Summary Basis of Decision for Carvykti

Clinical Pharmacology

Carvykti (ciltacabtagene autoleucel) consists of autologous T cells genetically modified using a lentiviral vector to express a unique chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is primarily expressed on the surface of late-stage B cells, plasma cells, and malignant B-lineage cells.

The pharmacokinetics of ciltacabtagene autoleucel was evaluated in 97 patients with multiple myeloma who received ciltacabtagene autoleucel in Study MMY2001 (described in the Clinical Efficacy section). Following a single infusion at the median dose of 0.71 x 10⁶ CAR-positive viable T cells/kg (range: 0.51 x 10⁶ to 0.95 x 10⁶ CAR-positive viable T cells/kg), ciltacabtagene autoleucel exhibited an initial expansion phase followed by a rapid decline and then a slower decline. The data showed high interindividual variability. After the cell expansion, the persistence phase of the ciltacabtagene autoleucel levels was observed for all patients. Among 65 patients, the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range: 28 to 365 days) after the infusion.

Age, sex, body mass index, and ethnicity did not have a significant impact on the pharmacokinetics of ciltacabtagene autoleucel. Dedicated hepatic impairment and renal impairment studies of ciltacabtagene autoleucel were not conducted.

The infusion of ciltacabtagene autoleucel led to elevated serum levels of interleukin 6 (IL-6), IL-10, interferon gamma, and IL-2 receptor alpha that peaked at 7 to 14 days post infusion and returned to baseline 2 to 3 months post infusion.

As any biologic product, ciltacabtagene autoleucel has the potential to induce anti-drug antibodies. In Study MMY2001, 19 of the 97 patients (19.6%) developed treatment-emergent anti-CAR antibodies. There was no clear evidence to suggest that the observed anti-CAR antibodies impact the exposure, efficacy, or safety of Carvykti.

For further details, please refer to the Carvykti Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Carvykti in adult patients with relapsed or refractory multiple myeloma who have received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody was supported by data derived from an open-label, single-arm, Phase Ib/II study, MMY2001 (CARTITUDE-1). Ninety-nine percent (99%) of the patients had multiple myeloma refractory to the last line of therapy prior to study entry, 88% had triple-refractory multiple myeloma (i.e., refractory to an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug), and 42% had a penta-refractory multiple myeloma (refractory to an anti-CD38 monoclonal antibody, at least two proteasome inhibitors, and at least two immunomodulatory drugs). There were 113 patients who underwent apheresis and were enrolled in the study. Of these, 101 patients received a conditioning regimen (a lymphodepleting chemotherapy with cyclophosphamide and fludarabine) and 97 patients received Carvykti infusion at a median dose of 0.71 x 10⁶ CAR-positive viable T cells/kg (range: 0.51 x 10⁶ to 0.95 x 10⁶ CAR-positive viable T cells/kg). Sixteen patients were not treated with Carvykti due to withdrawal by the patient (five patients), progressive disease (two patients), or death (nine patients). Following apheresis and prior to administration of Carvykti, 73 of the 97 patients (75%) received bridging therapy. The most commonly used agents as bridging therapies included dexamethasone, bortezomib, cyclophosphamide, and pomalidomide. No patients had a complete response following bridging therapy, prior to receiving Carvykti.

The primary endpoint of overall response rate, defined as the proportion of patients who achieved a partial response or better, assessed by an independent review committee according to the International Myeloma Working Group (IMWG) response criteria, was considered appropriate for a single-arm oncology trial, when seeking conditional authorization of a drug product in relapsed or refractory disease settings with limited effective treatment options. Based on the available data up to the cut-off date of February 11, 2021, with a median follow-up of 18 months, the treatment with Carvykti resulted in an overall response rate of 97.9%, i.e., 95 of the 97 treated patients in the All-Treated group achieved a partial response or better. The overall response rate for the 113 patients in the All-Enrolled group, including 16 patients who did not receive a Carvykti infusion, was 84.1%.

Key secondary endpoints considered evaluable in this submission were very good partial response or better rate, stringent complete response rate, duration of response, and time to response. The very good partial response or better rate, defined as the proportion of patients who achieved a stringent complete response, a complete response, or a very good partial response (according to the IMWG response criteria), was 94.8% in the All-Treated population. The median duration of response was 21.8 months (95% confidence interval [CI]: 21.8 months, non-estimable). The median time to first response was 0.95 months, the median time to best response was 2.6 months, and the median time to stringent complete response was 2.63 months (all complete responses were stringent complete responses).

Overall, the submitted efficacy results of Study MMY2001 are considered promising for the target patient population. In order to confirm the clinical benefit of Carvykti, the sponsor will provide the final study results from Study MMY2001 (with a longer follow-up period) and from the Phase III randomized study MMY3002 (CARTITUDE-4) comparing Carvykti versus the combination regimen of pomalidomide, bortezomib, and dexamethasone or the combination regimen of daratumumab, pomalidomide, and dexamethasone in patients with relapsed and lenalidomide-refractory multiple myeloma.

Indication

The New Drug Submission (NDS) for Carvykti was filed by the sponsor with the following indication:

Carvykti is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

After a thorough review of the NDS, Health Canada approved the following indication:

Carvykti is indicated for the treatment of adult patients with multiple myeloma, who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, and who are refractory to their last treatment.

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

Clinical Safety

The assessment of the safety profile of Carvykti was based on the data from 97 patients with relapsed or refractory multiple myeloma who received Carvykti in the open-label, single-arm, Phase Ib/II study, MMY2001 (CARTITUDE-1) (described in the Clinical Efficacy section). All patients received Carvykti infusion at a median dose of 0.71 x 10⁶ CAR-positive viable T cells/kg (range: 0.51 x 10⁶ to 0.95 x 10⁶ CAR-positive viable T cells/kg). Safety data were available as of the cut-off date of February 11, 2021, with a median follow-up of 18 months.

The most commonly reported non-laboratory adverse reactions in patients treated with Carvykti (with an incidence of at least 20%) were pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections with an unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infections, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most commonly reported Grade 3 or higher non-laboratory adverse reactions (with an incidence of at least 10%) were infections with an unspecified pathogen (18%), pneumonia (12%) and hypotension (10%).

Serious adverse reactions occurred in 54% of the patients. The most commonly reported serious adverse reactions (with an incidence of at least 5%) were cytokine release syndrome (21%), infections with an unspecified pathogen (15%), encephalopathy (10%), pneumonia (7%), sepsis (7%), and viral infections (6%).

Cytokine release syndrome occurred in 94.8% of patients (number of patients [n] = 92). Ninety percent of these events (n = 87) were Grade 1 or 2 in severity and 4% (n = 4) were Grade 3 or 4 in severity. There was one Grade 5 (i.e., fatal) event (1%) due to cytokine release syndrome.

Neurologic toxicities, which included immune effector cell-associated neurotoxicity syndrome, movement and neurocognitive toxicity with signs and symptoms of parkinsonism, Guillain-Barré syndrome, peripheral neuropathies, and cranial nerve palsies, were reported in 20.6% of patients (n = 20). Two fatal events (2%) occurred: one due to immune effector cell-associated neurotoxicity syndrome and one due to movement and neurocognitive toxicity with signs and symptoms of parkinsonism. In addition, three patients had fatal outcomes with ongoing neurologic toxicity at the time of death. Two of these deaths were due to infection in patients with ongoing signs and symptoms of parkinsonism, and one death was due to respiratory failure.

Cytopenias, which are common following lymphodepletion and CAR T-cell therapy, were reported for all patients. Prolonged and recurrent cytopenias were observed. Prolonged Grade 3 or 4 cytopenias that had not resolved by Day 30 following Carvykti infusion included thrombocytopenia (41%), neutropenia (30%), and lymphopenia (12%). Furthermore, after Day 60 following administration of Carvykti, 31%, 12%, and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia.

Other important safety concerns associated with the use of Carvykti include hypogammaglobulinemia, infections (including life-threatening or fatal infections), viral reactivation, and hypersensitivity.

Overall, data available from the single-arm Study MMY2001, with a median follow-up of 18 months, indicate that the safety profile of Carvykti is generally consistent with that of other authorized CAR T-cell therapies. Further evaluation of Carvykti will take place upon the submission of the final study results of Study MMY2001 and the Phase III randomized study MMY3002 (CARTITUDE-4) comparing Carvykti versus the combination regimen of pomalidomide, bortezomib, and dexamethasone or the combination regimen of daratumumab, pomalidomide, and dexamethasone in patients with relapsed and lenalidomide-refractory multiple myeloma.

Appropriate warnings and precautions are in place in the approved Carvykti Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights the risks of cytokine release syndrome, neurologic toxicities (immune effector cell-associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, and other neurologic toxicities), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome, all of which could be fatal or life-threatening. It is also stated that Carvykti should be administered by experienced health professionals at qualified treatment centres.

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

The medicinal ingredient in Carvykti, ciltacabtagene autoleucel, consists of autologous human T cells genetically modified ex vivo with a lentiviral vector to express a chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is primarily expressed on the surface of multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. Antigen-specific activation of ciltacabtagene autoleucel results in CAR-positive T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In vitro assays evaluating cytotoxicity and cytokine release have demonstrated on-target functional activity of ciltacabtagene autoleucel towards BCMA-expressing human multiple myeloma cell lines. There were no off-target effects towards BCMA-negative human cell lines. A potential off-target binding interaction observed between ciltacabtagene autoleucel and claudin-9 (CLDN9) that was expressed by engineered cells in an in vitro plasma membrane protein array screen was not confirmed with donor-derived primary cells that endogenously express CLDN9. In addition, no binding to CLDN proteins closely related to CLDN9 was observed. These data suggest a low risk of off-target functional consequences of ciltacabtagene autoleucel in treated patients.

Results from in vivo efficacy studies using immunodeficient mice with human multiple myeloma xenografts demonstrated a statistically significant tumour inhibition and a significant survival benefit. Rechallenge with tumour cells did not induce a tumour regrowth. Increases in the CAR gene copy number in whole blood from these mice indicated expansion and persistence of ciltacabtagene autoleucel in this animal model. Allometric scaling methods or predictive pharmacokinetic and pharmacodynamic models are not currently available to allow translations of effective doses demonstrated in this animal model to predict therapeutically active clinical doses of ciltacabtagene autoleucel. Furthermore, due to the restricted expression of the BCMA target, which is primarily abundant in blood and bone marrow, the biodistribution of ciltacabtagene autoleucel was not evaluated and is expected to be similar to distributional patterns previously reported for other CAR T-cell products.

Traditional genotoxicity and carcinogenicity assessments of ciltacabtagene autoleucel were not conducted. There is a risk of insertional mutagenesis due to the transduction of autologous human T cells with lentiviral vector during the manufacture of ciltacabtagene autoleucel. This risk was assessed by evaluating the integration pattern of the vector in pre-infusion ciltacabtagene autoleucel. The genomic insertional site analysis was performed on ciltacabtagene autoleucel products from 7 patients and 3 healthy volunteers. There was no evidence for preferential integration of the lentiviral vector near genes of concern. Additionally, the potential for enhanced proliferation of Carvykti was assessed in an in vitro cytokine-independent growth assay. The integration of lentiviral vector into the primary T-cell genome during transduction did not lead to cytokine-independent uncontrolled growth in the absence of interleukin 2 (the cytokine that regulates T-cell growth and promotes T-cell survival). The data indicate a low risk of development of second primary malignancies resulting from insertional mutagenesis in patients infused with ciltacabtagene autoleucel.

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

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

Characterization of Carvykti

Carvykti (ciltacabtagene autoleucel) consists of autologous human T cells genetically modified ex vivo with a lentiviral vector encoding a chimeric antigen receptor (CAR) for B-cell maturation antigen (BCMA). The CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain, and a CD3-zeta (CD3ζ) signalling cytoplasmic domain.

Flow cytometry data show that Carvykti is a highly pure T-cell product, mostly with low or no detectable levels of B cells or natural killer (NK) cells. The transduced T cells consist of CD4⁺ helper and CD8⁺ cytotoxic T cells, and mostly less mature T cells (naïve and central-memory T cells). There is no clear correlation between these T-cell subpopulations and the available clinical efficacy and safety data. In vitro assays indicate that ciltacabtagene autoleucel is capable of binding to the BCMA-expressing tumour cells, resulting in the proliferation of the CAR-positive T cells, the secretion of inflammatory cytokines (i.e., interferon gamma and tumour necrosis alpha) and survival cytokines (i.e., interleukin 2 [IL-2]), and the triggering of a cytotoxic response to eliminate BCMA-expressing multiple myeloma tumour cells.

Carvykti contains low levels of product- and process-related impurities. Product-related impurities may include non-viable cells and other cell types, while process-related impurities may include residual reagents, residual IL-2, and particulates.

Manufacturing Process of Carvykti and Process Controls

The manufacturing of Carvykti is a continuous process, without a clear delineation between the drug substance and drug product.

Apheresis material (i.e., peripheral blood mononuclear cells collected from a patient) and a replication-incompetent lentiviral vector encoding a CAR for BCMA are starting materials for the manufacture of Carvykti.

The apheresis material is collected from each patient at qualified collection sites according to site-specific procedures. It is formulated and cryopreserved at a cryopreservation center, and subsequently shipped to the drug product manufacturing site. The manufacturing of Carvykti is initiated by thawing the cryopreserved apheresis material, followed by T-cell enrichment and activation. This is followed by transduction of the activated T cells with lentiviral vector carrying the ciltacabtagene autoleucel CAR gene and by expansion of the transduced T cells. The cells are then harvested, washed, formulated with dimethyl sulfoxide-containing cryomedia, filled into bags, cryopreserved under controlled conditions, and stored in the vapour phase of liquid nitrogen at or below -120 °C.

Operating process parameters (process inputs) were described for each unit operation, including a set point and/or proven acceptable range. The robustness of the manufacturing process was assessed in process characterization studies, whereby the impact of varying critical operating process parameters on critical product quality attributes was systematically evaluated and used to support the proven acceptable range. The consistency of the manufacturing process was demonstrated by executing eight process performance qualification runs, five of which were successful and consecutive. In the successful process performance qualification runs, all critical process parameters were maintained within the proven acceptable range or predefined operating ranges, all in-process controls met acceptance criteria, and the resulting drug product batches met the release specification. A continued process verification program is in place to provide ongoing assurance that the manufacturing process remains in a state of control during commercial production.

Manufacturing Process of the Lentiviral Vector and Process Controls

The lentiviral vector is encoded by one transfer plasmid (encoding the CAR transgene) and three helper plasmids (required for the lentiviral vector assembly). It is designed based on the human immunodeficiency virus (HIV-1), using the third generation of lentiviral vector production systems. The manufacturing process of the lentiviral vector includes the initiation of preculture of mammalian cells expanded from a thawed working cell bank and subsequent expansion and inoculation of production bioreactors. The bioreactor cell cultures are transiently transfected with the four plasmids. This is followed by harvest clarification, a series of purification steps, concentration and diafiltration, and fill and storage steps.

Data from three consecutive, commercial-scale process validation batches demonstrated that the lentiviral vector manufacturing process consistently maintained critical process parameters within ranges defined in process validation protocols, met acceptance criteria for all in-process controls and for all routine release tests, and maintained process parameters within the proven acceptable range and/or acceptance criteria. A continued process verification is in place to provide ongoing assurance that the process remains in a state of control during the commercial manufacture.

Control of Carvykti

The release specification for Carvykti is consistent with relevant guidelines and includes tests for appearance, purity, identity, quantity, and potency. Analytical methods used to evaluate the drug product characteristics were selected based on their performance capability and suitability for routine and reliable use; these methods were appropriately validated. The acceptance criteria were appropriately justified.

Carvykti is a Schedule D (biologic) drug and is, therefore, 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 Carvykti

Based on the stability data submitted, the proposed shelf life of 9 months at or below -120 °C for Carvykti is considered acceptable. Once thawed, Carvykti must be administered immediately, and the infusion must be completed within 2.5 hours. The thawed product must not be shaken, refrozen or refrigerated.

The compatibility of the drug product with the container closure system was demonstrated through long-term and in-use stability studies. The container closure system met all validation test acceptance criteria.

Facilities and Equipment

Due to travel limitations, Health Canada conducted a virtual evaluation of the Carvykti manufacturing facility. An on-site evaluation of the viral vector manufacturing facility was not recommended as per a risk-based determination.

The design, operations, and controls of the facilities and equipment involved in the production of Carvykti are considered suitable for the activities and products manufactured. The manufacturing sites for the viral vector and Carvykti are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of Carvykti involves materials that are of human origin, that contain components of animal or human origin, or that contacted components of animal or human origin. The potential risks of introducing viral and non-viral adventitious agents in the manufacturing process are managed by the following strategies: control of the animal- and human-derived raw materials (as evidenced by relevant certificates of their origin and suitability), use of a qualified working cell bank that is not known to express endogenous viruses, use of closed systems or performing open manipulations under controlled environmental conditions, use of single-use materials, validated aseptic processes, routine in-process testing, and routine release testing.

No excipients of human origin are used in the manufacture of the cryopreserved drug product. Lactobionic acid, present in the cryopreservation medium Cryostor CS5, is the only component of animal origin in the formulation. Lactobionic acid is manufactured from lactose derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this component does not pose a risk of contamination with transmissible spongiform encephalopathy agents.