The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

Immunobridging for Pemivibart, a Monoclonal

Antibody for Prevention of Covid-19
To the Editor: On March 22, 2024, the Food had reduced in vitro activity against the B.1.1.529
and Drug Administration issued Emergency (omicron) subvariants BA.1 and BA.1.1 and no
Use Authorization (EUA) for the monoclonal activity against the BA.2, BA.3, BA.4–BA.5 sub-
antibody pemivibart as preexposure prophylaxis variants and did not receive EUA. In the EVADE
for Covid-19 in certain adults and adolescents trial, adintrevimab provided 71% protection from
with moderate-to-severe immunocompromise. symptomatic Covid-19 (primarily due to the
The EUA was issued on the basis of safety and delta variant) through 3 months.1 The primary
immunobridging data from the CANOPY trial immunobridging results in the CANOPY trial
(ClinicalTrials.gov number, NCT06039449), which showed that the day 28 geometric mean ratio
included two cohorts: an open-label cohort of between the titer that was calculated for pemivi-
306 persons with moderate-to-severe immuno- bart against pseudotyped JN.1 and the protec-
compromise, who received an initial intrave- tion titer (reference) that was calculated for ad-
nous infusion of a single 4500-mg dose of intrevimab against authentic delta variant was 0.70
pemivibart followed by a second infusion at the (90% confidence interval, 0.68 to 0.72) (Fig. 1A).
same dose approximately 90 days later, and a A complementary immunobridging method that
placebo-controlled cohort of persons without used data from a meta-analysis showed that the
immunocompromise, who were randomly as- titer values for pemivibart in the CANOPY trial
signed to receive either pemivibart or placebo were consistent with the ranges observed in pre-
on the same schedule. Additional information is vious clinical trials of monoclonal antibodies with
provided in the protocol and Supplementary Ap- proven clinical efficacy (Fig. 1B).2-4
pendix, both of which are available with the full Important adverse events included infusion-
text of this letter at NEJM.org. related and hypersensitivity reactions in 25 of
The analysis of the primary end point was 306 immunocompromised participants (8.2%)
performed by means of an immunobridging who received pemivibart and anaphylaxis in 4 of
method, which allowed for a comparison of the 623 participants (0.6%) who received any dose of
neutralizing antibody titers calculated for pemi- pemivibart; 2 of the 4 participants had serious
vibart with those calculated for the monoclonal cases. All other infusion-related and hypersensi-
antibody adintrevimab. Adintrevimab had shown tivity reactions were mild or moderate.
efficacy against the B.1.617.2 (delta) variant but Covid-19 monoclonal antibodies are needed
to protect immunocompromised persons who
may not mount an adequate vaccine response
this week’s letters and who are historically excluded from trials.
Previous work assessing monoclonal antibody
1860 Immunobridging for Pemivibart, a Monoclonal
neutralizing titers as a correlate of protection was
Antibody for Prevention of Covid-19
critical for the immunobridging method and rapid
1863 Pemivibart Activity against Recent SARS-CoV-2 development of pemivibart. The use of neutraliz-
JN.1 Sublineages ing titers calculated on the basis of pharmaco-
kinetic data leverages immunobridging concepts

1860 n engl j med 391;19 nejm.org November 14, 2024

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 Correspondence

A Immunobridging Method 1

Evaluation based on adintrevimab historical EVALUATE

data Clinical efficacy of the reference monoclonal antibody (adintrevimab)
Adintrevimab, 300 mg 71% Reduction in
Single intramuscular dose Adintrevimab, as compared with placebo, showed a 71% reduction relative risk at day 90
in the relative risk of RT-PCR–confirmed symptomatic Covid-19 due
to the delta variant through day 90.

Completed phase 3 trial CALCULATE

(EVADE) Protection titer threshold at day 90
Serum concentration of adintrevimab at day 90 (GMT) divided by =3514
the IC50 value for adintrevimab against the authentic delta variant
(7 ng/ml)

Extrapolation based on pemivibart pharmaco- EXTRAPOLATE

kinetic modeling Adintrevimab-extrapolated protection sVNA titer (reference) at day 28
Pemivibart, 4500 mg Protection sVNA titer (GMT) for pemivibart as extrapolated from the =8944
IV infusion on day 1 and day 90 protection titer for adintrevimab at day 90 and based on the half-life
of pemivibart

Completed phase 1 study

and ongoing phase 3 trial
(CANOPY)

Assessment based on pemivibart EUA data CALCULATE

sVNA titer for pemivibart at day 28
Pemivibart, 4500 mg =6278
IV infusion on day 1 Serum concentration of pemivibart at day 28 (GMT) divided by (90% CI, 6093–6469)
the IC50 value for pemivibart against the pseudotyped JN.1 variant
(74.6 ng/ml)
Ongoing phase 3 trial (CANOPY)
ASSESS
The full analysis set included all
6278÷8944=0.70
participants who received a full Immunobridging for pemivibart
(90% CI, 0.68–0.72)
dose at the initial administration The immunobridging end point was a ratio between the GMT for
and had a quantifiable serum pemivibart against the pseudotyped JN.1 variant at day 28 and the
concentration result at day 28. protection titer (reference) for adintrevimab against the authentic
delta variant at day 28. Immunobridging was established if the lower
limit of the two-sided 90% confidence interval of the ratio of the
GMT values was greater than 0.8.

B Immunobridging Method 2
100

90

80

70

60
Efficacy (%)

50 Monoclonal Antibody
Casirivimab+imdevimab — Isa et al.
40
Casirivimab+imdevimab — O’Brien et al.
30 Casirivimab+imdevimab — Herman et al.
20 Cilgavimab+tixagevimab — Levin et al.
Adintrevimab — Schmidt et al. (delta)
10
Adintrevimab — Schmidt et al. (omicron)
0
100 1000 10,000
Antibody Concentration (normalized by the in vitro IC50 value)

n engl j med 391;19 nejm.org November 14, 2024 1861

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 1 (previous page). Two Immunobridging

that are frequently used in vaccine development
Methods Used in the Assessment of Pemivibart. and facilitates evaluation at an earlier time point.
Panel A shows immunobridging method 1, in which the Several important concepts from this program
efficacy of pemivibart was assessed through immuno- may inform future development efforts. First,
bridging to a reference monoclonal antibody (adintrev- the meta-analysis approach may more effectively
imab), with the use of a single defined threshold value. capture the conferred range of protection than
The evaluation was based on the results of the EVADE
trial.1 The pharmacokinetic modeling in the extrapola-
choosing a single value for a protection thresh-
tion used data from a completed phase 1 trial (A Study old, which may imply that protection is binary
to Investigate the Safety, Tolerability, and Pharmacoki- (i.e., that protection exists only above that thresh-
netics of the Monoclonal Antibody VYD222 in Healthy old). Second, there are methodologic differences
Adult Participants; ClinicalTrials.gov number, NCT05791318) within cell-based assays that could lead to vari-
and the ongoing phase 3 CANOPY trial (NCT06039449).
The half-maximal inhibitory concentration (IC50) for adin-
ability in the determination of half-maximal in-
trevimab against the delta variant was determined with hibitory concentrations (IC50s) and limit the
an authentic virus neutralization assay. The IC50 for pe- usefulness of a single value for a protection
mivibart against the JN.1 variant was determined with a threshold. Third, the use of neutralizing titers
pseudotyped viruslike particle neutralization assay. CI calculated on the basis of serum monoclonal
denotes confidence interval, GMT geometric mean titer,
IV intravenous, RT-PCR reverse-transcriptase–polymerase-
antibody concentration and a specific IC50 allows
chain-reaction, and sVNA serum virus neutralizing anti- for an immunobridging approach to be used in
body. Panel B shows immunobridging method 2, in future assessments of new variants.
which the efficacy of pemivibart was assessed through The immunobridging end point used for the
immunobridging to multiple reference monoclonal anti- authorization of pemivibart is the first for Covid-19
bodies on the basis of a meta-analysis and the range of
titers after IV administration of a 4500-mg dose of pemi-
monoclonal antibodies. We believe that this ap-
vibart. The graph shows the range of calculated titers proach, combined with continued postauthoriza-
(antibody concentration divided by the in vitro IC50 value tion surveillance of new variants, can meet the
of each antibody) and protective efficacy of adintrevimab challenge of keeping pace with viral evolution,
and two monoclonal antibody combinations (one com- while providing monoclonal antibodies with ac-
posed of casirivimab and imdevimab and one composed
of tixagevimab and cilgavimab) against symptomatic
tivity against contemporary variants to clinicians
Covid-19; the dose–response relationship was demon- and patients.
strated by Stadler et al.2 in a published meta-analysis.
Pete Schmidt, M.D.
Data from the earliest time interval in the trials are rep-
resented by faded symbols. The black line is the estimat- Yong Li, Ph.D.
ed dose–response relationship that was determined by Myra Popejoy, Pharm.D.
fitting a logistic model with maximum of 1 (i.e., maximal Invivyd
efficacy of 100%) to the data and estimated 95% confi- Waltham, MA
dence interval with the use of parametric bootstrapping yli@​­invivyd​.­com
(curved gray shading). The vertical beige-shaded area Supported by Invivyd.
shows the range of the GMTs after IV administration of Disclosure forms provided by the authors are available with
a single 4500-mg dose of pemivibart at the end of infu- the full text of this letter at NEJM.org.
sion on day 1, at month 1, and at month 3 (20,246, 6278,
and 2839, respectively). A specific estimate of efficacy 1. Ison MG, Weinstein DF, Dobryanska M, et al. Prevention of
cannot be claimed on the basis of the comparison of the COVID-19 following a single intramuscular administration of
ranges of pemivibart titer values and the curve depicted adintrevimab: results from a phase 2/3 randomized, double-
in this figure. Full details of the assessment, including blind, placebo-controlled trial (EVADE). Open Forum Infect Dis
the references for Isa et al. (supplementary reference 2023;​10(7):​ofad314.
2. Stadler E, Burgess MT, Schlub TE, et al. Monoclonal anti-
16), O’Brien et al. (supplementary reference 18), Her-
body levels and protection from COVID-19. Nat Commun 2023;​
man et al. (supplementary reference 15), Levin et al. 14:​4545.
(supplementary reference 17), and Schmidt et al. (sup- 3. Follmann D, O’Brien MP, Fintzi J, et al. Examining protective
plementary reference 13), are provided in the Supple- effects of SARS-CoV-2 neutralizing antibodies after vaccination or
mentary Appendix. Panel B was modified from Figure 2 monoclonal antibody administration. Nat Commun 2023;​14:​3605.
of the article by Stadler et al.,2 which is used under a 4. Schmidt P, Narayan K, Li Y, et al. Antibody-mediated protec-
Creative Commons Attribution 4.0 International License tion against symptomatic COVID-19 can be achieved at low serum
(https://creativecommons​.­org/​­licenses/​­by/​­4​.­0/​­deed​.­en). neutralizing titers. Sci Transl Med 2023;​15(688):​eadg2783.
DOI: 10.1056/NEJMc2404555

1862 n engl j med 391;19 nejm.org November 14, 2024

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on November 18, 2024. For personal use only.
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