ABSTRACT
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 inNONMEMVersion 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 concentrationtime 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.
ABSTRACT
Background. Peak SARS-CoV-2 viral replication occurs in the upper respiratory tract in presymptomatic and early symptomatic phases. Administration of a monoclonal antibody may be most beneficial in the early time period immediately after symptom onset. Here we describe the effect of early therapy on efficacy in patients receiving ADI. Methods. High risk patients with mild or moderate COVID-19 were enrolled in the ADI treatment study (STAMP), with primary endpoint of COVID-19 related hospitalization or all-cause death through Day 29 in patients with disease due to confirmed or suspected SARS-CoV-2 variants other than Omicron. Patients were randomized 1:1 to receive ADI or placebo administered by a single intramuscular (IM) injection. For this subgroup analysis, patients that had received therapy within 3 days of symptom onset were evaluated. Results. In the overall population, the study met the primary endpoint demonstrating 66% relative risk reduction of COVID-19 hospitalization or all cause death in 336 patients. Among 261 patients receiving therapy within 3 days of symptom onset (n=133 ADI, n=128 placebo), ADI was associated with a statistically significant reduction in the risk of COVID-19-related hospitalization or all-cause death through Day 29 compared with placebo (4 [3%] vs. 15 [11.7%], standardized risk difference -8%, 95% CI: -14.11, -1.86, p=0.0106), demonstrating a 72% standardized relative risk reduction in favor of ADI. When given as early therapy, ADI provided a greater reduction in viral load from baseline to Day 5 compared with placebo as assessed by saliva samples, with an adjusted least-squares mean difference of -0.97 log10 copies/mL (95% CI: -1.540, -0.391;p=0.0011). No study drug related SAEs, including deaths, and no hypersensitivity reactions were reported. Conclusion. Early therapy with a single dose of ADI 300 mg IM provided a 72% reduction in the risk of COVID-19 related hospitalization and all-cause death compared to placebo in high-risk ambulatory patients with mild to moderate COVID-19. Therapy within the first 3 days also led to a greater reduction in viral load compared to placebo and favorable outcomes in patients who are at high risk for progression of disease.
ABSTRACT
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, inter compartmental 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 (alpha1.71 [1.18-2.46];beta 125 [117-149]), Phase 2/3 prevention (alpha 1.86 [0.640-3.13];beta 136 [105-209]), and Phase 2/3 treatment (alpha 1.89 [0.631-3.01];beta 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 unbiasedfit 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.