Summary Basis of Decision for Blenrep

Clinical Pharmacology

Belantamab mafodotin (the medicinal ingredient in Blenrep) is an antibody-drug conjugate (ADC) consisting of a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody conjugated with a microtubule inhibitor, maleimidocaproyl monomethylauristatin F (mcMMAF). Belantamab mafodotin binds to the cell surface B-cell maturation antigen (BCMA), a protein expressed on the cell surface of normal B lymphocytes and overexpressed on the surface of multiple myeloma cells. It is rapidly internalised, and once inside the cell, the cytotoxic agent (cys-mcMMAF) is released. This disrupts the microtubule network and leads to cell cycle arrest and cell apoptosis.

The belantamab antibody also enhances recruitment and activation of immune effector cells, killing cells by antibody-dependent cellular cytotoxicity and phagocytosis. Apoptosis induced by belantamab mafodotin is accompanied by markers of immunogenic cell death, which may contribute to an adaptive immune response to the target cells.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of belantamab and cys-mcMMAF have been well characterized. The maximum concentration (C_max) of belantamab mafodotin ADC occurred at or shortly after the end of infusion, while the C_max of cys-mcMMAF occurred approximately 24 hours after dosing. The accumulation of belantamab mafodotin ADC was minimal to moderate (geometric means: 1.13 for C_max and 1.58 for exposure as measured by the area under the concentration-time curve [AUC]) as observed in clinical studies with dosing every 3 weeks. In vitro, cys-mcMMAF exhibited low protein binding (56% to 86% unbound) in human plasma. Metabolism of the monoclonal antibody portion of belantamab mafodotin is expected to occur via proteolysis. The cys-mcMMAF component had limited metabolic clearance in human hepatic S9 fraction incubation studies. In clinical studies, the fraction of cys-mcMMAF excreted in urine was approximately 18% (not considered substantial) after the Cycle 1 dose, with no evidence of other MMAF-related metabolites.

Belantamab mafodotin exhibits approximately dose-proportional pharmacokinetics over the recommended dose range up to 4.6 mg/kg. In the population pharmacokinetic model, the dose-proportionality was observed in the C_max, AUC and trough concentration (C_trough) parameters for ADC and cys-mcMMAF across the relevant dose range.

Renal function (estimated glomerular filtration rate [eGFR]: 12 to 150 mL/min) was not a significant covariate in population pharmacokinetic analyses with respect to all model parameters that included patients with normal renal function, mild, moderate or severe renal impairment, or kidney failure.

Belantamab mafodotin is not expected to be removed via dialysis due to its molecular size. While free cys-mcMMAF may be removed via dialysis, cys-mcMMAF systemic exposure is very low.

No formal studies have been conducted in patients with hepatic impairment. Hepatic function, as per National Cancer Institute Organ Dysfunction Working Group classification, was not a significant covariate in population pharmacokinetic analyses with respect to all model parameters that included patients with normal hepatic function, mild hepatic impairment or moderate hepatic impairment.

Body weight (37 to 170 kg) was a significant covariate in population pharmacokinetic analyses with respect to some model parameters of ADCs such as central volume of distribution, peripheral volume of distribution, clearance, and intercompartmental clearance. However, this effect is not clinically relevant with the weight‑proportional dosing regimen.

Belantamab mafodotin did not have a significant effect on cardiac repolarization. Belantamab mafodotin (ADC) or cys-mcMMAF had no meaningful QTc prolongation (greater than 10 ms) at the recommended dose of 2.5 mg/kg once every 3 weeks, nor at doses as high as 3.4 mg/kg once every 3 weeks.

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

Clinical Efficacy

DREAMM-7, a Phase III randomized and open-label study, was designed to evaluate the clinical efficacy of Blenrep in combination with bortezomib and dexamethasone (BVd) versus (vs.) daratumumab, bortezomib, and dexamethasone (DVd) for the treatment of relapsed or refractory multiple myeloma (RRMM). Patients were randomized in a 1:1 ratio to either the BVd or DVd treatment groups (243 and 251 patients, respectively). Patients were stratified according to the number of prior lines of therapy (1 vs. 2 or 3 vs. 4), prior treatment with bortezomib (yes vs. no), and revised international staging system classification (I vs. II or III). Crossover between groups was not allowed.

Eligible patients must have received at least one prior line of systemic therapy. No more than 50% of enrolled subjects could have received two or more prior therapies. Additionally, patients had to have an Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. Patients were ineligible for the study if they were intolerant to daratumumab or bortezomib, known to be refractory to any anti-cluster of differentiation 38 (CD38) therapy, or had received prior B-cell maturation antigen (BCMA)-directed therapy.

Patients randomized to the BVd treatment group received a 2.5 mg/kg dose of Blenrep administered intravenously every three weeks. Patients randomized to the DVd treatment group received a 16 mg/kg dose of daratumumab administered intravenously on a weekly basis during cycles 1 to 3, every three weeks during cycles 4 to 8, and every four weeks from cycle 9 onward. Both daratumumab and Blenrep were to be administered until disease progression or unacceptable toxicity occurred. In both treatment groups, bortezomib and dexamethasone were administered for up to 8 cycles.

The median duration of exposure was 15.9 months in the BVd treatment arm and 12.9 months in the DVd treatment arm. It should be noted that the median dose intensities were significantly different (50.89% for Blenrep and 94.76% for daratumumab) due to the frequent need for dose delays for patients in the BVd treatment arm. Dose reductions were also common. Despite this difference, BVd was associated with significant improvements in clinical outcomes. Treatment was withdrawn for 35% of patients in the BVd group and 19% of patients in the DVd group.

The primary efficacy endpoint was progression-free survival (PFS) evaluated by a blinded independent review committee (BIRC), defined as the time from randomization until the earliest date of documented disease progression or death due to any cause. The key secondary efficacy endpoints were the restricted mean duration of response (DoR), overall survival (OS), and the minimal residual disease (MRD)-negativity rate.

A multiple testing strategy was employed to control type I error across PFS, restricted mean DoR, OS, and MRD-negativity rate. A statistically significant improvement in PFS was observed at the time of the first interim analysis. A 59% reduction in the risk of disease progression or death was associated with BVd, compared to DVd (hazard ratio [HR] = 0.41, 95% confidence interval [CI]: 0.31, 0.53, p<0.00001). The median PFS was 36.6 months (95% CI: 28.4, not estimable [NE]) for patients treated with BVd, and 13.4 months (95% CI: 11.1, 17.5) for patients treated with DVd. The PFS result was statistically robust and represents a significant improvement in an endpoint that is acceptable in the setting of RRMM after at least one prior line of therapy.

The median OS, tested at the first interim analysis, was not estimable (95% CI: NE, NE) in either treatment arm. The hazard ratio was 0.57 (95% CI: 0.40, 0.80, p<0.00049). The result did not cross the boundary for statistical significance (0.00037). The strong trend towards OS improvement at the first interim analysis provides support for the PFS benefit observed at the first interim analysis. Several future analyses of OS are planned with alpha adjustment, to account for multiple interim analyses, using the Lan DeMets approach.

Improvement in the median DoR was observed in the BVd treatment group compared to the DVd treatment group. The median DoR, measured in patients who achieved at least a partial response, was 35.6 months (95% CI: 30.5, not reached [NR]) for patients in the BVd treatment group and 17.8 months (95% CI: 13.8, 23.6) for patients in the DVd treatment group. Based on these findings, the replacement of daratumumab with Blenrep is associated with longer lasting response to treatment.

The MRD-negativity rate was descriptively analyzed, as OS did not reach statistical significance at the interim analysis, precluding formal hypothesis testing of MRD negativity. Among patients who achieved a complete response or stringent complete response, MRD negativity was achieved in 24.7% of BVd-treated patients and 9.6% of DVd-treated patients.

Treatment with BVd was associated with improvements in other efficacy endpoints including the complete response and overall response rates.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Blenrep (belantamab mafodotin for injection) is indicated for the treatment of multiple myeloma in combination with: bortezomib and dexamethasone in adult patients who have received at least one prior therapy.	Blenrep (belantamab mafodotin for injection) is indicated, in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy.

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

Clinical Safety

The clinical safety of Blenrep, in combination with bortezomib and dexamethasone, was assessed in the safety population of the DREAMM-7 study (discussed in the Clinical Efficacy section), which included all subjects who were administered at least one dose of study intervention (242 BVd-treated patients and 246 DVd-treated patients). Although all patients reported at least one adverse event, the rate of Grade 3 and 4 adverse events was higher in BVd-treated patients than in DVd-treated patients (95% versus 76%), as was the rate of serious adverse events (50% versus 37%).

The most common adverse events that were Grade 3 severity or higher, and which were reported at higher rates in BVd-treated patients than in DVd-treated patients, were thrombocytopenia, blurred vision, decreased platelet count, and pneumonia. The most common serious adverse events were pneumonia and coronavirus disease 2019 (COVID-19). Fatal adverse events occurred in 10% of BVd-treated patients and 8% of DVd-treated patients. The most common fatal adverse event was pneumonia, which occurred in 7 BVd-treated patients and 2 DVd-treated patients. The next most common adverse event-related causes of death were COVID-19 (3 BVd-treated patients and 5 DVd-treated patients) and COVID-19 pneumonia (2 BVd-treated patients and 5 DVd-treated patients).

Ocular toxicities were frequently observed in BVd-treated patients, and are associated with the cytotoxic portion (cys-monomethyl auristatin F [MMAF]) of belantamab mafodotin. Under the Common Terminology Criteria for Adverse Events (CTCAE) reporting scheme, ocular adverse reactions were observed in 79% of BVd-treated patients and 29% of DVd-treated patients. The protocol was amended to implement dosing based on the results of ocular examinations with grading by the keratopathy and visual acuity (KVA) scale. The KVA scale considers corneal exam findings and changes in vision based on the best corrected visual acuity (BCVA) to report a grade for each component and an overall KVA grade. Based on overall KVA grading, ocular adverse reactions occurred in 84% of BVd-treated patients. A maximum overall Grade 3-4 event was observed in 178 of 242 patients (74%). Blenrep dose reductions and/or interruptions/delays were implemented in 32% and 88% of patients, respectively, in response to ocular adverse reactions.

Considering the individual components of the KVA grading, corneal events occurred in 83% of patients while 81% of patients had BCVA events (worsening visual acuity). Severe bilateral worsening of vision (to 20/200 or worse) was observed in 5 BVd-treated patients (2.1%) while Grade 4 corneal events were reported in 40 BVd-treated patients (20%).

Additional risks of the BVd regimen include infusion reactions, increased thrombocytopenia and an increased risk of infections that may be severe, including opportunistic infections.

To mitigate the risks of treatment with Blenrep, the Product Monograph includes a Serious Warnings and Precautions box highlighting the risk of ocular adverse reactions and clear guidance is given to prescribers regarding the need for individualized dosing. Dosing should be guided by frequent ophthalmic evaluations. Dose delays due to adverse events such as thrombocytopenia and/or infection may also be required. The sponsor is developing patient and prescriber education materials that will further inform of the risks, particularly ocular toxicity.

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

The non-clinical studies submitted for belantamab mafodotin include pharmacological in vitro and in vivo characterization studies, pharmacokinetic and toxicokinetic evaluations, and a targeted toxicology program.

In pharmacology studies, belantamab mafodotin was rapidly internalized upon binding to the cell surface. Once inside the cell, the free cytotoxic drug is released with the linker attached (cys-maleimidocaproyl monomethylauristatin F [mcMMAF]), disrupting the microtubule network, and leading to cell cycle arrest and apoptosis. Belantamab mafodotin was shown to mediate apoptosis of tumour cells expressing B-cell maturation antigen (BCMA) through antibody-dependent cell-mediated cytotoxicity (ADCC), which enhances the recruitment and activation of immune effector cells. In mouse tumour models, anti-tumour activity lasted during treatment and, in some animals, lasted up to the last measurement taken approximately 5 weeks after the last dose of belantamab mafodotin.

There were no clinically relevant findings in safety pharmacology evaluations that examined the potential effects of belantamab mafodotin on the cardiovascular, respiratory and central nervous systems. Increases in heart rate (16%) in male monkeys, observed after 5 weekly doses of belantamab mafodotin at 10 mg/kg, were considered related to their deteriorating clinical condition.

Three- and 13-week repeat-dose toxicity studies were conducted in rats and monkeys. Belantamab mafodotin was administered once weekly in the monkey study, and once every three weeks (modeling the clinical dosing regimen) in the 13-week rat study. In both species, the principal adverse findings were body weight loss/reduced gain, tubular degeneration/regeneration and glomerulopathy in the kidney associated with proteinuria and enzymuria (which was dose-limiting in the rat studies and the single-dose and 13-week monkey studies), increased macrophages in several organs associated with inflammatory clinical pathology changes, and degeneration and atrophy of the seminiferous tubules. In the monkey, signs of hepatocellular necrosis were observed, along with correlated increases in liver enzymes. In the rat, observations included decreased cellularity of the bone marrow with toxic and adaptive effects on the hematopoietic system and in one animal, eosinophilic material in the lung associated with neutrophilic alveolar inflammation and type 2 pneumocyte hypertrophy/hyperplasia.

Although considered non-adverse, increased mitosis of corneal epithelial cells, with bilateral single-cell necrosis, was observed in rats at doses of 3 mg/kg or higher and in rabbits at doses of 15 mg/kg or higher. In an additional investigative study, inflammation of the corneal stroma correlating with ophthalmic observations of superficial haze and vascularization were also noted in 2 of 6 rabbits following doses of 30 mg/kg for 4 weeks, followed by 15 mg/kg for 3 further doses.

Reproductive and developmental studies were not conducted. Cytotoxic drugs such as belantamab mafodotin, which target rapidly dividing cells, are expected to be embryotoxic/fetotoxic and teratogenic. In rats, weekly dosing for 3 weeks at doses greater than or equal to 10 mg/kg resulted in degeneration and atrophy of seminiferous tubules in the testes and luteinized nonovulatory follicles in the ovaries. Findings in females were reversible, but findings in the males were not reversible at the end of the 12-week recovery period following weekly dosing or dosing every 3 weeks for 13 weeks at doses greater than or equal to 10 mg/kg. In male monkeys, the highest dose tested (10 mg/kg, given weekly for 13 weeks) resulted in seminiferous tubule degeneration in the testes that was fully reversed following the 12-week recovery period. The dosing represents approximately 4 times the clinical recommended dose.

Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes. This observation is consistent with the pharmacological effect of cys-mcMMAF binding to tubulin and causing microtubule disruption, which would affect a developing embryo which has rapidly dividing tissue. No studies have been conducted to assess the potential carcinogenicity of belantamab mafodotin.

No relevant safety pharmacology effects were observed for cys-mcMMAF. No inhibition of the human ether-a-go-go-related gene (hERG) was observed with cys-mcMMAF, and it was well tolerated at exposures greater than 850 times the clinical maximum plasma concentration (C_max). It was rapidly absorbed, had moderate clearance, displayed low plasma protein binding, and was mainly excreted via bile. Metabolism was primarily non-enzymatic, with no unique human metabolites. Repeat-dose studies in rats revealed corneal opacity and increased lung weights at doses higher than 1 mg/kg/day, with persistent lung changes. In monkeys, high doses led to delayed time to reach C_max in females and earlier hematologic changes. Additionally, cys-mcMMAF was cytotoxic to human corneal and kidney cells in vitro but showed no mutagenic or genotoxic potential.

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

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

Characterization of the Drug Substance

Blenrep (belantamab mafodotin) consists of belantamab, an afucosylated humanized anti-B-cell maturation antigen (BCMA) immunoglobulin G1 (IgG1) kappa monoclonal antibody, conjugated to a microtubule-disrupting agent, monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker (together, MMAF and the maleimidocaproyl linker are referred to as mcMMAF or SGD-1269). Belantamab and mcMMAF are drug substance intermediates, and belantamab mafodotin is the drug substance.

Detailed characterization studies were performed on belantamab and belantamab mafodotin to provide assurance that they consistently exhibit the desired characteristic structure and biological activity. Characteristics including primary and higher order structure, glycosylation, size heterogeneity, charge variants, and post-translational modifications were all examined. Biological properties were also assessed.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

Belantamab, the monoclonal antibody intermediate, is manufactured using a recombinant Chinese hamster ovary (CHO) cell line and standard antibody production methods. A cell culture is initiated from CHO cells that have been genetically engineered to express belantamab, and is allowed to expand under fed-batch conditions. The culture is harvested when the cells reach the targeted density, and belantamab is purified, concentrated, and formulated through a series of chromatography, viral inactivation, and filtration steps. The formulated belantamab is then filtered, filled into bags, and stored frozen at -35 °C or lower.

The drug substance manufacturing process involves conjugating belantamab to the mcMMAF drug linker. The resulting belantamab mafodotin material is purified and formulated. The formulated bulk drug substance is then filtered, filled into bags, and stored frozen at -35 °C or lower.

The manufacturing process for both drug product strengths involves thawing, pooling, and diluting the drug substance to produce bulk drug product solution. It then undergoes sterile filtration and aseptic filling into vials, which are partially stoppered before lyophilization. The vials are then fully stoppered, crimped, and visually inspected before long-term storage at 2 °C to 8 °C.

Process validation studies were conducted using consecutive batches of each of the monoclonal antibody intermediate, drug substance, and drug product at the proposed commercial scales and manufacturing sites. All critical process parameters, in-process controls, and release testing results met pre-established acceptance criteria and specification limits across all validation batches. Collectively, the data demonstrate that the commercial manufacturing processes consistently produce monoclonal antibody intermediate, drug substance, and drug product batches that meet predefined specifications and 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 belantamab mafodotin with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy for Blenrep includes control of materials, process parameters, in-process controls, release specifications, and facility and equipment controls.

The cell line is well-characterized, clonally derived, and demonstrates consistent product quality. Qualification of the master and working cell banks was done in accordance with the relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and the results of those studies have confirmed their identity, sequence integrity, purity, and safety.

The analytical procedures used in the release and stability testing of belantamab (the antibody intermediate), the Blenrep drug substance, and the drug product were adequately validated according to ICH guidelines. Compendial methods were satisfactorily verified under conditions of use. The corresponding specifications were set using compendial guidelines, product and process knowledge, and statistical analyses of release and stability data. The established release and stability specifications are considered appropriate and in accordance with ICH guidelines. The reference standards have been well characterized and an appropriate program is in place to qualify new working reference material in the future.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in ICH guidelines and 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 negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

Blenrep 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 lyophilized powder should be stored at 2 °C to 8 °C and must not be frozen. The reconstituted solution can be stored for up to 4 hours at room temperature (20 °C to 25 °C) or in a refrigerator (2 °C to 8 °C). It must not be frozen, and must be discarded if not diluted within 4 hours of reconstitution. If not used immediately, the diluted solution can be stored in a refrigerator (2 °C to 8 °C) prior to administration for up to 24 hours. It must not be frozen. If refrigerated, the diluted solution must be allowed to equilibrate to room temperature prior to administration. The diluted solution may be kept at room temperature (20 °C to 25 °C) for a maximum of 6 hours (including infusion time). Additional storage, special handling, and disposal instructions are included in the Product Monograph for Blenrep.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations (OSE) of the manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

All raw and starting materials used in the manufacture of the belantamab cell banks, drug substance intermediate, drug substance, and drug product have been assessed as having negligible risk for transmissible spongiform encephalopathy (TSE) transmission.

Data from small-scale viral clearance studies indicate that the level of clearance is consistent with expectations listed in ICH guidelines and support the viral safety of Blenrep.