Summary Basis of Decision for Talvey

As outlined in the What steps led to the approval of Talvey? section, the review of the clinical component of the New Drug Submission for Talvey was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The clinical review of the New Drug Submission for Talvey was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Talquetamab (the medicinal ingredient in Talvey) is a humanized immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody. It is directed against G protein-coupled receptor class C group 5 member D (GPRC5D), which is expressed on multiple myeloma cells and the CD3 receptor expressed on T cells. Talquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing T cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent lysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with minimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple myeloma cells particularly. The GPRC5D protein is also expressed in healthy tissues such as epithelial cells in keratinized tissues of the skin and tongue.

The pharmacokinetic profile of talquetamab was characterized based on data from multiple treatment cohorts within MonumenTAL-1. This study was a Phase I/II, first-in-human, open-label, dose escalation study, which provided the data used to estimate pharmacokinetic parameters for both the non-compartmental analysis and the population pharmacokinetic model from patients with relapsed or refractory multiple myeloma.

Data from 33 treatment cohorts were submitted covering a range of doses from 0.0015 to 0.18 mg/kg once weekly and 0.0005 to 0.00338 mg/kg once every 2 weeks administered by intravenous infusion, and from 0.005 to 0.8 mg/kg once weekly, 0.8 to 1.2 mg/kg once every 2 weeks, and at 1.6 mg/kg monthly administered by subcutaneous injection. The population pharmacokinetic model analyzed the combined set of unique doses: 18 administered by subcutaneous injection (number of patients [n] = 392) and 15 administered by intravenous infusion (n = 100). In total, 5,354 measurable serum talquetamab concentration records were obtained from 492 patients.

Exploratory plots of the concentration-versus-time profiles revealed complex responses to the administered doses, more so for doses administered via subcutaneous injection than for those administered by intravenous infusion. As expected of drugs in the bispecific T-cell engagers (BiTE) class, no intuitive relationship was observed between the administered dose and the pharmacokinetic parameters of exposure (minimum concentration [C_min], maximum observed serum concentration [C_max], average concentration [C_avg], and the area under the concentration-time curve over the dosing interval [AUC_tau]).

The population pharmacokinetic analysis took the form of a three-compartment model with sequential zero-order absorption for intravenous infusion and a first-order absorption for subcutaneous administration from an injection site depot. The estimates provided by the model met the standard for acceptable accuracy (90% of predictions within ± 30% observed value). However, it only presented the drug concentration in plasma, without consideration of the formation of combinations more relevant to treatment, such as the dimers and the essential trimer between T-cell and receptor. Without a pharmacodynamic component, the model was considered of limited value.

The final dosing regimens were adjusted to place the C_min pharmacokinetic parameter several orders of magnitude above a threshold value of 353 ng/mL, the EC90 value established through ex vivo trials as the concentration associated with the 90% maximal drug effect. The model produced simulations comparing the proposed once weekly and once every two weeks dosing regimens as overlapping bands of concentration-versus-time profiles. This visual demonstration implies clinical similarity of the two proposed dosing regimens.

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

Clinical Efficacy

Data supporting the clinical efficacy of Talvey were obtained in the pivotal study, MonumenTAL-1, a Phase I/II, first-in-human, open-label dose escalation study of talquetamab. Patients enrolled in the pivotal study had relapsed or refractory multiple myeloma (RRMM). Patients in Phase I had progressed on, or could not tolerate, all previous lines of therapy. Patients in Phase II had received at least three prior lines of therapy, and must have previously received a proteasome inhibitor, an immunomodulatory imide drug, and an anti-CD38 monoclonal antibody. All patients in the pivotal cohorts were naive to T cell redirecting therapies such as chimeric antigen receptor (CAR) T cells or other bispecific antibodies.

Patients eligible for the study were 18 years of age or older, had an Eastern Cooperative Oncology Group (ECOG) score of 2 or lower (or 1 or lower in Phase I), had measurable disease, and had received at least 3 prior lines of therapy. Beginning in Phase II, patients must have previously received an immunomodulatory imide drug (IMiD), a proteasome inhibitor, and an anti-CD38 monoclonal antibody at least once in their prior treatment experience. Key exclusion criteria included prior cases of cytokine release syndrome (CRS) of Grade 3 severity or higher related to any T cell redirection or any prior therapy targeted at G protein-coupled receptor class C, group 5, member D (GPRC5D), and an inadequate washout time for prior multiple myeloma therapy.

During the study, patients in the dose expansion part of Phase I and patients in Phase II (Part 3) began treatment with step-up regimens before receiving their treatment dose on a weekly or biweekly schedule. Patients were not randomized between the two regimens, as they were initiated at different times as the study progressed. Several regimens were employed in both Phase I and Phase II:

• Phase I, Part 2 (Dose Expansion)

  • Subcutaneous administration of Talvey 0.405 mg/kg weekly, on Days 1, 8, and 15 of a 21-day cycle (preceded by step-up doses of 0.01 and 0.06 mg/kg) (n = 21); or

  • Subcutaneous administration of Talvey 0.8 mg/kg once every 2 weeks, on Days 1 and 15 of a 28-day cycle (preceded by step-up doses of 0.01, 0.06, and 0.3 mg/kg) (n = 36)

• Phase II, Part 3

  • Subcutaneous administration of Talvey 0.4 mg/kg weekly, on Days 1, 8, and 15, and 22 of a 28-day cycle (preceded by step-up doses of 0.01 and 0.06 mg/kg) (n = 122); or

  • Subcutaneous administration of Talvey 0.8 mg/kg once every 2 weeks, on Days 1 and 15 of a 28-day cycle (preceded by step-up doses of 0.01, 0.06, and 0.3 mg/kg) (n = 109).

For the purposes of the efficacy evaluation, patients enrolled in Phases I and II were combined if they were treated according to the same or very similar regimens. The total evaluable populations for efficacy for each dosing regimen were 143 patients receiving Talvey 0.4 mg/kg weekly and 145 patients receiving Talvey 0.8 mg/kg once every 2 weeks.

The primary efficacy endpoint was the objective response rate (ORR), defined as the proportion of patients who achieved a partial response or better according to internationally recognized Myeloma Working Group 2016 response criteria. Response was assessed by an independent review committee.

A high rate of response was observed for both treatment regimens. The estimated ORR for the 143 patients who received 0.4 mg/kg weekly was 74.1% (95% confidence interval [CI]: 66.1%, 81.1%). The proportion of patients with a stringent complete response (sCR) was 23.8%, while 9.8% had a complete response (CR), and 25.9% had a very good partial response (VGPR). The ORR among the 145 patients who received 0.8 mg/kg once every 2 weeks was comparable to the weekly regimen, at 71.7% (95% CI: 63.7%, 78.9%). The proportion of patients with a sCR was 29.7%, while 9.0% had a CR and 22.1% had a VGPR.

With a median follow-up time of 18.9 months, the median duration of response among responders who received the weekly dosing regimen was estimated to be 9.5 months (95% CI: 6.7, 13.3). The median duration of response for responders who received talquetamab once every 2 weeks (0.8 mg/kg) was not estimable (NE; 95%CI: 13.0, NE), with a median follow-up time of 12.7 months.

Participants treated weekly had a median time to response of 1.2 months (range: 0.2 to 10.9 months) and a median time to best response of 2.2 months (range: 0.8 to 12.7 months). In the group of participants treated once every two weeks, the time to response was 1.3 months (range: 0.2 to 9.2 months) for first response and 3.0 months (range: 0.3 to 12.9 months) for best response. The results are indicative of rapid responses that tend to deepen with longer follow-up.

Overall, the efficacy results are promising given the high overall rates of response, observed with two regimens, in combination with reasonable durability.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Talvey (talquetamab injection) 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 monoclonal antibody.	Talvey (talquetamab injection) 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 monoclonal antibody, and have demonstrated disease progression on or after the last therapy.

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

Clinical Safety

Evaluation of the clinical safety of Talvey was primarily based on data from the two treatment regimens from the pivotal study MonumenTAL-1 (0.4 mg/kg weekly and 0.8 mg/kg once every 2 weeks) and included a cohort of patients who had previously received T-cell redirecting therapy such as CAR T cells or anti-B cell maturation antigen (BCMA)/anti-CD3 bispecific antibodies.

Due to similar rates of adverse events between regimens, the review focused mainly on the combined results rather than on safety findings by regimen. The safety population was comprised of 339 patients. All patients experienced adverse events, with Grade 3-4 adverse events reported for 79.6% of patients. Serious adverse events occurred in 51.6% of patients. The Talvey safety profile is characterized by several adverse events that are common with bispecific T-cell-engaging antibodies, including cytokine release syndrome (CRS) and neurological toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS). Both CRS and ICANS are highlighted in a Serious Warnings and Precautions box in the Talvey Product Monograph.

Cytokine release syndrome was reported in 76.7% of patients, and was of low grade (Grade 1-2 in severity) in the vast majority of affected patients. The rate of Grade 3 CRS was 1.5%. No patients were reported to have Grade 4 or 5 CRS. Tocilizumab was used to treat CRS in 38.6% of cases, while corticosteroids were employed in 5.3% of cases. Forty-five cases of CRS (13.3%) were considered serious.

The patient population in which ICANS was assessed was limited to the patients enrolled in Phase II (n = 265), as ICANS grading was not performed for patients in Phase I. Of the patients included in the assessment, ICANS of any grade was reported in 9.8% of patients, Grade 3 ICANS was reported in 1.9% of patients, and Grade 4 ICANS was reported in 0.4% of patients. No patients were reported to have Grade 5 ICANS. Ten cases of ICANS (3.8%) were considered serious adverse events. Notably, neurotoxicities that were not considered to be ICANS were also frequently reported, and are addressed in the Talvey Product Monograph.

Although no cases of Grade 5 ICANS were reported, a review of narratives identified 2 patients who died while experiencing ICANS. Both deaths were attributed to disease progression; however, a potential contribution of ICANS in these deaths cannot be ruled out. The Talvey Product Monograph appropriately reflects that ICANS occurs commonly and can be life-threatening and/or fatal.

Talquetamab, the medicinal ingredient in Talvey, is associated with oral, skin, and nail toxicity that is not common with bispecific antibodies targeting BCMA and CD3. These toxicities are likely related to the expression pattern of the target, GPRC5D.

Oral toxicities were reported in 80% of patients included in the safety analysis, including the preferred terms stomatitis, dysgeusia, dry mouth, dysphagia, and oral pain. Oral toxicities can lead to other complications such as loss of appetite and weight loss, which can be significant. Weight loss was frequently observed, with 62% of patients losing 5% or more of their body weight and 29% of patients losing 10% or more of their body weight. Management options for the observed oral toxicity include the reduction of dosing frequency and the use of saliva stimulating agents, steroid mouth washes, and consultation with a nutritionist. Healthcare professionals are advised to counsel patients regarding this risk and to monitor patients during treatment.

Skin and nail toxicities were very common, and were represented by a wide variety of preferred terms. Skin and nail toxicities which were observed in at least 20% of patients include nail disorder (56%), skin disorder (43%), rash (39%), xerosis (32%), and pruritus (23%).

Although the risks of cytopenias and serious infections are inherent with RRMM, they are also commonly associated with products that target plasma cells, such as talquetamab. Cytopenias reported in more than 20% of patients included anemia (47%), neutropenia (35%), thrombocytopenia (30%), and lymphopenia (27%). Grade 3 or 4 infections were reported in 19% of patients. These risks are described in the Talvey Product Monograph, along with recommendations for mitigation and management, including screening for infections, withholding treatment until infections resolve, and the use of prophylactic antimicrobials.

This submission was issued a Notice of Compliance under the Guidance Document: Notice of Compliance with Conditions (NOC/c) on the basis of the promising nature of the clinical evidence. As such, additional studies will be required to verify the clinical benefit of Talvey.

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

As outlined in the What steps led to the approval of Talvey? section, the review of the non-clinical component of the New Drug Submission for Talvey was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the non-clinical component of the New Drug Submission for Talvey was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The in vitro and in vivo data from the pharmacology studies adequately supports talquetamab as a bispecific antibody that selectively promotes the T cell-mediated elimination of GPRC5D-positive cells, including efficacy in vivo in humanized murine multiple myeloma tumour models. The IgG4 bispecific antibody was designed with a PAA mutation (Ser228Pro/Phe234Ala/Leu235Ala) to abrogate binding to some FC-gamma receptors (alanine mutations) and stabilize the hinge domain (proline) of the bispecific antibody.

Toxicology assessments of talquetamab were challenging due to the inability of this bispecific antibody to bind to GPRC5D in species other than humans. To attempt to overcome these challenges, a tool molecule was created that interacted with GPRC5D in cynomolgus monkeys together with binding to CD3 on monkey T cells. However, due to anti-drug antibody (ADA) responses against the tool molecule in the monkeys, only acute toxicological assessments were possible and with little correlation of findings to the clinical safety concerns of this antibody.

Normal (non-diseased) human tissue expression studies were conducted to detect GPRC5D messenger ribonucleic acid (mRNA) by in situ hybridization and GPRC5D protein by immunohistochemistry. In human skin, GPRC5D protein is expressed in epithelial cells of hair follicles and eccrine sweat glands. This pattern of expression is consistent with adverse events observed in the clinical setting following the administration of Talvey, including skin exfoliation, dry skin, and nail disorder. The GPRC5D protein was also detected in filiform papillae of the tongue and plasma cells of the oral cavity. On-target off-tumour binding of GPRC5D by talquetamab at these sites is consistent with the oral toxicities associated with this bispecific antibody.

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

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

As outlined in the What steps led to the approval of Talvey? section, the review of the quality component of the New Drug Submission for Talvey was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the quality component of the New Drug Submission for Talvey was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Talquetamab is a novel, humanized, bispecific antibody based on a human immunoglobulin G4 (IgG4) framework. It is directed against the G protein-coupled receptor, class C, group 5, member D (GPRC5D) protein which is expressed on multiple myeloma cells, and against the CD3ε chain of the T cell receptor complex on T cells. Reduction-oxidation of two independent parental monoclonal antibodies under controlled reaction conditions results in the formation of talquetamab bispecific antibody.

The proposed mechanism of action involves simultaneous binding of talquetamab to GPRC5D on target myeloma cells, and to CD3 on the surface of cytotoxic T cells. Bispecific binding induces T cell activation, resulting in killing of the malignant cells. Functions mediated by the fragment crystallizable (Fc) region (i.e., antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) do not contribute to the mechanism of action of talquetamab. Accordingly, the Fc region of the molecule contains specific design modifications which impair its binding to Fc gamma receptors (FcγRs I, II, and III), complement (C1q) and minimize effector functions.

Talvey 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 monoclonal antibody (mAb), and have demonstrated disease progression on or after the last therapy. Talvey is administered by a healthcare professional via subcutaneous injection.

The primary structure, post translational modifications, disulfide bonding, charge and size heterogeneity, higher order structure, and biological activity of talquetamab were evaluated by a panel of analytical methods. The characterization results demonstrated that talquetamab has the expected structure and functional properties.

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

Talquetamab, the drug substance, is a bispecific antibody. The two parental antibodies (anti-GPRC5D and anti-CD3 monoclonal antibodies) are manufactured in the initial stages, using separate but parallel processes. The two parental antibodies (drug substance intermediates) are then joined to create the bispecific antibody.

Each of the parental antibodies is produced from a separate recombinant Chinese hamster ovary cell line. One cell line is engineered to express the anti-GPRC5D monoclonal antibody, and the other is engineered to express the anti-CD3 monoclonal antibody. Each parental monoclonal antibody batch is produced from a single vial thawed from the corresponding working cell bank, and cells are cultured in a chemically defined medium. The cell cultures are transferred through a series of successively larger vessels as they grow, and the unprocessed preharvest cell culture fluid is tested to ensure viral and microbial safety. When the cell cultures reach the targeted volume and density, they are harvested and clarified through centrifugation and filtration. Each parental monoclonal antibody is purified through chromatography, filtered into polycarbonate containers, and stored frozen at -70 °C (±10 °C) to -40 °C (±10 °C) until further processing.

The anti-GPRC5D and anti-CD3 monoclonal antibody intermediates are thawed, filtered, pooled separately, and then combined. The mixture is adjusted for pH, diluted to a target protein concentration and the inter-disulfide bonds are reduced. Subsequently, the thiol groups are oxidized and the disulfide bonds reform preferentially between one half of an anti-GPRC5D monoclonal antibody and one half of an anti-CD3 monoclonal antibody, which produces the talquetamab bispecific antibody. The preferential heterodimerization between the two different heavy chains is facilitated by the design mutations engineered into the monoclonal antibodies and the reduction-oxidation conditions of the reaction.

The reaction mixture is then concentrated, filtered, and treated to inactivate viruses. The solution is further purified through multiple chromatography steps, and then undergoes viral filtration, concentration, buffer exchange, and formulation. The formulated bulk drug substance is filtered to reduce bioburden and then filtered into polycarbonate containers for storage at -70 °C (±10 °C) to -40 °C (±10 °C).

The drug product manufacturing process begins with thawing of the drug substance and dilution with formulation buffer to achieve the target protein concentration (2 mg/mL or 40 mg/mL). Multiple drug substance batches could be combined into one drug product batch. After mixing, the bulk drug product is filtered to reduce bioburden, then sterile filtered and aseptically filled into glass vials. The filled vials are capped, crimped, and the sealed vials are visually inspected. The drug product is stored at 5 ± 3 °C.

The drug substance manufacturing process was validated through the manufacture of multiple consecutive batches at commercial scale. Multiple independent batches of the monoclonal antibody intermediates were used to manufacture the drug substance batches used for process validation. The process parameters were maintained within established limits for all monoclonal antibody intermediate and drug substance batches. All in-process controls met the predefined acceptance criteria for product quality, with the exception of minor deviations that were investigated and deemed not to impact product quality. All drug substance batches met the release and stability specifications. The validation studies demonstrated that the manufacturing process is capable of consistently manufacturing talquetamab drug substance of acceptable quality.

Both drug product vial presentations are manufactured using the same equipment, process steps and in-process controls with the main differences being the protein concentration, fill volume, and vial size. In-process fill weight checks are conducted at regular intervals to control filling within the defined limits. Based on the fill weight data for the process validation batches and the results of the extractable volume studies performed, the target fill volumes are acceptable and will assure that the labelled nominal volumes (1.5 mL or 1 mL) can be withdrawn from the vials.

Process validation studies for the drug product involved the manufacturing of multiple consecutive drug product batches of each strength. All predefined limits and acceptance criteria for process parameters and controls were met with no deviations. All results for release and stability testing were within specifications and demonstrated that the process is able to consistently manufacture drug product that meets all quality attributes.

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 talquetamab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The established control strategy includes in-process controls and process parameters, control of raw materials, adventitious agents and microbial contamination control, and specifications, to assure the consistent production of high quality drug substance and drug product.

Materials used in the manufacturing process are purchased from qualified suppliers and compendial grade material is used whenever possible. The raw materials are routinely tested according to internal procedures and materials must meet compendial requirements (United States or European Pharmacopoeia) and/or in-house specifications.

Release and stability specifications were appropriately defined for the drug substance and drug product and ensure that Talvey meets all critical quality attributes, including criteria for identity, purity, potency, and product safety. The corresponding analytical methods were adequately validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and compendial methods were qualified for use.

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 substance and/or drug product are considered low, and confirmatory testing was not required.

Talvey 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 the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory.

For the talquetamab drug substance, the stability data support the proposed shelf life of 24 months when stored in polycarbonate containers at -70 °C (±10 °C) to -40 °C (±10 °C).

The stability data support the proposed shelf life of 24 months for both Talvey drug product presentations (3 mg/1.5 mL and 40 mg/mL vials) when stored at 5 °C ± 3 °C and protected from light.

Additional storage and special handling instructions are included in the Talvey Product Monograph and are supported by in-use stability and compatibility studies.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations were not deemed necessary for any of the manufacturing sites.

Adventitious Agents Safety Evaluation

No animal-derived raw materials or excipients were used in the manufacturing of talquetamab. The master and working cell banks were established in accordance with ICH guidelines. Qualification studies confirmed that the starting materials were free from microbial and viral adventitious agents, and met all acceptance criteria for identity, culture purity, and genetic stability. The cell banks are suitable for use in the production of the drug substance.

Viral clearance steps using orthogonal mechanisms are incorporated into the manufacturing process. Viral clearance was validated using scaled-down studies, four model viruses, representative commercial material derived from manufacturing scale batches, and tested under worst-case process conditions. Based on the small-scale viral clearance studies, the estimated retrovirus-like particles (RVLP) load is below the acceptable threshold.