Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines-Selecting Compounds for Clinical Evaluation in Coronavirus Disease 2019 Clinical Trials

Abstract

Given the urgent need for coronavirus disease 2019 therapeutics, early in the pandemic the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership rapidly designed a unique therapeutic agent intake and assessment process for candidate treatments of coronavirus disease 2019. These treatments included antivirals, immune modulators, severe acute respiratory syndrome coronavirus 2 neutralizing antibodies, and organ-supportive treatments at both the preclinical and clinical stages of development. The ACTIV Therapeutics-Clinical Working Group Agent Prioritization subgroup established a uniform data collection process required to perform an assessment of any agent type using review criteria that were identified and differentially weighted for each agent class. The ACTIV Therapeutics-Clinical Working Group evaluated over 750 therapeutic agents with potential application for coronavirus disease 2019 and prioritized promising candidates for testing within the master protocols conducted by ACTIV. In addition, promising agents among preclinical candidates were selected by ACTIV to be matched with laboratories that could assist in executing rigorous preclinical studies. Between April 14, 2020, and May 31, 2021, the Agent Prioritization subgroup advanced 20 agents into the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines master protocols and matched 25 agents with laboratories to assist with preclinical testing.

Figure 1.

Process of collecting and classifying agents to allow for optimal triage and scoring by preset criteria. Step I for wave 1-collected potential compounds and data from publicly available sources to allow for expedited review of potential candidates. In wave 2 and beyond, information for this step was supplied by responses to the Accelerating Coronavirus Disease 2019 (COVID-19) Therapeutic Interventions and Vaccines (ACTIV) public portal submissions. Step II divided the agents into therapeutic classes to allow for assignment to appropriate panels of recruited experts in that field versed in both preclinical and clinical data needed for agents to be viable COVID-19 treatments. Finally, step III assembled expert panels for triage review and subsequent scoring according to criteria developed and refined by the ACTIV Therapeutics-Clinical working group. nAb = neutralizing antibody.

Figure 2.

Sources for initial candidates. Databases from which initial candidate agents were assembled for evaluation. BIO = the trade organization for biotechnology companies, NIH = National Institutes of Health, R&D = Research & Development.

Figure 3.

Clinical readiness–screening process. Clinical readiness screening applied five screening tests to identify drugs available for phase 2 or 3 studies; drugs must pass all the triage steps to move to the next review phase. The tests are the following: 1) is the drug investigational new drug (IND)-enabled or Food and Drug Administration (FDA)-approved? 2) Is the mechanism of action relevant to coronavirus disease 2019 (COVID-19) and are other agents with the same mechanism of action already tested in clinical trials? 3) Is there clinical and/or preclinical evidence that the drug may treat COVID-19? 4) Is the drug already being tested in robust, sufficiently powered clinical trials? 5) Is the drug suitable for populations prioritized by Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)? MOA = mechanism of action, No Go = this agent not tenable – stop scoring, SARS-CoV-2= severe acute respiratory syndrome coronavirus 2.

Figure 4.

Initial prioritization scoring criteria. The seven categories used for prioritization were: 1) rationale for the mechanism of action (MOA) relevant to COVID-19, 2) existing data from published clinical trials, 3) preclinical data in relevant in vitro and/or in vivo models, 4) pharmacokinetics/pharmacodynamics (PK/PD) data for the compound in the given route of administration, 5) safety data for the compound, 6) drug-drug interactions (DDI), and 7) availability of the compound to allow the start of clinical trials and the scalability of the compound. After a first round of prioritization, draft criteria focused on scientific rationales were reassessed for each class of compounds (antivirals, immunomodulatory, and organ-supportive therapies) to ensure that criteria are completely matched to the class: different weights were assigned to different prioritization criteria (e.g., score for in vitro viral inhibition specific to antivirals), ensuring that the most relevant criteria drive decision-making. All reviewers evaluated the same data, which was posted in one location to aid efficient, consistent reviews. Sequenced prioritization workflow was used, where each reviewer for each agent class scored agents individually and then convened with all other reviewers for that agent class to discuss; this allowed reviewers to amend scores based on additional or emerging information (e.g., new data published from a clinical trial). RCTs = randomized control trial, SARS-CoV-2= severe acute respiratory syndrome coronavirus 2.

Figure 5.

Overview of the full agent prioritization process for wave 1. A first list of candidates was completed. The initial agent prioritization process was used to narrow more than 450 agents to 6. An evaluation of clinical readiness for a confirmatory study was conducted to narrow to 170. These 170 were reviewed by triage criteria; if one agent in a class was determined to already be well studied, all agents in that class were triaged. The remaining 39 agents were evaluated by the prioritization criteria; agent classes were reviewed by experts for that class. Six agents were prioritized after the wave 1 agent prioritization was completed. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines, bioRX = bioRxiv (a Cold Spring Harbor Publication), FDA = Food and Drug Administration, IND = investigational new drug, LMWH = low-molecular-weight heparin, NIH = National Institutes of Health, PI = Principal Investigator, R&D = Research and Development, UK = United Kingdom.

Figure 6.

Final gating criteria for severe acute respiratory syndrome coronavirus 2 monoclonal antibodies (mAb) established by the neutralizing antibody (nAb) review subteam. *Relevant if intent is to first enter phase 2 of ACTIV clinical trials. **Can be provided after initial information submission. Ab = antibody, ACTIV = Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines, ADA = antidrug antibody, ADE = antibody-dependent enhancement, Fc = fragment, crystallizable, FDA = Food and Drug Administration, IC50 = half-maximal inhibitory concentration, IC90 = 90% maximal inhibitory concentration, IM = intramuscular, SAE = serious adverse event, SoC = standard of care, SQ = subcutaneous, TCR = tissue cross-reactivity.

Figure 7.

Wave 2 and current wave 3 prioritization results. As of January 31, 2021, 161 agents have been assessed in these later waves, and 17 agents have been selected for placement in Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines (ACTIV) master protocols. Another 32 agents have been selected for rapid follow-up and further data requests from the submitters to determine if they have the right potential for an ACTIV trial. Forty-seven agents have been deferred to allow for the submitters to complete more preclinical or clinical studies needed to advance the agent to a large confirmatory trial. Finally, 84 agents have been deemed unsuited for study in the ACTIV master protocols. BMS = Bristol Myers Squibb, GSK = GlaxoSmithKline, IFN = interferon, RU = Rockefeller University, SAB = SAB Therapeutics, VIP = vasointestinal peptide, Vir = Vir Biotechnology..

Figure 8.

From portal to product: linking the Preclinical and Clinical Pathways. Compounds came to the Preclinical Working Group for evaluation by two main routes: 1) submitted directly via the Accelerating Coronavirus Disease 2019 (COVID-19) Therapeutic Interventions and Vaccines (ACTIV) COVID-19 Clinical and Preclinical Candidate Compound Portal and 2) from the clinical group. The preclinical group focused on the novelty of the mechanism, likelihood of success of that mechanism, observed data in cellular and in vivo models, and coverage of preclinical safety and pharmacokinetic data. Based on the potential for success, if experimental data were needed, the group attempted to help the sponsor obtain those results. After the results were generated, the agent was reevaluated and a decision was made to move the review back to the clinical group for inclusion in a trial. BSL = biosafety levels, MOA = mechanism of action, PK/PD = pharmacokinetics/pharmacodynamics.