Summary Basis of Decision for Covifenz

The New Drug Submission for Covifenz (virus‑like particles [VLPs] of severe acute respiratory syndrome coronavirus 2 [SARS‑CoV‑2] spike protein) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Covifenz, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the product.

Clinical Pharmacology

Covifenz is an adjuvanted vaccine composed of plant‑based VLPs that closely mimic native SARS‑CoV‑2 and activate local innate immune responses. The vaccine then elicits both neutralizing antibody and cellular immune responses to the spike antigen, which may contribute to protection against coronavirus disease 2019 (COVID‑19).

Pharmacokinetic studies to demonstrate absorption, distribution, metabolism, and excretion of coronavirus‑like particles (CoVLPs) were not conducted and are typically not required for vaccines.

The pharmacodynamics of CoVLPs in Studies 019 and 021 (both ongoing, described in the Clinical Efficacy section) is being assessed through evaluations of both humoral and cell‑mediated immunity induced in CoVLP‑immunized subjects.

For further details, please refer to the Covifenz Product Monograph, 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 Covifenz was evaluated in Study 021, a randomized, placebo‑controlled Phase II/III study in participants 18 years of age and older. The primary efficacy data were obtained in Phase III, while immunogenicity data were collected in Phase II, and are being collected in Phase III at the time of authorization. Data from a Phase I dose‑finding study, Study 019, were also submitted to support the dosing regimen used in Study 021 (two doses of 3.75 mcg VLPs adjuvanted with adjuvant system 03 [AS03], administered 21 days apart).

Phase III of Study 021 was designed to evaluate the efficacy, immunogenicity, and safety of Covifenz relative to placebo in participants 18 years of age and older. This phase of the study was event‑driven and observer‑blinded, with participants randomized in a 1:1 ratio to receive either Covifenz or placebo. Demographic and baseline characteristics were balanced between the two treatment groups. The date of the first participant visit was March 15, 2021. At the time of authorization, this study was ongoing.

Participants with pre‑existing stable chronic disease (including but not limited to obesity, documented hypertension, and diabetes) were included in the study. Stable chronic disease was defined as no new onset or exacerbation of pre‑existing chronic disease three months prior to vaccination. Individuals who had a previous laboratory‑confirmed diagnosis of COVID‑19 were excluded from the study.

As of the efficacy data cut‑off date of August 20, 2021, 24,141 participants were randomized to receive two doses of either Covifenz (12,074 participants) or placebo (12,067 participants), separated by 21 days (19‑23 days, as per study protocol). At this time point, 24,076 participants (99.7%) had received at least one dose of either Covifenz or placebo. Premature discontinuations occurred in both groups, including 1,508 of the 12,074 participants who received Covifenz (12.5%) and 4,567 of the 12,067 participants who received the placebo (37.9%).

After receiving the second dose, 9,599 participants who received Covifenz (79.8%) and 6,963 participants who received the placebo (57.8%) had received follow‑up for at least two months. The median follow‑up time after the second dose was 3.1 months (range: 0 to 6.8 months) for participants who received Covifenz and 2.5 months (range: 0 to 6.8 months) for participants who received the placebo. Participants will continue to be followed up for 12 months after the second dose to evaluate safety and the persistency of the immune response.

The primary endpoint was the first occurrence of laboratory‑confirmed (by reverse transcription polymerase chain reaction [RT‑PCR]) symptomatic SARS‑CoV‑2 infection (detected 7 days or longer after the second vaccination) at the time of the primary vaccine efficacy analysis. In the per‑protocol population of 20,090 participants, 157 participants had laboratory‑confirmed SARS‑CoV‑2 infection detected 7 days or longer after the second dose. Thirty‑nine cases were confirmed in participants who received Covifenz, and 118 cases were confirmed in participants who received the placebo. Based on these data, the success criteria for vaccine efficacy were met, as the estimate for vaccine efficacy was 71.0% (95% confidence interval [CI]: 58.7, 80.0).

Two participants, both of whom received the placebo, had severe COVID‑19 detected 7 days or longer after the second dose. In healthy adults 65 years of age and older (127 participants), only two cases of COVID‑19 were identified 7 days or longer after the second dose, with one case in each treatment group.

As of December 3, 2021, SARS‑CoV‑2 genome sequencing was completed for 114 of the 157 cases of COVID‑19 (72.6%) detected in the per‑protocol population. Sequencing could not be completed for 21 of the 157 cases (13.4%). In participants who received Covifenz, 11 cases of SARS‑CoV‑2 infection were caused by the Delta variant and 6 cases were caused by the Gamma variant. In participants who received the placebo, 5 cases of COVID‑19 were caused by the Alpha variant, 39 cases were caused by the Delta variant, 46 cases were caused by the Gamma variant, 3 cases were caused by the Lambda variant, and 4 cases were caused by the Mu variant. None of the detected cases of COVID‑19 for which sequencing was completed were caused by the original SARS‑CoV‑2 strain.

At the time of authorization of Covifenz, the Omicron variant was of interest due to its increasing prevalence worldwide. An additional live virus neutralization assay was conducted in participants who received two 3.75 mcg doses of Covifenz to evaluate cross reactivity of neutralizing antibodies against the original SARS‑CoV‑2 strain with the Alpha, Beta, Gamma, Delta, and Omicron variants. The neutralizing antibody geometric mean titers (GMTs) against the various strains were obtained at 21 days and 6 months after the second dose. Limited data showed that the neutralizing antibody GMTs against the Omicron variant at 21 days and 6 months after the second dose were 47‑fold and 12‑fold lower, respectively, than the neutralizing antibody GMTs against the original SARS‑CoV‑2 strain. The exact impact of the lower levels of neutralizing antibodies on vaccine efficacy against the Omicron variant remains unknown. More data are required to assess the efficacy of the vaccine against the Omicron variant.

Immunogenicity

Phase II of Study 021 examined the immunogenicity and safety of Covifenz (3.75 mcg VLPs adjuvanted with AS03) relative to placebo in participants 18 years of age and older. Participants were randomized in a 5:1 ratio to receive either Covifenz or placebo as two intramuscular injections, 21 days apart.

Immunogenicity was assessed through the analysis of GMTs of neutralizing antibodies. Study participants were grouped into three populations:

• Population 1, consisting of 259 healthy adults 18 to 64 years of age,
• Population 2, consisting of 235 healthy adults 65 years of age and older, and
• Population 3, consisting of 138 adults with significant comorbidities 18 years of age and older.

For Covifenz recipients, the baseline levels of GMTs of neutralizing antibodies in Populations 1, 2, and 3 were 5.3, 5.2, and 8.9, respectively. Three weeks after the first dose, GMTs were calculated as 44.3, 29.7, and 49.1. These increased further to 2,033.6, 1,917.7, and 1,962.0 three weeks after the second dose. The seroconversion rates (i.e., the proportions of participants experiencing a rise of 4‑fold or greater in neutralizing antibody titers) in Populations 1, 2, and 3 were 99.2%, 97.7%, and 95.8%, respectively, three weeks after the second dose. Covifenz induced a type 1 cell‑mediated immune response after the first vaccination, which increased three weeks after the second vaccination. A similar type 2 cell‑mediated immune response was observed after the second vaccination, demonstrating that Covifenz induced a balanced cell‑mediated immune response.

Indication

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

• Covifenz is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) cause by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), for individuals 18 years and older.

Although the proposed indication was for individuals 18 years of age and older, the available data in individuals 65 years of age and older are not sufficient to demonstrate the efficacy and safety of Covifenz in this population. Accordingly, Health Canada approved the following indication:

• Covifenz is indicated for active immunization to prevent coronavirus disease 2019 (COVID‑19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in individuals 18 to 64 years of age.

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

Clinical Safety

Evidence of the clinical safety of Covifenz was mainly provided by data from the Phase III portion of Study 021, which is described in the Clinical Efficacy section. As of the safety data cut‑off date of October 25, 2021, the safety analysis set included 24,076 participants who had received at least one injection of either Covifenz (12,036 participants) or the placebo (12,040 participants). A second dose had been administered to 22,087 (91.7%) participants.

Solicited local and systemic adverse reactions were more frequently reported in participants who received Covifenz than in those who received the placebo. In adults 18 to 64 years of age, the most frequently reported solicited local and systemic adverse reactions after receiving the first and/or second dose of Covifenz were pain at the injection site (92.5%), headache (68.5%), muscle aches (67.8%), fatigue (64.7%), feeling of general discomfort (63.8%), chills (46.7%), joint aches (40.0%), swelling at the injection site (38.0%), swelling in the neck (22.2%), erythema at the injection site (20.1%), swelling in the axilla (15.1%) and fever (9.7%). The adverse reactions were usually mild or moderate in intensity and resolved within 1 to 3 days. Solicited local and systemic adverse reactions of Grade 2 or higher intensity were more frequently reported after the second dose than after the first dose. Less than 1.6% of solicited adverse reactions were of Grade 3 or higher intensity.

In the safety analysis set, the 11,933 participants who received Covifenz and the 11,924 participants who received the placebo were between 18 and 64 years old. Unsolicited adverse events (both non‑serious and serious) were reported in 3,140 Covifenz recipients (26.3%) and 2,759 placebo recipients (23.1%). Serious adverse events were reported in 47 participants (0.4%) who received Covifenz and 38 participants (0.3%) who received the placebo. There were no notable patterns or significant numerical imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to Covifenz. Medically attended adverse events were reported in 5.8% of participants who received Covifenz and 5.6% of participants who received the placebo. Adverse events leading to study withdrawal were reported in five participants (<0.1%) who received Covifenz and 13 participants (0.1%) who received the placebo. No deaths or serious adverse events related to Covifenz were reported.

Potential immune‑mediated diseases (pIMDs) were reported in 21 participants (<0.1%) who received Covifenz and 10 participants who received the placebo (<0.1%). The pIMDs that were reported only in participants who received Covifenz included pharyngeal swelling (5 cases), psoriasis (3 cases), arrhythmia (1 case), and deep vein thrombosis (1 case). Bell’s palsy/facial paralysis was reported in three participants who received Covifenz and one participant who received the placebo. One case of myocarditis was reported in each treatment group. The case of myocarditis in the Covifenz treatment group was in a participant who tested positive for COVID‑19. No cases of anaphylaxis were reported. The information available at the time of authorization was not sufficient to determine whether a causal relationship exists between pIMDs and the Covifenz vaccine.

The efficacy and safety data available in participants 65 years of age and older are limited. The efficacy analysis was based on 20,090 participants in total, 188 of whom were 65 years of age and older. The safety analysis was based on 24,076 participants 18 years of age and older, 219 of whom were 65 years of age and older. As the data were not sufficient to support an indication for individuals in this age group, Health Canada approved Covifenz for individuals 18 to 64 years of age.

Risk Management Plan

A Core Risk Management Plan (RMP) and a Canadian RMP Addendum for Covifenz were submitted by Medicago Inc. to Health Canada as part of the submission for authorization. The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The following information relates to the RMP submitted by Medicago Inc. as part of the New Drug Submission for Covifenz. It is the sponsor’s responsibility to monitor the safety profile of this vaccine and to submit an update to the RMP if there is a significant change to the benefits, harms or uncertainties associated with this vaccine. Updates to the RMP will be reflected in the Post‑Authorization Activity Table for Covifenz.

Based on results from non‑clinical and clinical studies, the RMP included no important identified risks and three important potential risks: anaphylaxis and severe allergic reactions; vaccine‑associated enhanced disease, including vaccine‑associated enhanced respiratory disease; and pIMDs. There were seven areas of missing (limited/no clinical data) information identified: "use in pregnant and breastfeeding women", "use in pediatric population", "use in immunocompromised subjects", "use in patients with autoimmune or inflammatory disorders", "use in frail subjects with unstable health conditions and comorbidities", "interaction with other vaccines", and "long‑term safety". The proposed routine and additional pharmacovigilance activities for the above risks are considered to be acceptable and the sponsor confirmed that they would be applied in the Canadian context. Additional pharmacovigilance activities include continued safety surveillance of ongoing clinical trials as well as three planned post‑authorization studies: two studies to assess the safety of Covifenz using electronic health record databases, and one pregnancy exposure registry. Routine risk minimization measures (i.e., Product Monograph and labelling) are also considered to be appropriate.

Based on Health Canada’s review of the RMP, it was recommended to add “long‑term effectiveness” as missing (limited/no clinical data) information. The sponsor is expected to provide an updated Core RMP and Canadian Addendum in a timely manner if a signal of safety issue is identified in ongoing post‑authorization surveillance.

In addition, the sponsor will provide the following information in the post‑market period:

• Older adults: Older adults were included in the clinical development program. The sponsor will submit monthly safety reports to Health Canada, which will include analyses of subpopulations by age and gender.
• Children: Children were not included in the clinical development program. This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. Studies of Covifenz in children are planned.
• Pregnant women: More information is needed about the use of the vaccine in pregnant women. This subpopulation was identified as missing information in the RMP. The sponsor will monitor and submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
• Breastfeeding women: This subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada. The sponsor will assess outcomes in pregnancy and lactation as part of ongoing and planned studies, including a pregnancy exposure registry.
• Immunocompromised individuals and patients with chronic or debilitating conditions: These individuals were not included in the clinical development program. The subpopulation was identified as missing information in the RMP. The sponsor will submit monthly safety reports to Health Canada.
• Anaphylaxis: The risk of anaphylaxis was identified as an important potential risk in the RMP. This risk will be assessed via routine pharmacovigilance activities, and reported in monthly safety reports.
• Indigenous population in Canada: Adverse drug reactions (ADRs) from all subpopulations, including Indigenous, will be reported as expeditiously as applicable, and will be assessed in the monthly safety reports.

The sponsor is required to promptly report adverse reactions and provide Monthly Safety Summary Reports. These reports will be reflected in the Post‑Authorization Activity Table for Covifenz.

Results related to safety and effectiveness from ongoing and planned studies will be submitted for review as they become available and will include information related to special populations, for example, pregnant women. Together, the results from these studies and the monthly safety summary reports are expected to address data gaps related to the long‑term safety and effectiveness of the vaccine, interactions with other vaccines, and specific subpopulations (e.g., pregnant and breastfeeding women, pediatric populations younger than 18 years of age, patients with autoimmune or inflammatory disorders, immunocompromised patients and frail patients with comorbidities).

Collectively, the results of the clinical safety evaluation demonstrated that the Covifenz vaccine met the vaccine safety requirements as specified in Health Canada's Guidance for Market Authorization Requirements for COVID‑19 Vaccines. The vaccine was determined to be safe and well tolerated in participants 18 to 64 years of age when administered according to the recommended dosage regimen. The Phase III portion of Study 021 is ongoing. A follow‑up period of up to 12 months is planned for all participants in this study, for continued assessments of safety and efficacy of the vaccine. The authorization is accompanied by terms and conditions to manage uncertainties and mitigate risks related to the drug. Appropriate warnings and precautions are in place in the Covifenz Product Monograph to address the identified risks.

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