Summary Basis of Decision for Kavigale

Clinical Pharmacology

Sipavibart, the medicinal ingredient in Kavigale, is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that provides passive immunization by binding the spike protein receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; BA.2). Sipavibart is a long-acting monoclonal antibody, with amino acid substitutions to extend antibody half-life and to reduce antibody effector function and the potential risk of antibody-dependent enhancement of disease. Through its binding to the RBD of SARS-CoV-2 (BA.2), sipavibart blocks the RBD from binding to the human angiotensin-converting enzyme 2 (ACE2) receptor. This results in a blockade of virus entry and effective neutralization of the SARS-CoV-2 virus.

In pharmacological studies, a higher bioavailability was seen with intramuscular injection in the anterolateral thigh when compared to gluteal administration, which led to its preferential recommendation for administration.

The general pharmacology and pharmacokinetics of sipavibart were well described in terms of maximum concentration (C_max), time to maximum concentration (T_max), area under the concentration-time curve (AUC), (absorption, distribution, metabolism, and elimination [ADME]), half-life (t_1/2), bioavailability (F), etc. This allowed for the development of a population pharmacokinetic (PK) model. The population PK model provided an adequate characterization of sipavibart and the ability to simulate expected serum exposure to sipavibart in adult participants. This model was validated through simulations and goodness of fit (GOF)/prediction-correct virtual predictive check (pcVPC) plots. The exposure-response analysis did not identify any clear and consistent serum sipavibart exposure-response relationship for efficacy. However, because of the limited number of events, a relatively narrow exposure range from the studied one dose level of 300 mg, and the availability of PK data for only a subset of the sipavibart arm in the pivotal SUPERNOVA study main cohort (discussed in the Clinical Efficacy section), the possibility of an undetected significant relationship could not be completely ruled out. No definite conclusion could be made on the exposure-efficacy relationship.

Anti-drug antibody effects on serum exposure were not well characterized due to the low event rate.

Since sipavibart is a monoclonal antibody, no drug-drug interactions are expected via cytochrome P450, other metabolizing enzymes, or transporters; therefore, no formal drug‑drug interaction studies have been performed.

Sipavibart PK profiles were assessed graphically for different immunocompromising conditions. These profiles appeared to be similar in participants in the SUPERNOVA main cohort with and without solid tumors, hematological malignancies, and B cell-depletion. No dosage adjustments are considered necessary for immunocompromised versus immunocompetent populations.

No PK data were available for adolescent participants. Simulations based on the population PK model were conducted to estimate the exposure in adolescents 12 to 17 years of age. The simulation showed that sipavibart exposure is comparable in adolescents and adults weighing at least 40 kg, albeit approximately 25% higher in adolescents.

Clinical data were only available for the dosing regimen of 300 mg every 6 months. Data from simulations were provided comparing the extent of exposure (AUC during a dosing interval [AUC_tau]) between a 300 mg every 6 months dose versus a dose of 300 mg every 3 months. The simulations performed for the 300 mg intramuscular or intravenous every 3 months regimen resulted in an AUC_tau that would be lower than that of the worst-case toxicology exposure (1,200 mg intravenous) assessed as part of a clinical study.

The clinical pharmacology data support the use of Kavigale for the recommended indication. For further details, please refer to the Product Monograph for Kavigale, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Efficacy

The clinical efficacy of Kavigale was primarily evaluated in the pivotal SUPERNOVA study. SUPERNOVA was a Phase III, randomized, double-blind, comparator-controlled clinical study that evaluated treatment with Kavigale for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in immunocompromised adults and adolescents 12 years of age and older. The efficacy analysis was based on 3,280 participants randomized 1:1 and treated with either Kavigale 300 mg (total number of patients [n] = 1,649) or the comparator (placebo or tixagevimab/cilgavimab; n = 1,631) every six months. The study excluded participants who had received a COVID-19 vaccine or who had a history of laboratory-confirmed or rapid-test confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 3 months prior to the first visit.

The baseline demographics were balanced across the Kavigale and comparator treatment arms. The median age was 60 years with 36.3% being 65 years of age or older. There were 15 participants who were between the ages of 12 to less than 18 years of age. Overall, 56.8% of participants were female, 43.2% were male, 74.1% were White, 6.5% were Asian, 12.1% were Black/African American, and 21.5% were Hispanic/Latino. All participants had at least one immunocompromising clinical condition.

The following dual primary efficacy endpoints compared the efficacy of Kavigale to tixagevimab/cilgavimab or placebo in the prevention of symptomatic COVID-19:

1. caused by the SARS-CoV-2 variants prevalent during the course of the study up to 181 days post last dose confirmed by reverse transcription polymerase chain reaction (RT-PCR), and

2. attributable to matched variants (variants that do not contain the F456L mutation based on viral sequencing data and are expected to be susceptible to sipavibart) up to 181 days post last dose confirmed by RT-PCR.

For each of the dual primary endpoints, a superiority test was performed to compare the relative risk of symptomatic COVID-19 between treatment arms. There was a relative risk reduction of 34.9% (97.5% Confidence Interval [CI]: 15.0, 50.1) within the treatment group (Kavigale) as compared to either tixagevimab/cilgavimab or placebo for symptomatic COVID-19 of susceptible variants (that were tested at the time of the study). The event rates were 122 (7.4%) for Kavigale, and 178 for the comparator (10.9%). Kavigale administration resulted in a 42.9% (95% CI 19.9, 59.3) relative risk reduction in the incidence of symptomatic COVID-19 attributed to matched variants vs comparator.

The variants evaluated prior to and during the conduct of the SUPERNOVA study using the in vitro pseudovirus neutralization assay were XBB.1.5, XBB.1.5.10 (XBB.1.5 + F456L), BA.2.86, JN.1, and JN.1.11.1/JN.1.16 (JN.1 + F456L). Kavigale does not retain in vitro neutralizing activity against Omicron variants containing the F456L mutation (such as KP.2 and KP.3). This information has been included in the Product Monograph for Kavigale.

Indication

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

Kavigale (sipavibart injection) is indicated for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents aged 12 years and older weighing at least 40 kg and:

• who are immunocompromised due to a medical condition or receipt of immunosuppressive medications or treatments, or

• for whom COVID-19 vaccination is not recommended.

For more information, refer to the Product Monograph for Kavigale, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

The clinical safety of Kavigale was evaluated in the pivotal SUPERNOVA study (described in the Clinical Efficacy section). In this study, the main cohort included 1,671 immunocompromised adult and adolescent participants 12 years of age and older and weighing at least 40 kg who were exposed to an initial dose of Kavigale 300 mg administered by intramuscular injection. The median duration of safety follow-up was 183.0 days for both Kavigale and comparator groups.

Approximately 50% of participants had at least one adverse event (AE) through Day 91 across all treatment groups, with the most common AEs being: COVID-19, cough, headache, and fatigue. Fewer AEs in the Kavigale group than the comparator group were considered by the investigator to be related to the treatment administered. Most AEs were mild to moderate in intensity and those that were Grade 3 or higher occurred at a similar frequency across the treatment groups. Immediate AEs reported within one hour of receiving the first dose of treatment were reported in similar proportions between the Kavigale (3.1%) and comparator (2.9%) groups.

Serious adverse events (SAEs) leading to death were reported by 20 (1.2%) and 13 (0.8%) participants in the Kavigale and comparator groups, respectively, through to the data cutoff. None of the deaths in the Kavigale group were considered related to treatment by the investigator. There was one death due to COVID-19, reported in the tixagevimab/cilgavimab (comparator) group. There was no pattern to the causes of death or to the timing of deaths in relation to administration of treatment.

Through Day 91, SAEs were reported by 7.2% and 7.3% of participants in the Kavigale and comparator groups, respectively. There were no adverse events of special interest of anaphylaxis/other serious hypersensitivity reaction in the Kavigale treatment group. The number of cardiovascular and thrombotic events was too small for a meaningful comparison. A thorough review did not suggest a causal association between these events and the administration of Kavigale. There were also no notable trends in hematology, clinical chemistry, urinalysis, or vital signs identified during the study.

Hypersensitivity reactions occurred within 14 days post dose. These reactions were mild to moderate in severity and most resolved within a few days. None of the hypersensitivity reactions were serious. Injection site reactions occurred within 7 days post dose, were mild in severity, and most resolved within a few days. Infusion site reactions occurred within 7 days post dose, were mild to moderate in severity, and resolved within a few days. Infusion-related reactions occurred during infusion or on the same day. These reactions were mild in severity, and resolved within a few days.

In the main cohort of the SUPERNOVA study, 886 participants received a second dose of 300 mg Kavigale 6 months after administration of the initial dose of 300 mg Kavigale. The overall safety profile for participants who received a second Kavigale dose remained similar compared to that following the initial dose.

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 participants who received Kavigale, 4.8% (29/604) were anti-drug antibody (ADA) positive at any time and 0.8% (5/604) were treatment-emergent ADA positive. The low rate of ADA‑positive participants does not allow for complete assessment of the impact of ADAs on the pharmacokinetics and safety of Kavigale.

Appropriate warnings and precautions are in place in the approved Product Monograph for Kavigale to address the identified safety concerns. For more information, refer to the Product Monograph for Kavigale, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

The non-clinical data package included the results of eleven pharmacology studies, one pharmacokinetic study, one repeat-dose toxicity study, and two tissue cross-reactivity studies.

The pharmacology data revealed that sipavibart binds to an epitope on the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2 spike protein with nanomolar affinity and is capable of sterically blocking RBD interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. Results from pharmacology studies indicated that hamsters administered sipavibart prior to challenge with the SARS-CoV-2 strain USA-WA1/2020 were protected from disease.

The fragment crystallizable (Fc) region of sipavibart has been engineered to include YTE and TM amino acid substitutions to extend antibody half-life and reduce Fc effector function, respectively. The YTE substitutions resulted in an expected increase in binding affinity to the neonatal Fc receptor (FcRn) at pH 6.0 and extended antibody half-life in transgenic mice expressing human FcRn. The TM substitutions resulted in an expected decrease in binding affinities to Fc gamma receptors and C1q complement. Sipavibart did not mediate antibody-dependent infection of cells and showed reduced or undetectable in vitro antibody-dependent effector functions. In addition, the substitutions did not alter the potency of sipavibart in vitro.

Sipavibart was found to have broad potency, with pseudovirus neutralization half maximal effective concentration (EC50) values ranging from 3.6 ng/mL (XBB.1 variant) to 25.0 ng/mL (BA.2.75 variant). However, a non-good laboratory practice (GLP) study to elucidate sipavibart resistant variants revealed three escape mutations within the RBD: T415I, K458E, and F456L. The SARS-CoV-2 Omicron sub-variants KP.2, KP.3, and LB.1 contain the F456L mutation which may affect the neutralization potential of sipavibart against these variants. The other mutations identified (T415I and K458E) have not emerged thus far in the evolutionary progression of the virus, however, if these mutations do arise in future circulating viral variants, sipavibart will likely be ineffective against variants with these mutations.

The pharmacokinetics (PK) of sipavibart was evaluated in Tg32 mice that express humanized neonatal Fc receptor (huFcRn) in place of the mouse FcRn. The animals received a single dose of 5 mg/kg by intravenous (IV) administration with blood samples taken up to 35 days post-dose. A maximum concentration (C_max) of 127 mcg/mL was observed at 0.0417 days after dosing and the area under the concentration-time curve from zero to the last quantifiable time-point (AUC_0-t) was approximately 1,130 mcg·day/mL. Serum concentrations declined in a multi-phasic fashion, with concentrations measurable through to the final sampling point at 35 days post dose for all treatments. The half-life (t_1/2) was estimated as 20.6 days following administration of sipavibart. The PK of sipavibart was similar to the control antibodies and similar to what has been observed with cilgavimab from a previous study. Similar PK was observed for sipavibart in the cynomolgus monkeys following intramuscular (IM) or IV infusion of 150 mg/kg of each monoclonal antibody from the GLP toxicology study.

The administration of AZD5156 (a 1:1 combination of sipavibart and cilgavimab) was not associated with any adverse local or systemic findings in a GLP repeat dose toxicity study in cynomolgus monkeys. The no-observed-adverse-effect level (NOAEL) was considered to be 300 mg/kg of AZD5156 (which included 150 mg/kg of sipavibart) for both IM and IV routes of administration. The data revealed a lack of adverse findings associated with the component monoclonal antibodies, sipavibart and cilgavimab. Further, sipavibart did not stain any adult or fetal human tissues in two separate GLP tissue cross reactivity studies. Based on the observed C_max in monkeys at Day 15, following the third IM dose (4,470 mcg/mL ± 974 mcg/mL), the NOAEL was approximately 180-fold above the predicted human C_max, and following the third IV dose (6,390 mcg/mL ± 608 mcg/mL), the NOAEL was approximately 20-fold above the predicted human C_max.

No developmental and reproductive toxicology (DART) study was conducted in line with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S6 (R1); however, given the nonhuman primates used in the repeat-dose toxicity study were considered juvenile with immature reproductive systems, no definitive conclusions regarding effects on reproductive organs and fertility-related endpoints could be drawn from the results of the repeat-dose toxicology study. Additionally, no conclusions on the potential impacts on lactation or the developing embryo/fetus could be drawn in the absence of a DART study. Nevertheless, no abnormal histopathological findings of the testis and epididymis in immature males, nor of the uterus, ovaries, and vagina in immature females, were observed in the repeat-dose toxicity study.

Overall, the non-clinical pharmacologic data support proof-of-concept that sipavibart is expected to demonstrate a favourable antibody profile against a broad range of SARS-CoV-2 variants and is anticipated to pose little risk for antibody-dependent enhancement of disease. Sipavibart was also shown to protect hamsters from SARS-CoV-2 disease in a prophylactic setting. The non-clinical program conducted for sipavibart is aligned with recommendations in regulatory guidance for monoclonal antibodies directed against foreign/viral targets. Based on the reduction in susceptibility to sipavibart of SARS-CoV-2 variants that harbour the F456L mutation, there is concern that Kavigale will be ineffectual against currently circulating strains such as KP.2 and KP.3. The non-clinical safety program was designed in line with the nature of the product that targets a foreign target that is not endogenously expressed. The non-clinical safety profile is considered favorable to support the proposed clinical use. The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Kavigale. In view of the intended use of Kavigale, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Product Monograph for Kavigale to address the identified safety concerns.

For more information, refer to the Product Monograph for Kavigale, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Characterization of the Drug Substance

Sipavibart is a human immunoglobulin G1 (IgG1) monoclonal antibody expressed in Chinese hamster ovary (CHO) cells. The CH2 domain of the heavy chain contains amino acid substitutions that reduce fragment crystallizable (Fc)-mediated effector functions and enhance affinity to neonatal Fc receptor. Sipavibart targets the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain, preventing binding of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2) and subsequent viral infection.

Detailed characterization studies were performed to provide assurance that sipavibart 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.

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

Drug Substance

The sipavibart drug substance is manufactured in CHO cells. The manufacturing of sipavibart consists of an upstream process of cell expansion to a fed-batch production bioreactor, followed by a downstream process for purification through a series of chromatography steps, viral inactivation and removal, and final filtration ahead of filling into polycarbonate storage containers.

Controls of critical steps of the drug substance manufacturing process were established during manufacturing development, based on a risk assessment and the results of process characterization. Process validation was conducted on multiple lots of drug substance manufactured at the commercial scale. The results of the process validation study demonstrate the manufacturing process is capable of consistently manufacturing drug substance with the desired product quality.

The drug substance and drug product specifications were set based on International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q6B, regulatory requirements, clinical experience, the manufacturing process capability, as well as release and stability data from clinical and commercial lots. The in-house analytical methods were validated according to ICH Q2 (R1) and compendial methods complied with pharmacopeial standards. All drug substance batches met the release and stability acceptance criteria through the proposed shelf life.

Drug Product

The Kavigale drug product (150 mg/mL) is a sterile, single-dose, preservative-free, solution for intramuscular injection or intravenous infusion and is provided as 300 mg/2 mL, filled in a Type I glass vial. The manufacturing process consists of thawing and mixing of the drug substance, bioburden reduction and sterile filtration, followed by filling and stoppering before labeling and packaging.

Controls of critical steps of the drug product manufacturing process were established during manufacturing development, based on a risk assessment, and the results of process characterization. Process validation included three consecutive batches and bracketed the proposed minimum and maximum manufacturing scale. The results of the process validation study demonstrate the manufacturing process is capable of consistently manufacturing drug product with the desired product quality.

All drug product batches met the release and stability acceptance criteria through the proposed shelf-life.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. 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 manufacturing process is 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 the sipavibart with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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.

Each lot of Kavigale drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

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 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.)

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Kavigale is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2 °C to 8 °C for Kavigale is considered acceptable.

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.

An on-site evaluation of the facility involved in the manufacture and testing of the drug substance (sipavibart) was not recommended as a virtual assessment of the facility was performed by Health Canada in 2021 and no observations were noted.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

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

Adventitious Agents Safety Evaluation

Adventitious agents are controlled through the control of raw materials, facilities and manufacturing processes, viral testing of the cell banks and the unprocessed bulk, and demonstrated viral clearance capacity during the purification process.

The excipients used in the drug product formulation are not of animal or human origin. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. Certification letters attesting to these claims were provided by the sponsor.