Casirivimab / Imdevimab (1) – Ronapreve®

• Clinical trials
  • The COV-2069 trial is a double-blind, randomised, placebo-controlled Phase III trial investigating the use of casirivimab/imdevimab for prevention in asymptomatic adults, adolescents and children who have had contact within their own household with a person infected with SARS-CoV-2 (index case with a positive SARS-CoV-2 test).

a) Adults and adolescents with a minimum body weight of 40 kg for post-exposure prophylaxis of COVID-19 following exposure to virus variants against which casirivimab/imdevimab does not demonstrate sufficient efficacy.

• An additional benefit is not proven.
• For adults and adolescents with a minimum body weight of 40 kg following exposure to virus variants against which Casirivimab/Imdevimab has not demonstrated sufficient efficacy against, based on in vitro neutralisation tests, no conclusions can be drawn regarding the additional benefit of post-exposure prophylaxis against COVID-19 with Casirivimab/Imdevimab.
• For this patient population, an additional benefit of casirivimab/imdevimab for post-exposure prophylaxis compared with the appropriate comparator therapy is not proven.

b) Adults and adolescents with a minimum body weight of 40 kg and who are not fully immunised, for post-exposure prophylaxis of COVID-19 following exposure to virus variants against which casirivimab/imdevimab demonstrates sufficient efficacy.

• For adults and adolescents who are not fully immunised following exposure to virus variants against which casirivimab/imdevimab demonstrates sufficient efficacy, there is evidence of limited added benefit for the post-exposure prophylaxis of COVID-19 with casirivimab/Imdevimab is a hint that there is a minor additional benefit.
• mortality
  • For adults and adolescents who are not fully immunised, the COV-2069 study shows no statistically significant difference between the treatment groups (cohorts A and B) for the endpoint of all-cause mortality.
• Morbidity – Symptomatic SARS-CoV-2 infections (broad definition; CDC definition; SARS-CoV-2 infection detected by RT-qPCR test)
  • In the COV-2069 study, for the endpoint of symptomatic SARS-CoV-2 infection (broad definition), a statistically significant advantage was observed between the treatment groups in favour of casirivimab/imdevimab in both Cohort A and Cohort B.
  • The results for the endpoint ‘symptomatic SARS-CoV-2 infection’ are comparable between the CDC definition and the broad definition.
  • In Cohort A, this positive effect is also evident in the additionally reported proportion of individuals with a positive SARS-CoV-2 RT-qPCR test, regardless of symptoms.
• Morbidity – Hospitalisation due to COVID-19
  • In Cohort A of the COV-2069 study, there was no statistically significant difference between the treatment arms for the endpoint of hospitalisation due to COVID-19, whilst in Cohort B, a statistically significant advantage for casirivimab/imdevimab can be observed.
  • In this therapeutic indication, patients with mild to moderate disease usually recover whilst isolating at home, whilst hospitalisation is generally only required if symptoms due to COVID-19 worsen. Therefore, hospitalisation in this case can be regarded as an approximation of the clinical condition of worsening symptoms.
• quality of life
  • Endpoints relating to health-related quality of life were not assessed in the study.
• Side effects – SUEs and severe AEs
  • When recording serious adverse events (SUEs) and severe adverse events, the COV-2069 study also included disease-related events. It remains unclear which events were classified as disease-related and were therefore not taken into account in the analyses.
  • However, based on the results for common SUEs and common severe AEs, and given the minor proportion of participants who experienced such events, no adverse effects of casirivimab/imdevimab are expected to an extent that could call into question the additional benefit of casirivimab/imdevimab.
• Side effects – discontinuation due to AEs
  • In the COV-2069 study, there were no discontinuations due to adverse events during the course of the study (cohorts A and B).
• Overall assessment
  • The benefit assessment of post-exposure prophylaxis with casirivimab/imdevimab is based on the double-blind, randomised, controlled study COV-2069, in which casirivimab/imdevimab was compared with placebo.
  • In the endpoint category of mortality, no statistically significant difference was observed in the overall analysis (cohorts A and B). No conclusion regarding additional benefit can be drawn for the mortality category.
  • For the endpoint of symptomatic SARS-CoV-2 infection (broad definition), a statistically significant advantage was observed for casirivimab/imdevimab (cohorts A and B). The extent of this advantage can only be assessed as minor, as the operationalisations chosen here also included mild symptoms (e.g. a runny nose or sneezing). Overall, the events included in the endpoint ‘symptomatic SARS-CoV-2 infection’ are classified as generally not serious.
  • A statistically significant advantage in favour of casirivimab/imdevimab was also observed for the endpoint of hospitalisation (in Cohort B).
  • Although the overall rates of SUEs and severe SUEs cannot be used to assess the side effects of casirivimab/imdevimab, based on the results for common SUEs and common severe SUEs – and given the minor proportion of participants experiencing events – no side effects of casirivimab/Imdevimab to an extent that could call into question the additional benefit of Casirivimab/Imdevimab. There were no discontinuations due to AEs in the study.
  • In summary, positive effects are evident in the morbidity category, with no adverse effects to counterbalance them.
  • Taking the results as a whole, and primarily on the basis of the positive effects observed in the endpoint of hospitalisation due to COVID-19, for adults and adolescents who are not fully immunised following exposure to virus variants against which Casirivimab/Imdevimab has demonstrated sufficient efficacy; a minor additional benefit of post-exposure prophylaxis for COVID-19 with Casirivimab/Imdevimab compared with the appropriate comparator therapy is inferred.
• Statistical certainty (probability of additional benefit)
  • The assessment of additional benefit is based on the randomised, double-blind COV-2069 trial.
  • The potential for bias in the submitted study is classified as low at the study level. The potential for bias in the results at the endpoint level is also classified as low.
  • Nevertheless, uncertainties remain regarding the generalisability of the study results to the current healthcare context in Germany.
  • Overall, therefore, significant uncertainties remain regarding the transferability to the current German healthcare context, which, when considered in the overall assessment of the certainty of the findings, justify the derivation of a hint of additional benefit.

c) Adults and adolescents with a minimum body weight of 40 kg and who are fully immunised, for post-exposure prophylaxis of COVID-19 following exposure to virus variants against which casirivimab/imdevimab demonstrates sufficient efficacy

• An additional benefit is not proven.
• For adults and adolescents with a minimum body weight of 40 kg and who have been fully immunised, for post-exposure prophylaxis of COVID-19 following exposure to virus variants against which casirivimab/Imdevimab has demonstrated sufficient efficacy, no conclusions regarding the additional benefit of post-exposure prophylaxis of COVID-19 with Casirivimab/Imdevimab can be drawn from the COV-2069 study, as the study exclusively included individuals without vaccination protection.
• For this patient population, the additional benefit of casirivimab/imdevimab for post-exposure prophylaxis compared with the appropriate comparator therapy is not proven.

Courtesy translation only, please refer to the German original.