ADAGIO THERAPEUTICS, INC.

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Adagio Therapeutics : ADG20, a half-life–extended monoclonal antibody in development for the prevention and treatment of COVID-19, demonstrated broad in vitro neutralisation against SARS-CoV-2 variants

06/13/2022 EDT

Poster P2161

ADG20, a half-life-extended monoclonal antibody in development for the prevention and treatment of COVID-19, demonstrated broad in vitro neutralisation against SARS-CoV-2 variants

Chengzi I. Kaku,1 Kristin Narayan,2 Pete Schmidt,2 Frank Engler,3 Yong Li,2 Laura M. Walker1,2

1Adimab LLC, Lebanon, NH, USA; 2Adagio Therapeutics, Inc., Waltham, MA, USA; 3Clinical Pharmacology, Certara, Bualo, NY, USA

INTRODUCTION

  • ADG20 is a fully human immunoglobulin (Ig)G1 monoclonal antibody (mAb) engineered to have improved potency and broad neutralisation against SARS-CoV-2 and other SARS-like CoVs with pandemic potential1-4
  • In addition, the Fc region of ADG20 has been modifi ed to provide an extended half-life1
  • ADG20 can be administered intramuscularly (IM) and is being assessed in 2 separate phase 2/3 clinical trials: the EVADE trial for prevention of COVID-19 in both post-exposure and pre-exposure settings and the STAMP trial for treatment of COVID-195,6
  • During the COVID-19 pandemic, variants of SARS-CoV-2 have rapidly emerged and dominated global populations, likely due to selective pressure from natural and vaccine-inducedimmunity7-9
  • Notably, some variants of concern (VOCs), including Omicron, exhibit enhanced transmissibility and/or decreased susceptibility to neutralisation by vaccine-elicited responses and some mAb therapies7-9
  • Here we report the in vitro neutralising activity of ADG20 against a panel of circulating SARS-CoV-2 variants, including Omicron and other VOCs with reduced susceptibility to some currently authorised mAbs
  • We also present serum virus neutralising antibody (sVNA) titres collected up to 6 months after a single 300 mg IM injection of ADG20 in healthy adults

KEY FINDINGS

ADG20 demonstrated broad in vitro neutralising activity against SARS-CoV-2 VOCs, including Alpha, Beta, Delta, Gamma, and the Omicron BA.1 and BA.1.1 sub-lineages

ADG20 displayed no detectable neutralising activity against the Omicron BA.2

METHODS

In vitro neutralising activity

  • In vitro neutralising activity of ADG20 against 38 SARS-CoV-2 variants encoding the full set of spike mutations in circulating lineages, including Alpha/B.1.1.7, Beta/B.1.351, Gamma/P.1, Delta/B.1.617.2, and Omicron lineages BA.1, BA.1.1, and BA.2, was assessed in an HIV lentiviral pseudovirus assay9-11
    • D614G, an early variant of SARS-CoV-2, was used as a reference to calculate the half maximal inhibitory concentration (IC50) fold change in neutralising activity for ADG20
  • In vitro neutralising activity of ADG20 against 27 SARS-CoV-2 variants, including those reported to exhibit reduced susceptibility to emergency-use authorised (EUA) mAbs, was assessed in a non-replicative vesicular stomatitis virus pseudovirus assay12,13
    • Fold reduction was calculated by dividing the IC50 of a variant by the mean IC50 (14.6 ng/mL) of the D614G reference strain

ADG20 sVNA titres

  • A phase 1 randomised, double-blind,placebo-controlled, single- ascending dose study was initiated at a single center in the United States in February 202114
    • Eligible participants were healthy adults aged 18-50 years at low risk of SARS-CoV-2 infection and with no evidence of prior or current SARS-CoV-2 infection
    • Three cohorts (n=10 per cohort) were randomised (8:2) to receive ADG20 or placebo; here, we report exploratory sVNA data for the cohort that received a single 300 mg ADG20 IM injection
    • As a non-prespecifi ed exploratory research analysis, the 80% neutralisation (MN80) sVNA titres following ADG20 administration were determined by a plaque reduction neutralisation test against authentic SARS-CoV-2 D614G (BavPat), Beta/B.1.351, and Delta/B.1.617.2 variants (Delta data are preliminary)
    • For each variant ADG20 sVNA titres were compared with peak responses 7-30 days after the second dose of the mRNA-1273 (Moderna) vaccine in a separate cohort of healthy volunteers

sub-lineage at the highest concentration tested

Anti-SARS-CoV-2 sVNA titres after a single 300 mg IM injection of ADG20 exceeded titres after 2-dosemRNA-1273 vaccination in healthy adults for variants tested

CONCLUSIONS

RESULTS

In vitro neutralising activity of ADG20

  • ADG20 displayed in vitro neutralisation activity within 0.5- to 5.1- fold of reference D614G strain for all pseudovirus variants tested (Figure 1A)
    • Delta plus/AY.1, Lambda/C.37, and Mu/B.1.621 variants remained sensitive to ADG20
  • ADG20 maintained neutralising activity against all tested SARS-CoV-2 variants incorporating mutations reported to confer increased resistance to EUA mAbs (Figure 1B)
    • IC50 values for ADG20 (within 0.6- to 2.4-fold of the D614G strain) were lower than those observed for bamlanivimab, etesevimab, casirivimab, imdevimab, and sotrovimab

Figure 1. In vitro ADG20 neutralising activity against SARS-CoV-2 variants

A. ADG20 neutralising activity against circulating SARS-CoV-2 variants

50D614G

100

50

/IC

50var

10

IC

5

change

1

Mean fold

0.1

A.23.1 A.27 AV.1;B.1.1.482 B.1.1.7/Alpha B.1.1.7 + D427N B.1.1.7 + L455F B.1.1.7 + E484K B.1.1.7 + F490S B.1.1.7 + Q493R B.1.1.7 + S494P B.1.214.2 B.1.351/Beta (RSA5321) B.1.351/Beta (RSA5325) B.1.1.523 B.1.523/B.1.526 + N440K B.1.525/Eta B.1.526/Iota B.1.429/Epsilon B.1.429 + P26S B.1.427/429 V1 + L455F B.1.427/B.1.429 + E484Q B.1.1.519 B.1.617.1/Kappa B.1.617.2/Delta AY.1/Delta plus AY.4/AY.11/B.1.617.2 B.1.619 A.VOI.V2 B.1.621.1/Mu B.1.621.1/B.1.623/Mu C.36 C.37/Lambda P.1/Gamma R.1

Adagio has utilised the non-clinical and pre-clinical services oered by the National Institute of Allergy and Infectious Diseases.

At least 2 independent experiments were performed for each variant. The bars represent standard deviation.

  1. ADG20 in vitro neutralising activity against SARS-CoV-2 variants associated with resistance to EUA mAbs

50D614G

100

/IC

50

50var

10

IC

5

change

1

Mean fold

0.1

P337R E340K E406W K417E K417N N439K N440D N440K K444Q V445A G446V L452R Y453F L455F N460K N460S G476S V483A E484K F486V F486I Y489H F490S Q493R Q493K S494P N501Y

Clinical-stage mAb

Bamlanivimab

variant neutralisation

Etesevimab

Reduced

Casirivimab

Imdevimab

susceptibility

Not aŠected

Sotrovimab

The points represent neutralising activity of ADG20 against SARS-CoV-2 variants.

  • ADG20 demonstrated in vitro neutralising activity against BA.1 and BA.1.1, but not BA.2, sub-lineages of Omicron (Figure 2)

Figure 2. In vitro ADG20 neutralising activity against the Omicron variant and subvariants

100

75

Variant

IC50 (µg/mL)

Neutralisation

50

D614G

0.00045

Omicron (BA.1)

0.145

Omicron+R346K (BA.1.1) 0.129

%

25

Omicron (BA.2)

>2000

0

0.0001

0.001

0.01

0.1

1

10

ADG20 concentration (µg/mL)

ADG20 sVNA titres

  • sVNA titres following a single 300 mg IM injection of ADG20 exceeded titres against D614G, Beta, and Delta variants 7-30 days after 2-dosemRNA-1273 vaccination, and this trend was maintained for at least 3 months (Figure 3)
    • By 6 months, ADG20 sVNA titres were 0.6-,1.4-, and 1.8-fold of peak titres induced by mRNA-1273 vaccination for variants tested

Figure 3. ADG20-associated sVNA titres against D614G, Beta, and Delta variants compared with peak responses following mRNA-1273 vaccination

D614G

Beta

Delta (preliminary dataa)

**

***

***

***

***

*** 895

975

834

1000

460

587

***

***

537

***

MN80 CI)

530

424

**

ns

**

405

***

315

130 167

180

176

219

Geometric mean log sVNA titre (95%

*

99

ns

100

50

70

10

mRNA-

Day 2

Day 7

Day 21

Month 3

Month 6c

1273b

ADG20 300 mg IM

(N=12)

(N=8)

aStatistical comparisons for Delta are based on preliminary results. bPeak vaccine response timepoint: 7-30 days post second dose.

cExcludes samples taken following SARS-CoV-2 vaccination from participants who received vaccination during the trial.

Statistical comparisons of titres achieved by ADG20 against each variant was performed using 2-sided Mann Whitney U tests: *P<0.05; **P<0.01; ***P<0.001; ns, non-signifi cant vs mRNA-1273 vaccination response against the corresponding variant.

  • ADG20 retained neutralising activity with varying potencies against SARS-CoV-2 variants tested, including Delta and Omicron BA.1 and BA.1.1 (but not BA.2) VOCs
  • sVNA titres from a phase 1 study support the potential for a single 300 mg injection of ADG20 to provide prolonged protection against symptomatic COVID-19 for susceptible SARS-CoV-2 variants
  • Preliminary data from phase 2/3 clinical trials demonstrated that in the pre-Omicron population, ADG20 met the primary endpoints with statistical signifi cance across pre- and post-exposure prophylaxis and treatment for COVID-19

REFERENCES

  1. Rappazzo CG, et al. Science. 2021;371:823-829.
  2. Dejnirattisai W, et al. Cell. 2021;184:2939-2954.
  3. Liu C, et al. Cell. 2021;184:4220-4236.e13.
  4. Kaku CI, et al. Presented at ISIRV-WHO; October 19-21, 2021; Virtual. Poster 130.
  5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04859517. Accessed April 4, 2022.
  6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04805671. Accessed April 4, 2022.
  7. Lauring AS, Hodcroft EB. JAMA. 2021;325:529-531.
  8. Liu L, et al. Nature. 2022;602:676-681.
  9. Lusvarghi S, et al. bioRxiv. 2021. DOI:/10.1101/2021.07.16.452748.
  10. Neerukonda SN, et al. PloS One. 2021;16:e0248348.
  11. ADG-DOF-007;Waltham, MA: Adagio Therapeutics, Inc.; 2022.
  12. ADG-DOF-008;Waltham, MA: Adagio Therapeutics, Inc.; 2022.
  13. ADG-DOF-009;Waltham, MA: Adagio Therapeutics, Inc.; 2022.
  14. Schmidt P, et al. Presented at ISIRV-WHO; October 19-21, 2021; Virtual. Poster 131.

DISCLOSURES

CIK is an employee of Adimab LLC. KN, PS, and YL are employees and stockholders in Adagio Therapeutics, Inc. FE has received consulting fees from Adagio Therapeutics, Inc. LMW is an employee of Adagio Therapeutics, Inc., and an inventor on a patent application submitted by Adagio Therapeutics, Inc., describing the engineered SARS-CoV-2 antibody.

Acknowledgments

The authors would like to thank Carol Weiss, MD, PhD, Laboratory of Immunoregulation, Oce of Vaccines Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, for performing the HIV-based pseudovirus assays.

Collection and processing of blood from mRNA-1273-vaccinated donors conducted at DartLab, the Immune Monitoring and Flow Cytometry Shared Resource at the Norris Cotton Cancer Center Dartmouth College, was supported by NCI Cancer Center Support Grant 5P30CA023108-42.

This study was funded by Adagio Therapeutics, Inc. Writing assistance was provided by Georgiana Manica, PhD, of Parexel, and was funded by Adagio Therapeutics, Inc.

Poster presented at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID); April 23-26, 2022; Lisbon, Portugal

Disclaimer

Adagio Therapeutics Inc. published this content on 13 June 2022 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 16 June 2022 18:52:01 UTC.


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