KOSTAIVE Powder for dispersion for injection Ref.[114806] Active ingredients: Zapomeran

Pharmacotherapeutic group: Vaccines, COVID-19 vaccines, RNA-based vaccine
ATC code: J07BN01

Mechanism of action

Kostaive is composed of a self-amplifying mRNA encoding the spike protein of SARS-CoV-2, encapsulated in lipid nanoparticles. The self-amplifying mRNA is designed to produce extra copies of mRNA within the host cells after intramuscular injection, to achieve enhanced expression of the spike protein antigen. This gives rise to neutralising antibody and cellular immune responses to the spike antigen, which contributes to protection against COVID-19. The mRNA self-amplification process is transient and does not generate infectious particles.

Clinical efficacy

Study ARCT-154-01 was a randomised, controlled, observer-blind, multicentre clinical study conducted in participants 18 years of age and older in Vietnam at a time when the dominant variant was delta.

The efficacy was evaluated in the mITT analysis set, including 15 458 participants, 7 762 in Kostaive (zapomeran) group and 7 696 in placebo group.

Randomisation was stratified by age (<60 or ≥60 years of age) and, for participants <60 years of age, by risk of severe COVID-19 (those with asthma, cancer, cerebrovascular disease, chronic kidney/liver/lung disease, cystic fibrosis, diabetes mellitus Type 1 or 2, cardiovascular conditions, mental health conditions, smoking, pulmonary fibrosis, Down syndrome, obesity, sickle cell disease, or substance abuse disorder). All participants ≥60 years of age were deemed to be at high risk for severe COVID-19. Among participants who received Kostaive, 5.5% (n=485) had significant underlying medical conditions, including cardiovascular diseases, diabetes, obesity, liver disorders, chronic obstructive pulmonary disease (COPD), and asthma. The study excluded participants who were immunocompromised, including those with a known diagnosis of the human immunodeficiency virus (HIV) or taking immunosuppressive medication, and those who had a previous clinical or microbiological diagnosis of COVID-19.

Participants with pre-existing acute or chronic medical conditions, including participants with known infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) disease, were eligible for inclusion. Demographic and baseline characteristics were similar between groups for individuals in the 2 age cohorts and by risk groups. Among the total participants who received Kostaive, 49% were male and 51% were female, 99.6% were Asian, and 0.4% were described as “other” for race, respectively. At the time of vaccination, the mean age of the population was 46.4 years (age range 18-89 years).

The overall primary efficacy endpoint was vaccine efficacy (VE), defined as the first occurrence of virologically confirmed, protocol-defined COVID-19 with onset between day 36 (7 days after dose 2) and day 92, inclusive.

For participants without evidence of SARS-CoV-2 infection prior to 7 days after dose 2, vaccine efficacy against confirmed COVID-19 occurring at least 7 days after dose 2 was 56.7% (95% confidence interval: 48.8% to 63.4%). The number of COVID-19 cases was 200 and 440 in the Kostaive and placebo groups, respectively. At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for in total 1 146 person-years for Kostaive and in total 1 120 person-years in the placebo group.

The information relating to the evaluation of overall vaccine efficacy is presented in Table 2.

Table 2. Vaccine efficacy against virologically confirmed, protocol-defined COVID-19 between day 36 and day 92 – modified intent-to-treat (mITT) population:

Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; N, number of participants at risk; n, number of participants with case reported; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VE, vaccine efficacy.
mITT, modified intent-to-treat (includes all participants who received all protocol-required doses of study vaccine (Kostaive or placebo) up to the evaluation timepoint, and who have no evidence of SARS-CoV-2 infection on day 1 or up to 7 days after the 2nd vaccination in the study).
‘At-risk’ was defined as individuals that are considered to have higher risk of developing severe COVID-19.
^a VE is calculated by 1-HR from cox regression adjusting for risk group and region of study site, or 1-RR when number of confirmed cases is 0 in the Kostaive group.
^b The surveillance time refers to the total person-time at risk in years for the given endpoint.

Efficacy against severe COVID-19

The efficacy of Kostaive for the prevention of virologically confirmed severe COVID-19, including death, was evaluated (Table 3). Severe COVID-19 comprised any of the following: respiratory rate ≥30 per minute, heart rate ≥125 per minute, oxygen saturation level (SpO₂) ≤93% on room air at sea level or arterial oxygen partial pressure (PO₂)/fractional inspired oxygen (FiO₂) <300 mm Hg, respiratory failure (defined as needing high flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)), shock (defined as systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requirement for vasopressors), significant acute renal, hepatic, or neurologic dysfunction, admission to an intensive care unit, death. The endpoint was the first occurrence of confirmed, protocol-defined severe COVID-19 with onset between days 36 and 92, inclusive.

Table 3. Vaccine efficacy against virologically confirmed, protocol-defined severe COVID-19 between day 36 and day 92 – modified intent-to-treat (mITT) population:

Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; N, number of participants at risk; n, number of participants with case reported; NE, not estimable; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VE, vaccine efficacy.
mITT, modified intent-to-treat (includes all participants who received all protocol required doses of study vaccine (Kostaive or placebo) up to the evaluation timepoint, and who have no evidence of SARS-CoV-2 infection on day 1 or up to 7 days after the 2nd vaccination in the study)
^a VE is calculated by 1-HR from cox regression adjusting for risk group and region of study site, or 1-RR when number of confirmed cases is 0 in the Kostaive group.
^b The surveillance time refers to the total person-time at risk in years for the given endpoint.

Immunogenicity in participants 18 years of age and older after booster dose

The evaluation of immunogenicity administered as a booster dose is based on the results of Study ARCT-154-J01, conducted in Japan, which compared the immune response that followed a booster dose of Kostaive (zapomeran) with that of the comparator (tozinameran, BNT162b2) in adult individuals who previously received the primary vaccination series and 1 booster dose with authorised COVID-19 mRNA vaccines. In this study, immunogenicity was assessed using a virus neutralisation assay against ancestral SARS-CoV-2 strain and Omicron BA.4/5 variant.

The primary objective of Study ARCT-154-J01 was to demonstrate the noninferiority of Kostaive compared to the comparator vaccine in terms of ratio of geometric mean antibody titres (GMTs) and difference in seroresponse rates (SRR) against ancestral SARS-CoV-2 strain on day 29 after vaccination. In case the noninferiority is demonstrated for ancestral strain, similar testing was to be performed for Omicron BA.4/5 variant. When the second noninferiority is demonstrated, the superiority of Kostaive versus the comparator for Omicron BA.4/5 variant was tested. Additional testing of GMTs up to 6 months was conducted to assess the duration of the antibody response.

A total of 828 participants were enrolled in the study and randomised (1:1) to Kostaive and comparator vaccine group. At the time of vaccination, the mean age was 48 years (age range 18-77 years). Of 828 participants, who were randomised and received the study vaccine, 759 participants were included in Per Protocol Set 1 (PPS-1), the analysis set for the primary immunogenicity endpoint.

The results of Study ARCT-154-J01 are presented in Table 4. One month after vaccination, Kostaive demonstrated noninferiority versus the comparator vaccine against ancestral SARS-CoV-2 strain and superiority against Omicron BA.4/5 variant. Longer term immunogenicity data showed that neutralising antibodies persisted, with approximately 2-fold higher GMTs detected for Kostaive compared to the comparator vaccine at 3 and 6 months after vaccination, for both strains.

Table 4. Summary of immune response against SARS-CoV-2 ancestral strain and Omicron BA.4/5 variant up to 6 months following administration of booster dose:

Abbreviations: CI, confidence interval; GMT, geometric mean titre; SARS-CoV-2, severe acute respiratory syndrome coronavirus; SRR, seroresponse rate.
Log-transformed neutralising antibody titre value for day 29 (1 month) was analysed using Analysis of Covariance (ANCOVA) model. Gender and period from last (3rd) vaccination (<5 months, ≥5 months) were used as factors as prespecified in the protocol. GMTs at baseline, 3 and 6 months are unadjusted.
If a measured antibody titre is below the lower limit of quantitation, the value was imputed as ½ of the quantitation limit.
Seroresponse is defined as at least 4-fold increase of post-booster neutralising antibody titres from the baseline titre or from half of the lower limit of quantitation if undetectable at baseline.
^a N = number of participants with valid assay results for the specific assay at the given sampling time point.
^b Pre-specified criteria were met for noninferiority: the lower limit (LL) of 95% confidence interval (CI) for ratio of GMTs (Kostaive/comparator) exceeds 0.67, and the LL of 95% CI for the difference in SRRs (Kostaive minus comparator) exceeds -10%. Superiority test for ancestral strain was not pre-specified. Analysis was conducted in the PPS-1.
^c Analysis was conducted in the PPS-1-ic, a modified version from PPS-1 in which participants with a positive nucleocapsid antibody test were excluded from all subsequent immunogenicity analyses.
^d Pre-specified criteria were met for both noninferiority and superiority. Superiority criteria: the LL of 95% CI for GMT ratio exceeds 1.0, and the LL of 95% CI for SRR difference exceeds 0%. Analysis was conducted in the PPS-1.
^* Comparator: tozinameran (BNT162b2)

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Kostaive in one or more subsets of the paediatric population in prevention of COVID-19 (see section 4.2 for information on paediatric use).