Summary Basis of Decision for Elrexfio

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 Foreign review Method 3 was used in the assessment of this submission, as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Elranatamab (the medicinal ingredient in Elrexfio) is a bispecific B-cell maturation antigen (BCMA)-directed T-cell engaging antibody that binds BCMA on plasma cells, plasmablasts, and multiple myeloma cells and CD3-epsilon on T cells leading to selective cytolysis of the BCMA-expressing cells. The anticancer activity of elranatamab involves selective therapeutic targeting and activation of T cells re-directed against BCMA‑expressing malignant plasma cells. Elranatamab activates T-cells, causes proinflammatory cytokine release, and results in multiple myeloma cell lysis.

The pharmacokinetic dataset included data from the dose escalation study (C1071001), dose finding studies (C1071002 and C1071009), and the pivotal study (C1071003). Sparse sampling protocols were employed in studies, which effectively permitted only a partial non-compartmental analysis (NCA). On average, total elranatamab exhibited approximately dose-proportional pharmacokinetics (exposure as measured by the area under the concentration-time curve [AUC], and the peak plasma concentration [C_max]) when administered intravenously (over the dose range of 0.1 to 50 mcg/kg) and subcutaneously (over the dose range of 80 to 1,000 mcg/kg). Additionally, a marked accumulation was observed from the almost linear increase in the minimum plasma concentration (C_min) with each dosing interval.

A population pharmacokinetic model, consisting of a simple two-compartment model, was used to describe the disposition of the free and total moieties of elranatamab and soluble BCMA (sBCMA). The dataset for clinical pharmacokinetics included 321 participants with relapsed/refractory multiple myeloma enrolled in four clinical studies, with 13,232 observations in total. Based on the population pharmacokinetic model at the 24-week dose, the model predicted a half-life of 22 days as a geometric mean, with the 20^th and 80^th percentiles as 12 and 36 days, respectively. None of the potential covariates were found to be clinically significant predictors of elranatamab exposure (i.e., formulation strength, immunogenicity, estimated glomerular filtration rate [eGFR], albumin, sBCMA, age, sex, and body weight).

A quantitative systems pharmacology (QSP) model estimated the concentrations of trimers between the drug, T cells, and tumour cells in the plasma and bone compartments. This mechanistic model linked the trimer concentration to expected tumor cell death. The model supported the clinical decision to change the dosing regimen after 24 weeks from 76 mg once weekly to 76 mg once every 2 weeks.

No formal studies of Elrexfio have been conducted in patients with hepatic impairment. Based on population pharmacokinetic covariate analysis, free elranatamab exposure in the model was not affected by mild hepatic impairment. No data are available in patients with moderate or severe hepatic impairment.

No formal studies of Elrexfio have been conducted in patients with renal impairment. Based on population pharmacokinetic covariate analysis, free elranatamab exposure in the model was not affected by mild or moderate renal impairment. Limited data are available in patients with severe renal impairment.

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

Clinical Efficacy

The clinical efficacy of Elrexfio was established primarily based on data from MagnetisMM-3, a Phase II study conducted in patients with relapsed or refractory multiple myeloma who had previously received an immunomodulatory imide drug (IMiD), a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

The primary efficacy endpoint was the objective response rate (ORR), as assessed by a blinded independent central review (BICR) according to International Myeloma Working Group (IMWG) guidelines. The primary cohort (cohort A; pivotal) enrolled patients who were naïve to B-cell maturation antigen (BCMA)-directed therapy. A secondary cohort (cohort B; supportive) enrolled patients who had previous experience with BCMA-directed treatments including belantamab mafodotin and/or chimeric antigen receptor (CAR) T-cell therapy. Other key inclusions were the presence of measurable disease at baseline, relapse or a refractory outcome to the last treatment regimen, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate hepatic, renal, and bone marrow function.

The key exclusion criteria were stem cell transplant in the 12 weeks prior to treatment with elranatamab or active graft-versus-host disease, active infections and previous treatment with a bi-specific anti-BCMA antibody.

In cohort A, the median age of patients was 68 years, with 19.5% of patients 75 years of age or older. Extramedullary disease was present in 32% of patients. Patients were heavily pre-treated. The median number of prior lines of therapy was 5 for patients in cohort A. In cohort A, 96% of patients had received 3 or more prior lines of therapy and 96% were triple-class refractory.

The treatment regimen employed in the clinical study of Elrexfio included step-up doses of 12 mg on Day 1 and 32 mg on Day 4 of Week 1, followed by the first treatment dose of 76 mg on Day 8, and then 76 mg weekly thereafter through Week 24. All doses were administered via the subcutaneous route. The step-up regimen was intended to reduce the risk and/or severity of cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS).

Patients who received at least 24 weeks of treatment, and achieved and maintained a response (i.e., a partial response or better that has been maintained for at least 2 months), transitioned to once every two week dosing. Treatment with Elrexfio continued until disease progression or unacceptable toxicity.

In the pivotal cohort (cohort A), the observed ORR was 61.0% (95% confidence interval [CI]: 51.8, 69.6) in 123 patients. Of all responders, 55.3% had a very good partial response (VGPR) or better, and 27.6% had a complete response (stringent complete response + complete response). The stringent complete response rate (sCR) was 13.0%.

The duration of response, calculated for the 75 responders in the pivotal cohort, suggested good durability. With a median follow-up time of 10.94 months after the first administration of Elrexfio, the median duration of response was not reached (95% CI: 12 months, not estimable [NE]). The Kaplan-Meier estimated probability of maintaining a response at 9 months was 84.4% (95% CI: 72.7, 91.4).

Indication

Sponsor's proposed indication

Health Canada-approved indication

Elrexfio (elranatamab solution for injection) is a B-cell maturation antigen (BCMA)-directed and CD3‑directed bispecific antibody indicated for: the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Elrexfio (elranatamab injection) is a B-cell maturation antigen (BCMA)-directed and CD3‑directed bispecific antibody indicated for: the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

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

Clinical Safety

The primary safety evaluation was based on 187 patients who received the recommended dose in cohorts A and B of the MagnetisMM-3 study. Four patients received Elrexfio using a different step-up dosing regimen than the recommended regimen (each received a single 44 mg dose instead of the usual 12 mg dose followed by a 32 mg dose). These four patients were summarized separately in presentations of CRS and ICANS, as the 12 mg/32 mg step-up dosing was expected to significantly mitigate these risks.

All subjects experienced at least one treatment-emergent adverse event. Serious adverse events were experienced by 68.4% of patients. Grade 3 or 4 adverse events were experienced by 71.1% of patients, while 19.8% of patients died due to an adverse event. Three deaths were considered treatment-related by investigators. Permanent discontinuation of Elrexfio occurred for 17.1% of patients, and dose interruptions occurred for 73.8% of patients.

The most commonly reported adverse events (30% of patients or more) were CRS, anemia, fatigue, neutropenia, injection site reaction, diarrhea, upper respiratory tract infection, thrombocytopenia, and pneumonia. The most commonly reported Grade 3 and 4 adverse events (in 10% of patients or more) were anemia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, pneumonia, and sepsis. The Grade 5 (fatal) adverse events that were considered by investigators to be treatment-related were one case each of pneumonia pseudomonal, septic shock, and failure to thrive.

Elranatamab (the medicinal ingredient in Elrexfio) is associated with CRS and ICANS, risks that are highlighted in a Serious Warnings and Precautions box in the Elrexfio Product Monograph. Both CRS and ICANS have been commonly observed after treatment with CAR T cells and bi-specific T-cell engagers, and are predicted toxicities for bi-specific antibodies engaging the T-cell compartment. In general, cases of CRS and ICANS observed in the MagnetisMM-3 study were of low grade and resolved with a combination of dose interruption and supportive treatments, which included anti-interleukin-6 monoclonal antibodies and/or corticosteroids in 40% of cases. The overall rate of CRS was 58.8% and the rate of ICANS was 4.3%. One patient experienced a Grade 3 CRS event, while the remaining cases of CRS were Grade 1 or 2 in severity. Notably, four patients who received a priming dose of 44 mg rather than the recommended step-up dosing regimen all experienced CRS, which supports the use of step-up dosing to mitigate this risk. Immune effector cell-associated neurotoxicity syndrome was reported in 8 of 187 patients, with 2 cases classified as Grade 3 in severity. All 6 of the patients who had ICANS and received the recommended step-up dosing had concurrent CRS.

Other neurological adverse events, which were commonly observed (in 10% of patients or more), included headache (18%), encephalopathy (14.2%), sensory neuropathy (12.6%), and motor dysfunction (14.2%). Other risks identified include hepatotoxicity and susceptibility to infection, including opportunistic infections (e.g., pneumocystis jirovecii, adenovirus), and hepatitis B reactivation.

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

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

In vitro, elranatamab binds to B-cell maturation antigen (BCMA) and CD3 with high affinity while blocking the interaction of BCMA with its ligands, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Elranatamab also interacts as expected with the neonatal fragment crystallizable (Fc) receptor (FcRn), which is involved in antibody recycling. However, elranatamab has little to no ability to bind Fc-gamma receptor 1 (FcγR1), which abrogates its ability to elicit antibody-dependent cell-mediated cytotoxicity. Elranatamab activated T cells against myeloma cell lines and patient samples, which was demonstrated through the measurement of cytokine levels after incubation. When expanded T cells were present, elranatamab also killed multiple myeloma cells and Chinese hamster ovary (CHO) cells engineered to express the BCMA receptor. Cells that did not express BCMA were unaffected.

In tumour xenograft models in mice, engraftment of human T cells followed by elranatamab treatment demonstrated tumour growth inhibition. A negative control bi-specific monoclonal antibody treatment did not affect tumour growth. Additionally, tumour growth did not correlate perfectly with BCMA expression level, suggesting that other factors also contribute to the efficacy of elranatamab treatment. Given the dual target mechanism of action of elranatamab, this was not unexpected.

The pharmacokinetics and toxicokinetics of elranatamab were evaluated in single- and repeat-dose toxicity studies in monkeys. Elranatamab exhibited dose-proportional pharmacokinetics over the dosing range tested. In repeat-dose studies (dosed weekly), accumulation was observed at least until Day 43. However, the data were not extensive enough to accurately determine when steady-state is achieved. The estimated volume of distribution was 0.1 L/kg based on the single-dose study, which is consistent with other immunoglobulin G (IgG) monoclonal antibodies.

Pivotal 1- and 3-month toxicity studies were conducted in cynomolgus monkeys using the subcutaneous route of administration. The key effects identified in these studies were increased cytokines, decreased BCMA-expressing cells (a subset of B cells and plasma cells), fluctuations in peripheral T cell and natural killer (NK) cell numbers, immunosuppression, and secondary infection.

In line with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] guidelines for biotechnology-derived pharmaceuticals (S6R1) and for anticancer pharmaceuticals (S9), carcinogenicity and reproductive toxicology studies were not undertaken.

The sponsor submitted a developmental and reproductive toxicity assessment and concluded that elranatamab administration during pregnancy carries an unacceptable risk. This risk has been communicated in the Product Monograph.

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

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

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

Characterization of the Drug Substance

Elranatamab (the medicinal ingredient in Elrexfio) is a recombinant, bispecific, humanized antibody based on a human immunoglobulin G2 (IgG2) framework. The molecule is derived from two different monoclonal antibodies: a monoclonal antibody directed against the human B-cell maturation antigen (BCMA), and a monoclonal antibody directed against the human CD3ε subunit of the T-cell receptor. Reduction-oxidation of the two monoclonal antibodies forms elranatamab, the bispecific antibody.

The proposed mechanism of action involves simultaneous binding of elranatamab to the BCMA on plasma cells, plasmablasts, and multiple myeloma cells, and to CD3 on the surface of cytotoxic T-cells. Bispecific binding induces T-cell activation, resulting in proinflammatory cytokine release, and targeted killing of the malignant cells. Functions mediated by the fragment crystallizable (Fc) region of the antibody (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) do not contribute to the mechanism of action of elranatamab. 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.

Extensive studies were conducted to characterize the drug substance batches manufactured by the commercial processes. The primary structure, post-translational modifications, disulfide bonding, charge and size heterogeneity, higher order structure, and biological activity of elranatamab were analyzed. The characterization results demonstrated that elranatamab has the expected structure and functional properties.

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

Manufacturing of the drug substance, elranatamab, involves two recombinant Chinese hamster ovary (CHO) cell lines: one expressing the anti-BCMA monoclonal antibody and the other expressing the anti-CD3 monoclonal antibody. The manufacturing process begins with the thawing of one vial from each working cell bank to initiate a separate cell culture from each cell line. The cells from each cell line are cultured and processed separately and moved to progressively larger vessels until the cell cultures reach the required density and volume.

The cultures are separately harvested and clarified through depth filtration, virally inactivated, and each monoclonal antibody is purified by chromatography. The separate eluates of each monoclonal antibody are neutralized, pooled, and mixed, and the inter-disulfide bonds are reduced. Through an oxidation reaction, the disulfide bonds reform preferentially between one half of anti-BCMA monoclonal antibody and one half of anti-CD3 monoclonal antibody to form elranatamab, a bispecific antibody. The preferential heterodimerization between the heavy chains of the two antibodies is facilitated by the design mutations engineered into the antibodies and the reduction-oxidation conditions of the reaction.

The reaction mixture is concentrated by ultrafiltration/diafiltration prior, purified through chromatography, and followed by viral filtration and concentration and buffer exchange to produce the formulated drug substance. The final monoclonal antibody bulk solution is filtered through a bioburden reduction filter into ethylene vinyl acetate (EVA) bags and stored at ‑20 °C ± 5 °C.

The frozen drug substance is shipped according to qualified processes to the drug product manufacturing site. The drug substance is thawed at 15 °C to 25 °C and diluted with formulation buffer (if necessary) to achieve the target protein concentration of 40 mg/mL. After mixing, the bulk drug product undergoes bioburden reduction filtration, followed by sterile filtration into glass vials. The filled vials are capped and crimped, and the sealed vials are visually inspected. The drug product is stored at 5 °C ± 3 °C.

Both drug product vial presentations (44 mg/1.1 mL and 76 mg/1.9 mL; both are 40 mg/mL) are manufactured using the same equipment, process steps, and in-process controls, with the only difference being the fill volume. In-process checks for the fill weight are conducted at regular intervals to control filling within the defined limits.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of elranatamab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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

Materials used in the manufacturing process are sourced from qualified suppliers and compendial grade material is used whenever possible. The raw materials are routinely tested and must meet compendial requirements (United States or European Pharmacopeia) and/or in-house specifications. No animal-derived raw materials or excipients were used in the manufacturing of elranatamab. The master and working cell banks were established according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Qualification studies confirmed that the starting materials were free from microbial and viral adventitious agents, and meet all acceptance criteria for identity, culture purity, and genetic stability. The cell banks are suitable for use in the production of the drug substance.

Release and stability specifications were appropriately defined for the drug substance and drug product and will ensure that Elrexfio meets all critical quality attributes, including criteria for identity, purity, potency, and product safety. The corresponding analytical methods were adequately validated according to ICH guidelines, and compendial methods were qualified for use.

A two-tiered in-house reference standard program has also been implemented. A Primary Reference Material and an initial Working Reference Material were characterized and qualified according to defined protocols. Testing protocols are in place to monitor reference material stability and will ensure the consistent quality of the standards.

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. No risk was identified for the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Accordingly, no confirmatory testing is required.

Elrexfio 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. The proposed 24-month shelf life at 5 °C ± 3 °C for Elrexfio is considered acceptable. The product must be protected from light until time of use and must not be frozen or shaken. Additional storage, reconstitution, and special handling instructions are included in the Elrexfio Product Monograph.

Facilities and Equipment

Based on risk assessments conducted by Health Canada, on‑site evaluations (OSEs) were not conducted for the drug substance or drug product manufacturing sites. Overall, the facilities are compliant with current good manufacturing practices and are considered suitable for the manufacturing of the drug substance and the drug product.

Adventitious Agents Safety Evaluation

The manufacturing process includes virus clearance steps which use orthogonal mechanisms. Viral clearance was validated using scaled-down studies, three model viruses, representative commercial material derived from manufacturing scale batches, and testing under worst-case process conditions. The process was demonstrated to be robust and effective at clearing adventitious viruses and endogenous retroviral-like particles (RVLP) to levels below the acceptable limits. Adequate control measures are in place to prevent contamination and maintain microbial control during manufacturing.