Summary Basis of Decision for Elahere

Clinical Pharmacology

Mirvetuximab soravtansine (MIRV), the medicinal ingredient in Elahere, is an antibody-drug conjugate (ADC) consisting of three components: an anti-folate receptor alpha (FRα) chimeric monoclonal antibody of immunoglobulin G1 (IgG1) subtype, covalently attached to the small molecule anti-tubulin agent DM4 (a cytotoxic maytansinoid), via a cleavable linker. The antibody portion of the ADC binds to FRα expressed on the surface of ovarian cancer cells. Upon binding, MIRV is internalized followed by the intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.

Pharmacokinetics

The pharmacokinetic (PK) properties of MIRV were evaluated from a combined dataset collected from 757 cancer patients who participated in four clinical studies (Study 0401 [a first-in-human study], and three Phase III Studies [Study 0403 {FORWARD}, Study 0417 {SORAYA} and the pivotal Study 0416 {MIRASOL}]). Only Study 0401 provided dense sampling suitable for reliable estimates of the PK parameters with a non-compartmental analysis. Studies 0417 and 0416 provided new information from a protocol with sparse sampling to re-estimate the parameters in an empirical population PK model.

The structural model of the population PK analysis consisted of two compartments to capture the biphasic PK profile of MIRV following intravenous infusion. The model assumed both linear and non-linear elimination from the central compartment for MIRV, a central and a target (tissue) compartment for the payload, and a central compartment for the metabolite. With each dosing, the initial drug-to-antibody ratio was fixed at 3.5. There was no pharmacodynamic component, which limited the model’s potential to compare alternate dosing regimens.

The prediction accuracy of the fitted model, based on a tally of successfully predicted observed values, met the minimum standard for the ADC analyte, but did not meet the standard of sufficient accuracy to predict the concentrations for either the payload or its primary metabolite. In general, the final population PK analysis is considered acceptable for the purpose of predicting exposure parameters of MIRV.

The recommended dose of Elahere is 6 mg/kg adjusted ideal body weight (AIBW) administered once every three weeks (21-day cycle) as an intravenous infusion until disease progression or the occurrence of unacceptable toxicity. Dosing based on AIBW reduces exposure variability for patients who are either underweight or overweight.

Dosing considerations include instructions to select patients for the treatment of platinum resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with Elahere based on tumour FRα positivity using a validated test. Folate receptor-alpha positivity is defined as 75% or more of viable tumour cells with moderate (2+) or strong (3+) staining intensity by immunohistochemistry.

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

Clinical Efficacy

The clinical efficacy of Elahere was primarily evaluated based on the results of the pivotal Study 0416 (MIRASOL), a Phase III, randomized, open-label, active-controlled study that evaluated the use of Elahere as compared to investigator’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin [PLD], or topotecan; hereafter referred to as IC Chemo) in adult female patients with platinum-resistant advanced, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers. All patients were required to have tumours with high expression of FRα (defined as 75% or more of viable tumour cells with moderate [2+] or strong [3+] staining intensity by immunohistochemistry). Each patient had received one to three prior systemic treatment regimens.

A total of 453 patients were randomized in a 1:1 ratio into the Elahere arm (total number [n] = 227) or the IC Chemo arm (n = 226). Patients in the Elahere arm were administered Elahere at a dose of 6 mg/kg (based on adjusted ideal body weight [AIBW]) every 3 weeks. Patients in the IC Chemo arm were administered one of four regimens: 1) paclitaxel (80 mg/m²) once every week with a 4‑week cycle, 2) pegylated liposomal doxorubicin (40 mg/m²) every 4 weeks, 3) topotecan (4 mg/m²) on days 1, 8 and 15 every 4 weeks, or 4) topotecan (1.25 mg/m²) for five consecutive days every 3 weeks. In both arms, patients continued to receive study drug until disease progression, the occurrence of unacceptable toxicity, withdrawal of consent, death, or study termination by the sponsor - whichever came first.

Tumour response assessments were conducted every 6 weeks for the first 36 weeks and every 12 weeks thereafter. Randomization was stratified by the following factors: number of prior lines of therapy (one vs. two vs. three) and chemotherapy (paclitaxel vs. PLD vs. topotecan) chosen prior to randomization.

Of the 453 randomized patients, the median age was 63 years (range: 29 to 88 years); 66% were White, 12% were Asian, 3% were Black or African American, and 18% did not report their race. Most patients (80%) had ovarian cancer of epithelial origin; 11% had cancer of the fallopian tube; 8% had primary peritoneal cancer; and all (100%) were of high-grade serous histology. Nearly all patients had an Eastern Cooperative Oncology Group Performance Status of 0 (55%) or 1 (44%). Fourteen percent of patients had received one prior line of systemic therapy, 39% of patients had received two, and 47% of patients had received three prior lines of systemic therapy. Sixty-two percent of patients received prior bevacizumab and 55% had received a prior poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitor. The platinum-free interval following the most recent line of therapy was 3 months or less in 41% of patients, and 3 to 6 months in 58% of patients.

The primary efficacy endpoint was investigator-assessed progression-free survival (PFS). Key secondary efficacy endpoints were investigator-assessed objective response rate (ORR) and overall survival (OS). The evaluation of PFS and ORR was conducted according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1.

At the time of final PFS analysis and interim OS analysis, statistically significant improvements were demonstrated for both the primary endpoint of investigator-assessed PFS and the secondary endpoints of investigator-assessed ORR and OS.

The median PFS was 5.62 months (95% Confidence Interval [CI]: 4.34, 5.95) in the Elahere arm compared to 3.98 months (95% CI: 2.86, 4.47) in the IC Chemo arm. The hazard ratio (HR) for investigator-assessed PFS was 0.65 (95% CI: 0.521, 0.808; p <0.0001), representing a 35% reduction in the risk of tumour progression or death in the Elahere arm.

The investigator-assessed ORR Investigator was 42.3% (95% CI: 35.8, 49.0) in the Elahere arm compared to 15.9% (95% CI: 11.4, 21.4) in the IC Chemo arm (p <0.0001). Of the responders, 12 (5%) were complete responses (CRs) and 84 (37%) were partial responses (PRs) in the Elahere arm compared to zero CRs (0%) and 36 PRs (16%) in the IC Chemo arm. With a median follow-up of 13.11 months and 204 of the 300 pre-specified target number of deaths (68%) observed, the median OS was 16.46 months (95% CI: 14.46, 24.57) for the Elahere arm compared to 12.75 months (95% CI: 10.91, 14.36) for the IC Chemo arm. The OS HR was 0.67 (95% CI: 0.504, 0.885; p = 0.0046), which represented a 33% reduction in the risk of death for patients treated with Elahere.

Indication

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

Elahere (mirvetuximab soravtansine for injection) as monotherapy is indicated for the treatment of adult patients with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.

Overall Analysis of Efficacy

Overall, the efficacy results of the pivotal study provide evidence of a statistically significant and clinically meaningful survival benefit for platinum-resistant ovarian cancer patients receiving Elahere.

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

Clinical Safety

The clinical safety of Elahere was primarily evaluated in the pivotal Study 0416 (MIRASOL; described in the Clinical Efficacy section). Patients received Elahere 6mg/kg (based on AIBW) once every three weeks until disease progression or unacceptable toxicity occurred. The median duration of treatment was 5 months (range: 0.69 to 27.4).

Safety data were analyzed at the time of primary analysis. The median duration of dosing was 4.98 months (7 cycles) in the Elahere arm and 2.96 months (3 cycles) in the IC Chemo arm. In total, 210 patients (96%) treated with Elahere and 194 patients (94%) treated with IC Chemo reported treatment-emergent adverse events (TEAEs) of any grade. The most common TEAEs (occurring with 20% incidence or higher) reported in patients treated with Elahere were blurred vision, keratopathy, abdominal pain, fatigue, diarrhea, dry eye, constipation, nausea, and peripheral neuropathy.

Ocular disorders, peripheral neuropathies, and pneumonitis were considered important identified risks associated with Elahere.

Ocular TEAEs were reported by 56% of patients receiving Elahere compared to 9% in the IC Chemo arm. In the Elahere arm, Grade 3 or higher ocular TEAEs occurred in 14% of patients. In a pooled safety analysis of 682 patients who received Elahere 6 mg/kg (based on AIBW), 59% reported at least one ocular TEAE. The majority of the ocular events were Grade 2 or lower in severity, with 73 patients (11%) experiencing a Grade 3 event and two patients experiencing Grade 4 events (less than 1%). Data for the pooled safety analysis was provided from four clinical studies (Study 0401 [a first-in-human study], and three Phase III Studies [Study 0403 {FORWARD}, Study 0417 {SORAYA} and the pivotal Study 0416 {MIRASOL}]).

In the pivotal study, peripheral neuropathy was reported by 37% of patients administered Elahere. Twenty percent (20%) of these events were Grade 1 in severity, 14% were Grade 2, and 4% were Grade 3. There were no Grade 4 events. In the pooled safety analysis, 36% of patients reported a peripheral neuropathy event, of which most were Grade 2 or lower (34%). Eighteen patients (3%) reported events Grade 3 or higher in severity. No Grade 4 or Grade 5 events occurred.

Pneumonitis was reported for approximately 10% of patients administered Elahere in the pivotal study, with most instances being Grade 2 or lower (90%) in severity. One patient reported Grade 3 respiratory failure and one patient experienced Grade 5 respiratory failure. In the pooled safety analysis, 10% reported a pneumonitis event including Grade 3 events (0.9%) and a Grade 4 event (0.2%).

In the pivotal study, serious adverse reactions occurred in 24% of patients treated with Elahere. The most common serious adverse events (occurring in 2% or more of patients) were pleural effusion (3%), abdominal pain (3%), intestinal obstruction (2%), ascites (2%) and small intestinal obstruction (2%).

Treatment-related fatal adverse events were reported for 7 patients (3%) in the Elahere arm. These included one case each of intestinal obstruction, dyspnea in the setting of subileus, neutropenic sepsis, cardiopulmonary failure, respiratory failure, ischemic stroke, and pulmonary embolus.

Appropriate warnings and precautions are in place in the approved Product Monograph for Elahere to address the identified safety concerns. A Serious Warnings and Precautions box describing the risk of severe ocular adverse reactions including blurred vision, keratopathy (corneal disorders), dry eye, photophobia, and eye pain has been included in the Product Monograph for Elahere.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Due to the limited number of patients with ADAs against MIRV in the pivotal study, no conclusions could be drawn concerning the potential effect of immunogenicity on overall safety.

Ocular disorders, peripheral neuropathy and pneumonitis are important safety concerns associated with Elahere treatment; however, these adverse events were generally manageable with the risk mitigation and dose modification measures implemented during the pivotal study. Overall, the results of the pivotal study provided evidence of a statistically significant and clinically meaningful survival benefit and an acceptable safety profile for platinum-resistant ovarian cancer patients receiving Elahere.

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

In humans, folate receptor alpha (FRα) is highly expressed in ovarian cancer cells while expression in normal tissue is limited. Target cells take up mirvetuximab soravtansine (MIRV), resulting in its processing to active maytansinoid catabolites and leading to induction of cell cycle arrest and cell death. The payload (DM4) and its main circulating metabolite (S-methyl-DM4) demonstrated strong cytotoxic potential in cell-based assays with half-maximal inhibitory concentration (IC50) values in the low nanomolar range. In vivo, administration of a single intravenous dose of MIRV to immunodeficient mice bearing FRα-positive human ovarian carcinoma xenografts resulted in dose-dependent anti-tumor activity and extended survival of the animals.

The pharmacokinetic profile of MIRV in cynomolgus monkeys was biphasic and exposure metrics (maximum concentration [C_max] and area under the concentration-time curve from zero to infinity [AUC_∞]) for the antibody-drug conjugate and total antibody both generally increased linearly with dose. There were no apparent differences in pharmacokinetics between genders. The PK profile of MIRV in Dutch Belted rabbits was similar to that in monkeys.

Biotransformation of DM4 and S-methyl-DM4 is predominantly mediated by cytochrome P450 (CYP) 3A4, with minor contributions of other CYP enzymes (2C19, 2C9). Overall, it is considered that the circulating levels of free DM4 derived from MIRV would be too low in patients for it to act as perpetrator in drug-drug interactions. However, the payload might be subject to drug-drug interaction as a victim. Accordingly, a potential for interactions with strong CYP3A inhibitors is included in the Product Monograph for Elahere. No other drug-drug interactions were identified from the data provided.

Toxicology findings were generally similar between single and repeat-dose studies and consisted of clinical dermal observations, effects on white and red blood cell pathology, and microscopic findings in the skin. Most of the findings reported in the toxicity studies had resolved by the respective recovery necropsies. Ocular toxicity studies in the rabbit reported ophthalmic findings of corneal microcysts, microscopic eye findings of slight attenuation, and degeneration/necrosis of the corneal epithelium. The severity of the ocular findings correlated with dose. At the three-week recovery necropsy, signs of recovery were noted for all of the findings.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Elahere. In view of the intended use of Elahere, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. Overall, the results of the non-clinical studies of MIRV support its use for the treatment of human cancer patients.

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

Characterization of the Drug Substance

The drug substance, mirvetuximab soravtansine (MIRV), is an antibody-drug conjugate (ADC) consisting of three components:

1. an anti-folate receptor alpha (FRα) chimeric monoclonal antibody of immunoglobulin G1 (IgG1) subtype, covalently attached to

2. the small molecule anti-tubulin agent DM4 (a cytotoxic maytansinoid), via

3. the cleavable linker sulfo-SPDB ((N-Succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate).

The function of the monoclonal antibody component of MIRV is to bind to FRα expressed on the surface of ovarian cancer cells. Upon binding, MIRV is internalized and DM4 (the payload) is released intracellularly following proteolytic cleavage of the sulfo-SPDB linker. The small molecule, DM4, is a microtubule inhibitor that disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.

Detailed characterization studies were performed to provide assurance that MIRV consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits. 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 risk of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes is considered negligible or low; therefore, no confirmatory testing is required. In addition, risk assessments for the potential presence of elemental and mutagenic impurities were conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. No risks were identified with Elahere; therefore, no confirmatory testing or mitigation is required.

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

Drug Substance

The drug substance, mirvetuximab soravtansine (MIRV), is an antibody-drug conjugate (ADC) composed of a monoclonal antibody intermediate, a sulfo-SPDB intermediate, and a DM4 (payload) intermediate.

Monoclonal Antibody Intermediate

The monoclonal antibody intermediate, mirvetuximab, is produced using a recombinant Chinese hamster ovary (CHO) cell line and standard monoclonal antibody manufacturing techniques. Cells from a cell bank are thawed and progressively expanded into vessels of increasing size to inoculate a production bioreactor. After the production bioreactor culture is harvested and clarified, mirvetuximab is subjected to downstream processing steps including chromatography, viral inactivation, and virus retaining filtration. Purified mirvetuximab is further concentrated and formulated by ultrafiltration/diafiltration. Formulated mirvetuximab is then filtered, filled into containers, and stored frozen.

Sulfo-SPDB intermediate

The sulfo-SPDB is a white to off-white powder. It is synthesized by a three-step linear chemical synthesis.

The manufacturing process was successfully validated with three process performance qualification (PPQ) runs that were carried out in accordance with a documented validation plan. Three consecutive sulfo-SPDB batches were produced at the commercial scale using different lots of starting material. The PPQ results demonstrate that the process operates consistently, is robust and reproducible, and generates sulfo-SPDB intermediate that meets the pre-determined specifications.

DM4 payload intermediate

The DM4 payload intermediate of the drug substance is chemically synthesized in a three‑step linear chemical synthesis.

Process validation reports for three commercial scale DM4 batches from multiple batches of the proposed regulatory starting materials were provided. As per Health Canada’s Quality (chemistry and manufacturing) guidance: New Drug Submissions and Abbreviated New Drug Submissions, given that there are no aseptic or sterilization processes in the DM4 drug payload manufacture, the reports have not been comprehensively reviewed as process validation and/or evaluation studies need not be provided in a regulatory submission. However, all critical and key process parameters for these batches were within predefined normal operating ranges and batches comply with DM4 specifications.

Antibody-Drug Conjugate

The mirvetuximab soravtansine ADC drug substance is produced through two sequential reactions involving the conjugation of mirvetuximab (the monoclonal antibody intermediate), the sulfo-SPDB linker intermediate, and the DM4 drug intermediate. The first reaction, an in-situ process, forms the drug-linker molecule. The second reaction, the conjugation step, attaches the drug-linker to mirvetuximab, yielding the ADC molecule. This molecule is then concentrated, purified, and formulated to 5 mg/mL mirvetuximab soravtansine in 10 mM acetate, 9% (w/v) sucrose, and 0.01% (w/v) polysorbate 20 at pH 5.0. Formulated bulk drug substance is then filtered and filled into bottles and frozen for long-term storage.

Drug Product

The drug product manufacturing process involves pooling bottles from a single drug substance batch, followed by sterile filtration and aseptic filling into vials, with no formulation steps. The resulting Elahere drug product is a concentrated solution for intravenous infusion that is sterile, preservative-free, clear to slightly opalescent, and colourless. It is supplied in 20 mL single-use vials at a strength of 100 mg. To ensure full withdrawal of 20 mL, the vials are overfilled. Prior to administration, Elahere must be diluted in 5% dextrose solution to achieve a final concentration of 1 to 2 mg/mL for intravenous infusion.

Process validation studies were conducted using at least three consecutive batches each of the monoclonal antibody intermediate, ADC drug substance, and Elahere drug product at the proposed commercial scales and manufacturing sites. Collectively, the process validation data demonstrated that the commercial manufacturing processes consistently produce monoclonal antibody intermediate, ADC drug substance, and Elahere drug product batches that meet predefined specifications and quality attributes.

During clinical development, different manufacturing processes and sites were used to produce the monoclonal antibody intermediate, ADC drug substance, and Elahere drug product. All processes were found to be comparable with respect to product quality and consistency, based on comparative analyses of lot release data, characterization studies, and stability results.

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

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

Control of the Drug Substance and Drug Product

Qualification of the mirvetuximab master cell bank was done in accordance with the relevant ICH guidelines and the results of these studies have confirmed its identity, sequence integrity, purity, and safety.

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with 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.

A two-tiered reference program has been established for mirvetuximab and Elahere, respectively. The reference standards have been well characterized, and an appropriate program is in place to qualify new working reference material as needed in the future.

Elahere 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 60-month shelf life is acceptable when Elahere is stored between 2 °C to 8 °C, and protected from light.

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

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

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

Adventitious Agents Safety Evaluation

The monoclonal antibody intermediate manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Scaled-down models of the monoclonal antibody intermediate commercial manufacturing process were employed to evaluate the specific processing steps to remove and/or inactivate potential viral contaminants. Operational parameters used for the viral clearance evaluations represented worst-case scenarios relative to the manufacturing scale operating ranges. The study was performed in accordance with ICH Q5A. The level of clearance is consistent with ICH Q5A(R2) expectations and supports the viral safety of Elahere.

No materials of animal or human origin are used in the manufacture of Elahere except for the CHO-derived mirvetuximab production cell line. All raw and starting materials used in the manufacture of mirvetuximab cell banks, monoclonal antibody intermediate, drug substance and drug product have been assessed as negligible risk for transmissible spongiform encephalopathy (TSE) transmission. The excipients used in the drug product formulation are not of animal or human origin.