the Drug Product Database.

The production of Casgevy (exagamglogene autotemcel) is a continuous manufacturing process without an isolated drug substance. The drug product is the final formulated autologous cell therapy.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that exagamglogene autotemcel drug substance consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Comparability of critical quality attributes of Casgevy lots produced by different manufacturers was adequately demonstrated.

Results from process validation studies indicate that product of sufficient quality could be consistently manufactured and impurities were controlled to acceptable levels.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Autologous apheresis starting material for the initiation of Casgevy production is collected at authorized treatment centres and shipped at 2 to 8 °C to one of the two cell product manufacturing sites. Prior to apheresis collection, each patient is treated with mobilization agents to stimulate the migration of CD34-positive (CD34+) human hematopoietic stem and progenitor cells (hHSPCs) from the bone marrow into the peripheral blood. Patients may undergo subsequent, additional mobilization and apheresis cycles to obtain sufficient cells for processing to achieve a full dose.

The Casgevy manufacturing process at both manufacturing sites is continuous, with no isolated drug substance or intermediate. The manufacturing process is initiated by CD34+ enrichment using a system that employs a separation column in which magnetically labeled CD34+ cells are retained when exposed to a magnetic field. The enriched CD34+ cells are subsequently eluted, centrifuged, and cultured at a target density. Next, the cells are combined with a ribonucleoprotein (RNP) complex (at a target ratio of SPY-101 guide ribonucleic acid [gRNA] to clustered regularly interspaced short palindromic repeats [CRISPR]-associated protein 9 [Cas9] nuclease). The electroporated cells are allowed to recover prior to a second culturing step. Edited CD34+ cells are then pooled and centrifuged. The cell pellet is resuspended into cryopreservation medium at a target concentration. The resulting formulated drug product is filled in vials which are transferred and stored in a controlled liquid nitrogen vapor container.

The materials used in the manufacture of the drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the exagamglogene autotemcel drug substance with the excipients is supported by the stability data provided.

Control of the Drug Product

The drug product is tested against suitable reference standards to verify that it meets approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

Each lot of Casgevy drug product must meet pre-determined release specifications with approved acceptance limits. The drug product is tested for appearance, identity, purity, potency (three assays), quality/content (viable cell concentration and viability), and microbial contaminants (sterility, mycoplasma, and endotoxin). Established test specifications and validated analytical test methods are considered acceptable.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug product are adequately addressed (e.g., with qualified limits and a suitable control strategy).

Casgevy is a Schedule D (biologic) drug assigned to Evaluation Group 4 and is therefore not subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product was adequately supported and is considered to be satisfactory. The proposed 24-month shelf life is acceptable when Casgevy is stored in vapor phase liquid nitrogen at (less than or equal to -135 °C).

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and manufacture of the product.

The drug product is manufactured at two different manufacturing sites, one in the United Kingdom and one in the United States of America. As the New Drug Submission (NDS) for Casgevy was subject to an expedited review process under the Priority Review of Drug Submissions Policy, only one manufacturing site could be evaluated. The North American manufacturing site was selected for a Virtual Evaluation of Process and Facility (VEPF) based on review of the United States Food and Drug Administration (FDA) Pre-Approval inspection report, the increased manufacturing activity at that site, and the likelihood of that site manufacturing product for the Canadian market.

The VEPF of the United States manufacturing site was conducted remotely. The activities focused on the witnessing of manufacturing steps, quality control and testing, quality systems, the quality agreement with the sponsor, review issues, facilities, and process performance qualification and manufacturing deviations. The manufacturing facility was deemed suitable to consistently manufacture a high quality drug product. The results of the VEPF supported a positive recommendation following the review of the quality data package of the Casgevy submission.

Although an on-site evaluation or VEPF of the United Kingdom manufacturing site was not performed, the FDA Pre-Approval inspection report was reviewed and taken into consideration during assessment.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

As the drug product Casgevy is cellular in nature, it would be adversely affected by virus inactivation technologies employed for other types of gene therapy and biological products (e.g., adeno-associated virus [AAV]-based gene therapies or monoclonal antibodies). As such, the manufacturing process does not have any process steps that involve viral purification or virus inactivation.

The sponsor has implemented appropriate risk mitigation measures to prevent the introduction of viruses into the product.

The excipients used in the drug product formulation are not of animal or human origin.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens.