Introduction Adintrevimab is a fully human immunoglobulin G1 extended half-life monoclonal antibody that was developed to have broad neutralization against SARS-CoV, SARS-CoV-2, and other SARS-like CoVs with pandemic potential. Here we report the safety, pharmacokinetics (PK), serum viral neutralizing antibody (sVNA) titers, and immunogenicity results of the first three cohorts evaluated in the first-in-human study of adintrevimab in healthy adults. Methods This is a phase 1, randomized, placebo-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged ≥ 18–55 years with no current or prior SARS-CoV-2 infection. Participants were randomized 8:2 to adintrevimab or placebo in each of three dose cohorts: adintrevimab 300 mg IM (cohort 1), 500 mg IV (cohort 2), and 600 mg IM (cohort 3). Follow-up was 12 months. Blood samples were taken predose and at multiple time points postdose up to month 12 to assess sVNA, PK, and antidrug antibodies (ADAs). Results Thirty participants received a single dose of adintrevimab ( n = 24; 8 per cohort) or placebo ( n = 6). All except one adintrevimab participant in cohort 1 completed the study. No participants in any treatment arm experienced a study drug-related adverse event. Across adintrevimab-treated participants, 11 (45.8%) experienced at least one TEAE. All but one TEAE were mild in severity, and all were either viral infection or respiratory symptoms. There were no serious adverse events, discontinuations due to adverse events, or deaths. Adintrevimab exhibited a linear and dose-proportional PK profile and extended serum half-life (mean 96, 89, and 100 days in cohorts 1, 2, and 3, respectively). Participants receiving adintrevimab demonstrated dose-dependent increased sVNA titers and breadth across multiple variants. Conclusion Adintrevimab at doses of 300 mg IM, 500 mg IV, and 600 mg IM was well tolerated in healthy adults. Adintrevimab demonstrated dose-proportional exposure, rapid development of neutralizing antibody titers, and an extended half-life. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00794-1.
Background Adintrevimab is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential. Adintrevimab is being assessed in two 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-19. Here we report higher doses being evaluated in a healthy volunteer study given that emerging variants may have varying susceptibilities to adintrevimab. Previous results 300 mg IM, 600 mg IM, and 500 mg IV cohorts have been reported. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 high dose cohorts (N=10/cohort: n=8 adintrevimab, n=2 PBO): adintrevimab 1200 mg IM, 1200 mg IV, and 4500 mg IV. Safety, tolerability, and pharmacokinetics (PK) were assessed up to 21 days post dose. Results Overall, 30 participants received adintrevimab (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK for 1200 mg IV are reported. Through 21 days post dose all doses were well-tolerated, with no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions reported. The observed PK profile of the 1200 mg IV dose included Cmax of 423±105 µg/ml. Comparison of 500 mg and 1200 mg IV doses indicate dose proportionality of Cmax and exposure (AUC Day 21). Conclusion A single dose of adintrevimab, up to 4500 mg, was well tolerated. These preliminary safety data and PK support potential use of higher doses of adintrevimab as needed to address emerging SARS-CoV-2 variants. Disclosures Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ed Campanaro, BSN, MSHS, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Deepali Gupta, B.Sc, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Frank Engler, PhD, Adagio Therapeutics: Advisor/Consultant Amanda Copans, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.
Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods The QSP model was fit in NONMEM Version 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; N=659, IM) and treatment (STAMP; N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results The QSP model provided an excellent fit to serum ADI concentration-time data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants. Disclosures Evan Tarbell, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Scott A. Van Wart, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ellie Hershberger, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Andrew Santulli, BSE, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President.
Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses with pandemic potential. Our objective was to develop a PPK model that describes the serum ADI concentration-time profile following intravenous (IV) and intramuscular (IM) administration. Methods The ADI PPK model was developed on PK data from a Phase 1 single-ascending dose study (24 adults, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; 659 adults, IM) and treatment (STAMP; 189 adults, IM) studies. 1,486 PK samples were included in the analysis. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI serum disposition were evaluated. Prediction-corrected visual predictive check (PC-VPC) plots were used to qualify the PPK model. Participant-specific ADI exposure estimates were generated using individual post hoc PK parameters. Results The PPK model is comprised of 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration and provided a robust fit to the data based on the PC-VPC plots and goodness-of-fit plots (data not shown). Body weight influenced clearance, intercompartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI clearance. The median [range] half-lives in days by study; Phase 1 (α1.71 [1.18-2.46]; β 125 [117-149]), Phase 2/3 prevention (α 1.86 [0.640-3.13]; β 136 [105-209]), and Phase 2/3 treatment (α 1.89 [0.631-3.01]; β 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. The figure shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI dose by study. Conclusion The PPK model provided a precise and unbiased fit to the observed ADI concentration-time data and will be useful for future PK-pharmacodynamic analyses. Moreover, ADI demonstrated high IM bioavailability and a median terminal elimination half-life of 125 to 136 days. Disclosures Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.
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