Summary Basis of Decision for Zynlonta

Clinical Pharmacology

Loncastuximab tesirine , the medicinal ingredient in Zynlonta, is an antibody-drug conjugate. It consists of a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody specific for human cluster of differentiation 19 (CD19), attached to the cytotoxic drug SG3199 (a pyrrolobenzodiazepine dimer) through a protease-cleavable linker. Upon binding to CD19 (which is expressed on the surface of B-lineage cells), loncastuximab tesirine is internalized and SG3199 is released via proteolytic cleavage. The released SG3199 binds to the deoxyribonucleic acid (DNA) minor groove and forms highly cytotoxic DNA interstrand cross-links, subsequently inducing cell death.

The clinical pharmacology of loncastuximab tesirine in adult patients with relapsed or refractory B-cell lymphoma was evaluated in the Phase II Study ADCT-402-201 and Phase I Study ADCT-402-101. A population pharmacokinetic analysis was conducted using data pooled from the two studies. In addition, in vitro studies of the free cytotoxic agent SG3199 evaluated its metabolism and its potential for drug-drug interactions (as a substrate or as an inhibitor of various human transporter proteins).

In general, the pharmacokinetics of loncastuximab tesirine was adequately described in Study ADCT-402-201, Study ADCT-402-101, and the population pharmacokinetic analysis. Serum concentrations of the payload SG3199 were only detectable (with the current analytical method) in some samples at the highest loncastuximab tesirine doses investigated. Hence, a complete description of the pharmacokinetics of SG3199 was not possible at this time. This uncertainty is not considered an issue in the context of the mechanism of action of loncastuximab tesirine (i.e., targeted delivery of SG3199 into CD19-expressing cells).

Based on the in vitro pharmacokinetic and drug interaction studies reviewed, no clinically important drug-drug interactions are expected for loncastuximab tesirine.

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). In the clinical studies, loncastuximab tesirine exhibited low immunogenicity. Anti‐loncastuximab tesirine antibodies were detected in 1 of 145 patients after treatment with Zynlonta in Study ADCT-402-201. Due to the low immunogenicity, the impact of ADAs on the pharmacokinetics, efficacy, and safety of Zynlonta is unclear. This uncertainty, however, does not affect the overall benefit-risk assessment of the drug.

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

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

Clinical Efficacy

The efficacy of Zynlonta monotherapy was primarily evaluated in an open-label, single-arm, multicentre, Phase II study (ADCT-402-201) in 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma after at least two prior lines of systemic therapy.

Eligible patients had measurable disease as defined by the Lugano 2014 classification criteria (the Lugano classification for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma), adequate organ function, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at baseline. The patients’ median age was 66 years (range: 23 to 94 years), and 14% of patients were 75 years of age and older. Eighty-five patients (58.6%) were male. Most patients were White (130 patients; 89.7%). The median body mass index was 25.97 kg/m² (range: 17.2 to 50.5 kg/m²). Ninety-four percent of patients had an ECOG performance status of 0 to 1.

Eighty-eight percent of patients had a diagnosis of diffuse large B-cell lymphoma not otherwise specified (including 20% with diffuse large B-cell lymphoma arising from low-grade lymphoma) and 7% of patients had high-grade B-cell lymphoma (with MYC and BCL2 and/or BCL6 rearrangements).

In the study population, the median number of prior lines of systemic therapies was three (range: two to seven); 43% of patients received two prior lines of therapy, 23% received three prior lines of therapy, and 33% received more than three prior lines of therapy. Twenty percent of patients had primary refractory disease (defined as no response to initial therapy), 17% received prior stem cell transplant, and 10% received prior chimeric antigen receptor (CAR) T-cell therapy.

All patients received Zynlonta 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles for up to 1 year or until disease relapse or progression, unacceptable toxicity, or other discontinuation criteria. For patients with a body mass index greater than or equal to 35 kg/m², the dose of Zynlonta was calculated based on the adjusted body weight. This adjusted dosing was implemented due to concerns about increased exposure to Zynlonta and the potential for increased toxicities if dosing were based on the actual body weight. The dosing regimen of Zynlonta used in Study ADCT-402-201 is consistent with the recommended dosing regimen for the intended patient population.

The primary efficacy endpoint was overall response rate, defined as the proportion of patients who achieved either a complete response or a partial response as best overall response assessed by an independent central review according to the 2014 Lugano classification criteria. An overall response rate of 48.3% (95% confidence interval [CI]: 39.9%, 56.7%) was reported in the study population. A complete response was achieved in 24.8% of patients. After a median follow-up time of 7.8 months (range: 0.3 to 42.6 months), the median duration of response was 13.4 months in all responders. Among patients who achieved a complete response, the median duration of response was not estimable and the probability of maintaining response at 9 months was 64.4%. In patients who had previously received CAR T-cell therapy, the overall response rate was 42.9% and the complete response rate was 21.4%.

The submitted efficacy results are considered promising for the intended patient population. To confirm the clinical benefit of Zynlonta, the sponsor will provide the results from an ongoing Phase III clinical study evaluating loncastuximab tesirine in combination with rituximab versus a control immunochemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation (Study ADCT-402-311).

Indication

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

Zynlonta (loncastuximab tesirine for injection) as monotherapy is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma arising from low-grade lymphoma, and high-grade B-cell lymphoma, who have received two or more lines of systemic therapy and cannot receive chimeric antigen receptor (CAR) T-cell therapy or have previously received CAR T-cell therapy.

Upon revisions to reflect solely the lymphoma entities in the pivotal study, Health Canada approved the following indication:

Zynlonta (loncastuximab tesirine) as monotherapy 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 arising from low-grade lymphoma, or high-grade B-cell lymphoma, who have received two or more lines of systemic therapy and have previously received or are unable to receive chimeric antigen receptor T-cell therapy.

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

Clinical Safety

The safety of Zynlonta monotherapy in adult patients with relapsed or refractory diffuse large B-cell lymphoma after at least two prior lines of systemic therapy was primarily evaluated in Study ADCT-402-201 (described in the Clinical Efficacy section). Among the 145 patients who received Zynlonta, the median duration of treatment was 45 days (range: 1 to 569 days) and the median number of treatment cycles was 3 (range: 1 to 26 cycles); 34% of patients received five or more treatment cycles.

The most frequently reported adverse reactions associated with Zynlonta (occurring in at least 20% of patients) were increased gamma-glutamyl transferase (GGT) (42.1%), neutropenia (40%), thrombocytopenia (33.1%), fatigue (27.6%), anemia (26.2%), nausea (23.4%), cough (22.8%), increased blood alkaline phosphatase (20%) and peripheral edema (20%).

The most frequent serious adverse reactions (occurring in at least 2% of patients) were febrile neutropenia (3.4%), pyrexia (2.8%), abdominal pain (2.1%), and pleural effusion (2.1%). Treatment-emergent events of fatal infections occurred in 2.1% of patients.

Dose delays due to adverse reactions occurred in 51% of patients. The most frequent adverse reactions leading to dose delay (occurring in at least 5% of patients) were increased GGT (21.4%), neutropenia (12.4%), and thrombocytopenia (9%). Dose reductions due to adverse reactions occurred in 6.9% of patients. The adverse reaction leading to dose reductions reported in two or more patients was increased GGT (3.4%). Permanent treatment discontinuation due to adverse reactions occurred in 24.8% of patients. The most frequent adverse reactions leading to treatment discontinuation (occurring in at least 2% of patients) were increased GGT (12.4%), peripheral edema (2.8%), localized edema (2.1%), and pleural effusion (2.1%).

Appropriate warnings and precautions are included in the Zynlonta Product Monograph to address the identified safety concerns.

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

Loncastuximab tesirine, the medicinal ingredient in Zynlonta, is an antibody-drug conjugate. The antibody component is a humanized immunoglobin G1 kappa (IgG1κ) monoclonal antibody specific for human cluster of differentiation 19 (CD19), a transmembrane protein expressed on the surface of cells of B-lineage origin. The cytotoxic drug, pyrrolobenzodiazepine dimer SG3199, is linked to the antibody through a protease-cleavable linker. After intravenous administration, loncastuximab tesirine binds to CD19 and undergoes receptor-mediated internalization, followed by lysosomal degradation which results in the intracellular release of SG3199. The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand cross-links, subsequently causing cell death.

The submitted non-clinical pharmacology data, including in vitro studies using CD19-expressing human cell lines and in vivo tumour models, support the mechanism of action of loncastuximab tesirine.

In the non-clinical toxicology studies, loncastuximab tesirine showed phototoxic potential and caused inflammatory toxicities in the lungs and kidneys.

Reproductive and developmental toxicology studies were not conducted with loncastuximab tesirine, which is in line with relevant guidelines for anticancer agents. The SG3199 component of loncastuximab tesirine exhibited genotoxicity through a clastogenic mechanism in both an in vitro micronucleus test and a chromosome aberration assay using human lymphocytes. These results are consistent with the pharmacological effect of SG3199 as a covalent DNA cross-linking agent, and suggest that loncastuximab tesirine has the potential to cause embryo-fetal toxicity and teratogenicity. Furthermore, repeated intravenous administration of loncastuximab tesirine in cynomolgus monkeys resulted in adverse findings that included decreased weight and/or size of the testes and epididymis, atrophy of the seminiferous tubules, germ cell degeneration, and/or reduced epididymal sperm content, indicating the potential for impaired male reproductive function and fertility.

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

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

Characterization of the Drug Substance

The drug substance, loncastuximab tesirine, is an antibody-drug conjugate. It consists of loncastuximab, a humanized immunoglobin G1 kappa (IgG1κ) monoclonal antibody specific for human cluster of differentiation 19 (CD19), conjugated via a protease-cleavable valine-alanine linker to a pyrrolobenzodiazepine dimer SG3199, which is a cytotoxic agent. The cytotoxic agent SG3199 attached to the linker is designated as SG3249 drug linker or tesirine. An average of 2.3 molecules of SG3249 are attached to each antibody molecule.

Detailed characterization studies were performed to provide assurance that the drug substance 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 presence of nitrosamine impurities was conducted according to the requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risk of the formation or introduction of nitrosamines during the monoclonal antibody intermediate, drug-linker intermediate, drug substance, and drug product manufacturing processes is considered negligible or low; therefore, no confirmatory testing is required.

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

Loncastuximab tesirine is produced by chemical conjugation of the monoclonal antibody intermediate loncastuximab to the drug-linker intermediate SG3249 (tesirine).

Loncastuximab is manufactured using a genetically engineered Chinese hamster ovary (CHO) cell line and standard monoclonal antibody production methods. Cells from a working cell bank are thawed and progressively expanded prior to the inoculation of a production bioreactor. After the production bioreactor culture is harvested, loncastuximab is purified by chromatography, viral removal, and viral inactivation. The purified loncastuximab is further concentrated and formulated by ultrafiltration/diafiltration. Subsequently, the formulated loncastuximab is filtered, filled into bottles, and stored frozen at or below -60 °C.

The drug-linker intermediate tesirine is manufactured by chemical synthesis.

Manufacturing of loncastuximab tesirine begins with thawing of the intermediates. Batches of loncastuximab undergo pooling, mixing, and pH adjustment, before the addition of a reducing agent to initiate reduction of the monoclonal antibody. The reduced loncastuximab is then subjected to a conjugation reaction with tesirine. The resulting conjugate is concentrated, formulated, filtered, filled into bottles, and stored frozen at or below -60 °C.

The drug product manufacturing process begins with thawing, pooling, and mixing of the drug substance. This is followed by bioburden reduction filtration, sterile filtration, and aseptic filling into vials, which are partially stoppered before lyophilization. After the lyophilization step, the vials are fully stoppered, crimped, and visually inspected before being stored at 2 °C to 8 °C. None of the non-medicinal ingredients (excipients) in Zynlonta are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of loncastuximab tesirine with the excipients is supported by the stability data provided.

Process validation studies were conducted by manufacturing consecutive batches of the monoclonal antibody intermediate, the drug substance, and the 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 for all validation batches. Non-conformances and deviations that occurred during process validation were investigated and determined to have no impact on the validation. All ancillary validation studies were deemed successful and supportive of in-process hold times, impurity clearance, resin and membrane reuse, extractables and leachables testing, filters, reprocessing, media fills, and shipping. Overall, the process validation data demonstrate that the established manufacturing processes can consistently produce monoclonal antibody intermediate batches, drug substance batches, and drug product batches that meet the predefined specifications for the desired quality attributes. A continuous process verification program has been implemented to ensure all commercial manufacturing processes remain within their validated states.

Control of the Drug Substance and Drug Product

The established release and stability specifications for the intermediates, Zynlonta drug substance, and Zynlonta drug product are considered appropriate and in accordance with relevant guidelines.

Analytical procedures used in the release and stability testing of the intermediates, drug substance, and drug product were adequately validated as per relevant guidelines. Compendial methods were satisfactorily verified under conditions of use.

The reference standards have been well characterized and appropriate programs are in place to qualify new primary and working reference material in the future.

Zynlonta 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 intermediates, Zynlonta drug substance, and Zynlonta drug product were adequately supported and are considered to be satisfactory.

The shelf life of 48 months at 2 °C to 8 °C for the Zynlonta drug product, when protected from light, is considered acceptable.

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

Facilities and Equipment

Based on a risk assessment performed by Health Canada, on-site evaluations of the manufacturing sites for the monoclonal antibody intermediate, drug-linker intermediate, Zynlonta drug substance, and Zynlonta drug product were not deemed necessary.

Overall, 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.

Adventitious Agents Safety Evaluation

The monoclonal antibody intermediate and drug substance manufacturing processes incorporate adequate control measures to ensure freedom from adventitious microorganisms (bacteria, fungi, mycoplasma, and viruses). Purification process steps designed to remove and inactivate any potential viral contaminants from the cell culture process are adequately validated.

Materials of biological origin are properly sourced and tested. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

No excipients of human or animal origin are used in the formulation of Zynlonta.