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To the Editor: On March 22, 2024, the Food and Drug Administration issued Emergency Use Authorization (EUA) for the monoclonal antibody pemivibart as preexposure prophylaxis for Covid-19 in certain adults and adolescents with moderate-to-severe immunocompromise. The EUA was issued on the basis of safety and immunobridging data from the CANOPY trial (ClinicalTrials.gov number, NCT06039449), which included two cohorts: an open-label cohort of 306 persons with moderate-to-severe immunocompromise, who received an initial intravenous infusion of a single 4500-mg dose of pemivibart followed by a second infusion at the same dose approximately 90 days later, and a placebo-controlled cohort of persons without immunocompromise, who were randomly assigned to receive either pemivibart or placebo on the same schedule. Additional information is provided in the protocol and Supplementary Appendix, both of which are available with the full text of this letter at NEJM.org.

s later, and a placebo-controlled cohort of persons without immunocompromise, who were randomly assigned to receive either pemivibart or placebo on the same schedule. Additional information is provided in the protocol and Supplementary Appendix, both of which are available with the full text of this letter at NEJM.org. The analysis of the primary end point was performed by means of an immunobridging method, which allowed for a comparison of the neutralizing antibody titers calculated for pemivibart with those calculated for the monoclonal antibody adintrevimab. Adintrevimab had shown efficacy against the B.1.617.2 (delta) variant but had reduced in vitro activity against the B.1.1.529 (omicron) subvariants BA.1 and BA.1.1 and no activity against the BA.2, BA.3, BA.4–BA.5 subvariants and did not receive EUA. In the EVADE trial, adintrevimab provided 71% protection from symptomatic Covid-19 (primarily due to the delta variant) through 3 months.1 The primary immunobridging results in the CANOPY trial showed that the day 28 geometric mean ratio between the titer that was calculated for pemivibart against pseudotyped JN.1 and the protection titer (reference) that was calculated for adintrevimab against authentic delta variant was 0.70 (90% confidence interval, 0.68 to 0.72) (Figure 1A). A complementary immunobridging method that used data from a meta-analysis showed that the titer values for pemivibart in the CANOPY trial were consistent with the ranges observed in previous clinical trials of monoclonal antibodies with proven clinical efficacy (Figure 1B).2-4

dence interval, 0.68 to 0.72) (Figure 1A). A complementary immunobridging method that used data from a meta-analysis showed that the titer values for pemivibart in the CANOPY trial were consistent with the ranges observed in previous clinical trials of monoclonal antibodies with proven clinical efficacy (Figure 1B).2-4 Important adverse events included infusion-related and hypersensitivity reactions in 25 of 306 immunocompromised participants (8.2%) who received pemivibart and anaphylaxis in 4 of 623 participants (0.6%) who received any dose of pemivibart; 2 of the 4 participants had serious cases. All other infusion-related and hypersensitivity reactions were mild or moderate.

lated and hypersensitivity reactions in 25 of 306 immunocompromised participants (8.2%) who received pemivibart and anaphylaxis in 4 of 623 participants (0.6%) who received any dose of pemivibart; 2 of the 4 participants had serious cases. All other infusion-related and hypersensitivity reactions were mild or moderate. Covid-19 monoclonal antibodies are needed to protect immunocompromised persons who may not mount an adequate vaccine response and who are historically excluded from trials. Previous work assessing monoclonal antibody neutralizing titers as a correlate of protection was critical for the immunobridging method and rapid development of pemivibart. The use of neutralizing titers calculated on the basis of pharmacokinetic data leverages immunobridging concepts that are frequently used in vaccine development and facilitates evaluation at an earlier time point. Several important concepts from this program may inform future development efforts. First, the meta-analysis approach may more effectively capture the conferred range of protection than choosing a single value for a protection threshold, which may imply that protection is binary (i.e., that protection exists only above that threshold). Second, there are methodologic differences within cell-based assays that could lead to variability in the determination of half-maximal inhibitory concentrations (IC50s) and limit the usefulness of a single value for a protection threshold. Third, the use of neutralizing titers calculated on the basis of serum monoclonal antibody concentration and a specific IC50 allows for an immunobridging approach to be used in future assessments of new variants.

al inhibitory concentrations (IC50s) and limit the usefulness of a single value for a protection threshold. Third, the use of neutralizing titers calculated on the basis of serum monoclonal antibody concentration and a specific IC50 allows for an immunobridging approach to be used in future assessments of new variants. The immunobridging end point used for the authorization of pemivibart is the first for Covid-19 monoclonal antibodies. We believe that this approach, combined with continued postauthorization surveillance of new variants, can meet the challenge of keeping pace with viral evolution, while providing monoclonal antibodies with activity against contemporary variants to clinicians and patients.