Summary Basis of Decision (SBD) for Epkinly

Clinical Pharmacology

Epcoritamab, the medicinal ingredient in Epkinly, is a humanized immunoglobulin G1 (IgG1) bispecific antibody that binds to CD20 expressed on the surface of lymphoma cells and healthy B-lineage cells and to CD3 expressed on the surface of T cells. Simultaneous engagement of CD20-expressing cells and CD3-expressing endogenous T cells by epcoritamab induces specific T-cell activation and T cell-mediated killing of CD20-expressing cells.

The pharmacodynamics, pharmacokinetics, and immunogenicity profiles of epcoritamab were characterized in patients with large B-cell lymphoma.

After the first full dose of 48 mg administered subcutaneously, epcoritamab induced a decrease in the number of circulating B cells to an undetectable level (fewer than 10 CD19 B cells/µL). The depletion was sustained during the treatment. Transient and modest elevations of circulating levels of cytokines (interferon gamma, tumour necrosis factor alpha, interleukin (IL)-6, and IL-10) were observed, mostly after the first full dose of 48 mg. The pharmacokinetics of epcoritamab was characterized by a two-compartment model with first order subcutaneous absorption and target-mediated drug elimination. Absorption of epcoritamab is slow (the time after dosing at which the maximum plasma concentration was observed [t_max] was 3 to 4 days). The geometric mean (percent coefficient of variation [CV%]) central volume of distribution is 8.27 L (27.5%) and the geometric mean (CV%) clearance is 0.441 L/day (27.8%). The estimated half-life ranged from 22 to 25 days for the full dose of 48 mg based on frequency of dosing (weekly, every two weeks, or every four weeks).

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). Among 158 patients who received the full dose (48 mg) of Epkinly in study EPCORE NHL-1 and were evaluable for ADAs, only 4 patients (2.5%) developed anti-epcoritamab antibodies, which were transient and of low titer. Covariate analyses indicate that exposures were similar between ADA-positive and ADA-negative patients. Tests for detecting neutralizing ADAs were not performed. Due to insufficient data, the potential impact of ADAs on the safety and efficacy of epcoritamab could not be evaluated.

Overall, the clinical pharmacology data support the use of Epkinly for the recommended indication.

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

Clinical Efficacy

Pivotal results supporting the efficacy of Epkinly as monotherapy in patients with relapsed or refractory large B-cell lymphoma after two or more prior lines of systemic therapy were provided from the dose-expansion part of the ongoing, open-label, single-arm, Phase I/II dose-escalation and dose-expansion study EPCORE NHL-1.

The efficacy population included 157 patients with relapsed or refractory disease comprising diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma transformed from indolent lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma Grade 3B. Twenty-nine percent of patients had received two prior therapies, 32% had received three prior therapies, and 39% had received four or more prior therapies. Twenty percent of patients had prior autologous hematopoietic stem cell transplants and 39% had received prior chimeric antigen receptor (CAR) T-cell therapy. Eighty-three percent of patients had disease refractory to their last therapy and 29% had disease refractory to CAR T-cell therapy.

The median age of patients was 64 years (range: 20 to 83 years), 60% were male, 61% were White, and 19% were Asian. Most patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (47.1%) or 1 (49.7%).

Patients received subcutaneous injections of Epkinly in 28-day cycles, starting with a priming dose of 0.16 mg on Day 1, an intermediate dose of 0.8 mg on Day 8, and a full dose of 48 mg on Day 15 and Day 22 of Cycle 1. Thereafter, the full dose was administered once weekly in Cycle 2 and Cycle 3, once every two weeks from Cycle 4 to Cycle 9, and once every four weeks from Cycle 10 onwards, until the occurrence of disease progression or unacceptable toxicity.

The primary efficacy outcome measure was overall response rate, whereas the key secondary efficacy outcome measures included complete response rate, partial response rate, duration of response, and duration of complete response. Response rates were assessed by an independent review committee using the Lugano 2014 classification criteria for the response assessment of non-Hodgkin lymphoma.

After a median follow-up of 10.7 months (range: 0.3 to 17.9 months), an overall response rate of 63.1% (95% confidence interval [CI]: 55.0, 70.6) was reported in the efficacy population (i.e., 99 of the 157 patients had a complete or partial response). Thirty-nine percent of patients (61 of the 157 patients) achieved a complete response. The median duration of complete response was 12 months (95% CI: 9.7, not reached).

The submitted efficacy results are considered promising for the intended patient population. To confirm the clinical benefit of Epkinly, the sponsor will provide the results from a randomized, open-label, Phase III study (GCT3013-05) designed to evaluate the efficacy of epcoritamab versus investigator’s choice of standard of care with the combination of rituximab, gemcitabine, and oxaliplatin or the combination of bendamustine and rituximab in adults with relapsed or refractory diffuse large B-cell lymphoma.

Indication

The New Drug Submission for Epkinly was filed by the sponsor with the following proposed indication:

Epkinly is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, where patient is unable to receive or has previously received chimeric antigen receptor T-cell therapy.

Health Canada revised the proposed indication to reflect the disease histological subsets in the studied patient population. Accordingly, Health Canada approved the following indication:

Epkinly is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma transformed from indolent lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma or follicular lymphoma Grade 3B after two or more lines of systemic therapy and who have previously received or are unable to receive chimeric antigen receptor T-cell therapy.

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

Clinical Safety

The safety of Epkinly as monotherapy in patients with relapsed or refractory large B-cell lymphoma after two or more prior lines of systemic therapy was evaluated in the single-arm pivotal Phase I/II dose-escalation and dose-expansion study EPCORE NHL-1 (see Clinical Efficacy section). Among the 157 patients who received at least one dose of Epkinly (48 mg) in the expansion part of EPCORE NHL-1, the median duration of exposure to Epkinly was 4.1 months (range: 0 to 18 months).

Fifty-seven percent of patients who received Epkinly experienced serious adverse reactions. The most frequently reported serious adverse reactions (occurring in at least 2% of patients) were cytokine release syndrome, infections (including sepsis, coronavirus disease 2019 [COVID-19], pneumonia, and upper respiratory tract infections), pleural effusion, febrile neutropenia, fever, and immune effector cell-associated neurotoxicity syndrome.

Fatal adverse reactions were reported in 3.8% of patients and included COVID-19, hepatotoxicity, immune effector cell-associated neurotoxicity syndrome, myocardial infarction, and pulmonary embolism.

Permanent discontinuation of Epkinly due to an adverse reaction occurred in 7.6% of patients. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome led to treatment discontinuation in one patient each. Dose delays due to an adverse reaction were reported in 34% of patients. Adverse reactions that led to dose delays were cytokine release syndrome, neutropenia, thrombocytopenia, pyrexia, and pleural effusion.

Overall, the safety profile of Epkinly is consistent with that expected for a T-cell engaging product and is considered acceptable for the intended patient population. Appropriate warnings and precautions in the approved Epkinly Product Monograph address the identified safety concerns, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, serious infections, and tumour lysis syndrome. Moreover, the risks of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome have been highlighted in a Serious Warnings and Precautions box along with a recommendation that patients should be monitored for 24 hours after the administration of the first full (48 mg) dose of Epkinly for signs and symptoms of these syndromes. The Epkinly Product Monograph also contains recommendations for premedication to reduce the risk of cytokine release syndrome and recommendations for prophylaxis against infections.

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

Epcoritamab, the medicinal ingredient in Epkinly, is a humanized immunoglobulin G1 (IgG1) bispecific antibody that binds to CD20 expressed on the surface of lymphoma cells and healthy B-lineage cells and to CD3 expressed on the surface of T cells. Simultaneous engagement of CD20-expressing cells and CD3-expressing endogenous T cells by epcoritamab induces specific T-cell activation and T cell-mediated killing of CD20-expressing cells.

The submitted non-clinical studies demonstrated the ability of epcoritamab to bind with high affinities to human CD20-expressing B cells and CD3-expressing T cells isolated from healthy human donors. In cynomolgus monkeys, the only pharmacologically relevant non-human species, epcoritamab was shown to induce B-cell depletion via T cell-mediated toxicity. In addition, epcoritamab exhibited antitumour activity in tumour models, when it was used as a single agent or in combination with other agents.

After a single subcutaneous administration of epcoritamab to cynomolgus monkeys, systemic exposure to epcoritamab increased in a greater than dose-proportional manner across the dose range of 0.1 mg/kg to 10 mg/kg, consistent with target-mediated drug disposition. The median time after dosing at which the maximum plasma concentration was observed (t_max) was approximately 72 hours in males and tended to be variable and up to 168 hours in females. The bioavailability of epcoritamab was 85% and 49% in males and females, respectively, after a single subcutaneous dose of 1 mg/kg.

Adverse clinical signs in cynomolgus monkeys administered epcoritamab intravenously or subcutaneously included vomiting, decreased activity, and hunched posture observed on Day 1, generally between 2 and 12 hours post dose, at doses greater than or equal to 0.1 mg/kg. Cytokine concentrations were markedly increased after the first dose. The increases in cytokine levels were less pronounced following subsequent doses. Decreased lymphoid cellularity was observed in the white pulp follicles of the spleen, lymph node follicles, and gut-associated lymphoid tissue at doses greater than or equal to 0.1 mg/kg. There was evidence of ongoing recovery of the histopathology findings after a 6-week post-dose observation period. One animal in the group administered epcoritamab at a dose of 1 mg/kg intravenously was euthanized prematurely at approximately 13 hours post dose due to poor general condition, which was considered associated with elevated cytokines. Based on these findings, the no-observed-adverse-effect level for epcoritamab administered intravenously was determined to be 0.1 mg/kg.

Reproductive and developmental toxicity studies were not conducted, partly due to the low epcoritamab concentrations resulting from neutralizing anti-epcoritamab antibodies developed upon repeated administration of epcoritamab. However, based on its mechanism of action, epcoritamab has the potential for embryo-fetal toxicity. Moreover, IgG1 antibodies, such as epcoritamab, can cross the placenta, resulting in fetal exposure. In addition, as IgG1 antibodies may be present in milk, a breastfed infant may be exposed to epcoritamab via lactational transfer. Accordingly, the sponsor has included this information in the Epkinly Product Monograph, along with recommendations for effective contraception in women of childbearing potential and discontinuation of breastfeeding during treatment with Epkinly and for at least four months after the last dose.

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

Characterization of the Drug Substance

Epcoritamab is a bispecific immunoglobulin G1 (IgG1) anti-CD20 and anti-CD3 antibody, derived from two parental monoclonal antibodies, a human anti-CD20 IgG1κ antibody and a humanized anti-CD3 IgG1λ antibody. It is composed of two heavy chains and two light chains. Epcoritamab carries inertness mutations to silence Fc-mediated effector functions. It has characteristics typical of a human IgG1antibody, including normal neonatal Fc receptor binding (FcRn) supporting in vivo stability.

Detailed characterization studies were performed to provide assurance that the biological intermediates (i.e., the parental IgG1 antibodies) and epcoritamab consistently exhibit the desired characteristic structures and biological activities.

The product- and process-related impurities that were reported and characterized were found to be within established limits.

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

Epcoritamab is manufactured from two biological intermediates (i.e., parental monoclonal antibodies), a human anti-CD20 IgG1κ antibody and a humanized anti-CD3 IgG1λ antibody which are produced separately in Chinese hamster ovary (CHO) cell lines using recombinant deoxyribonucleic acid (DNA) technology. Briefly, the manufacturing processes of the biological intermediates involve a series of cell culture expansion steps, followed by fed-batch cultivation in a production bioreactor and harvesting through depth filtration. The purification operations encompass chromatography, viral inactivation, and filtration steps. After final formulation and filtration steps, the purified biological intermediates are filled into bags and stored frozen at or below -60 °C.

The manufacture of epcoritamab drug substance includes thawing and pooling of the two biological intermediates, a reduction reaction to separate the antibodies into half-molecules, and a re-oxidation reaction to facilitate the antigen-binding fragments (Fab) exchange. Process-related impurities and residuals are removed through several ultrafiltration/diafiltration steps and a chromatography step. After formulation to adjust the final excipient composition and target protein concentration (60 mg/mL), the drug substance is filtered and stored frozen at or below -60 °C.

The drug product manufacturing process consists of drug substance thawing, pooling, mixing, sterile filtration, and aseptic filling into vials. The drug product is a sterile and preservative-free solution containing epcoritamab 5 mg/mL (4 mg/0.8 mL) or 60 mg/mL (48 mg/0.8 mL) in a single-dose vial. In the manufacturing process of epcoritamab 5 mg/mL drug product, a dilution step to achieve the final concentration of 5 mg/mL precedes the mixing step. The drug product is stored at 2 °C to 8 °C.

Acceptable ranges for critical process parameters and controls of critical steps of the manufacturing processes were appropriately established based on process characterization studies and risk assessments. Process validation was conducted with multiple consecutive batches of the biological intermediates, epcoritamab drug substance, and drug product. All process validation batches were manufactured at the intended commercial scales and manufacturing sites. The predetermined validation acceptance criteria were met for all tests and the process parameters remained within defined ranges, thereby demonstrating that the manufacturing processes are capable of consistently manufacturing the biological intermediates, epcoritamab drug substance, and drug product of acceptable quality.

Control of the Drug Substance and Drug Product

The release and stability specifications for the biological intermediates, drug substance, and drug product were established based on relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, historic manufacturing process knowledge, batch analyses data, and stability data.

The compendial test methods were qualified in accordance with applicable pharmacopeias by the applicable testing facility. In-house analytical methods were validated in accordance with relevant ICH guidelines.

A two-tiered reference material system comprising a primary reference standard and a working reference standard has been established for the biological intermediates and epcoritamab. The reference standards are well characterized and an appropriate program is in place to qualify future primary and working reference material.

Epkinly 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 stability data support the proposed shelf life of 30 months for the epcoritamab drug substance, when stored at or below -60 °C, and 24 months for the Epkinly drug product, when stored protected from light at 2 °C to 8 °C. In addition, data support the proposed in-use shelf life for diluted Epkinly of no more than 24 hours from the time of preparation, at 2 °C to 8 °C, and protected from light. Within these 24 hours, the solution may be stored for up to 12 hours at room temperature from the start of dose preparation to administration.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and extractables and leachables studies.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing sites are compliant with good manufacturing practices. On-site evaluations of the manufacturing sites of the biological intermediates, drug substance, and drug product were not deemed necessary.

Adventitious Agents Safety Evaluation

The manufacturing processes of the biological intermediates and epcoritamab incorporate adequate control measures to prevent contamination and maintain microbial control.

Master cell banks, working cell banks, end-of-production cell banks, and unprocessed bulk harvest undergo thorough testing for detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, endotoxins, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with a broad range of biochemical and biophysical properties.

No animal-derived and human-derived raw materials are used in the cell line development, cell bank preparation, and manufacture of the drug substance and drug product. In addition, the excipients used in the drug product formulation are not of animal or human origin.