Ongoing Covid-19 trials are adopting different strategies to sequence patient samples to identify the impact of emerging SARS-CoV-2 variants on the efficacy of monoclonal antibody (mAb) cocktails, investigators said.
The trial setting—treatment or prevention—is driving the sequencing strategy. While trials are collecting participant samples to ascertain the impact of emerging variants of concern (VOCs), the immediate focus remains mainly on clinical outcome measures, with sequencing data expected to be available later. Nonetheless, experts said preclinical data is providing necessary evidence on mAb efficacy against VOCs in a quick manner. mAb development in the context of VOCs is being closely watched, particularly given that the FDA Emergency Use Authorisation (EUA) of Eli Lilly’s bamlanivimab monotherapy was revoked on 16 April.
In large platform studies like the Phase II/III ACTIV-2, which is evaluating mAbs and other therapies in the nonhospitalised setting, sequencing of patient samples to identify VOCs is not done in real time, said ACTIV-2 Vice-Chair Dr David Wohl, professor of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill. Rather, stored specimens will be sampled for variant identification, he added. Data on each therapy’s efficacy rates against VOCs will likely only be available after overall efficacy is determined, Wohl explained.
Still, all the tested therapies are expected to be active against VOCs, Wohl said. Particularly in the treatment setting, which ACTIV-2 is testing, mAb cocktails are expected to be active against the known VOCs, said Dr Myron Cohen, director, Institute for Global Health & Infectious Diseases, UNC Chapel Hill.
Viral replication is expected to normally slow down even without treatment, and furthermore with mAbs, so if it persists in infected cases then there is an impetus to sequence those samples, said Cohen. The Phase II portion of the adaptive ACTIV-2 only has 110 patients in each investigational arm, so there is limited scope to perform subgroup analysis correlating efficacy to a particular variant at this stage, Wohl said.
The ACTIV-2 trial is currently evaluating six therapies including Durham, North Carolina-based Brii Biosciences’ monoclonal antibody cocktail of BRII-196/BRII-198; the mAb cocktail of C135-LS/C144-LS developed at Rockefeller University and licensed to Bristol Myers Squibb; AstraZeneca’s long-acting injectable mAb combo AZD7442, and Sioux Falls, South Dakota-based SAB Biotherapeutics’ polyclonal antibody SAB-185. In addition, the trial also includes treatment arms for Synairgen’s inhaled interferon-beta SNG001, and Schaumburg, Illinois-based Sagent Pharmaceuticals’ protease inhibitor camostat mesylate.
The strategy to sequence and identify variants is also driven by the setting in which the trial is being conducted, said experts. In the prevention setting, anyone acquiring an infection even after being given the mAb would need to have their samples sequenced, said Cohen, who was an investigator on Regeneron Pharmaceuticals’ REGEN-COV cocktail (casirivimab with imdevimab) in the post-exposure prophylaxis setting (NCT04452318). This Phase III trial tested subQ REGEN-COV’s potential to prevent SARS-CoV-2 infections in participants who had potential exposure to a Covid-19-positive individual. In case of breakthrough infections in such settings, sequencing has to be done prospectively so the Data and Safety Monitoring Board (DSMB) can evaluate whether the drug failed because of an existing resistant variant, the mAb has evoked a resistant variant or some unknown reason, said Cohen. REGEN-COV reduced the risk of symptomatic infections by 81% among participants compared to placebo through the 29-day endpoint, as per a 12 April press release.
Regeneron is sequencing samples from its prior and ongoing studies, said a spokesperson. The company will share VOC data with regulatory authorities and publish any data outlining REGEN-COV’s efficacy against different VOCs in the future, the spokesperson added.
The evocation of resistance or mAb failure hasn’t been seen with mAbs except in the case of Eli Lilly’s bamlanivimab, said Cohen. In its notice to revoke bamlanivimab’s EUA, the FDA noted a sustained increase of SARS-CoV-2 viral variants that are resistant to the therapy alone, increasing the risk of treatment failure. The bamlanivimab combination with etesevimab and REGEN-COV remain FDA-authorised.
However, more recently, the CDC detected a higher frequency of the P.1 variant, one of five identified by the agency as a VOC, in Illinois. In vitro assays suggest the bamlanivimab/etesevimab cocktail was not active against that variant, as per a 7 May US Department of Health and Human Services update. Consequently, the FDA recommends that physicians use the REGEN-COV cocktail instead.
Current protocols leave room for improvement
While there is a need to build in some real-time sequencing components in all trials, it is challenging since these trials are being done under exigency, said Cohen. Sequencing of isolates will still be done as fast as possible, but that may not be immediate, agreed Dr James Crowe, director, Vanderbilt Vaccine Center, Nashville, Tennessee, an investigator on AZD7442. Data on AZD7442 are pending from the 1,129-participant Phase III STORM CHASER (NCT04625972) in the postexposure prophylaxis setting, and 5,247-patient Phase III PROVENT (NCT04625725) in the pre-exposure prophylaxis backdrop, but the trials have finished recruitment. In these studies, in case of breakthrough infections, samples are sent to central laboratories where the variants and specific mutations would be identified, but that data is not expected in the immediate future, said investigator Dr Andrew Ustianowski, consultant in Infectious Diseases and Tropical Medicine at North Manchester General Hospital, United Kingdom.
The focus with these large studies has been to find an effective intervention rather than sequencing samples, said Dr Sanjay Sethi, chief, Pulmonary, Critical Care and Sleep Medicine, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, New York. Also, originally at the trial design stage, sequencing protocols were not in place because the magnitude and impact of VOCs were not fully understood, said Cohen.
Also, it takes a few weeks to generate the reagents to do an efficacy analysis of the mAbs against emerging variants, said Crowe. By the time an agent is tested against a variant, more variants emerge, he said, describing it as an ongoing “treadmill of testing.” Variants that are relevant may not be so a few months from now, he said.
Moreover, preclinical studies are giving necessary information about mAb cocktail efficacy against different variants faster than human studies, said Crowe. Cohen talked about the UNC laboratory sequencing positive samples to help understand infections in the community. If a clinical laboratory in a big hospital can do this, there is no reason it cannot be done in a clinical trial, he added.
Nonetheless, the capacity to do real-time sequencing for all Covid-19 patients is not adequate and currently, genome analysis to identify whether an infection is caused by a VOC or not is done at random, said Dr Sohail Rao, CEO, DHR Health Institute for Research & Development, College Station, Texas, who is involved with studying and providing access to mAbs. Rao described his institution’s ongoing efforts to coordinate with the Texas Department of Health and Human Services and the Baylor College of Medicine Human Genome Sequencing center to apply for grants as part of the nationwide initiative to spur variant sequencing. The Biden administration had announced an influx of $1.7bn to track variants and scale genomic sequencing efforts by allocating funds to the CDC, states, and other jurisdictions, as per an 16 April announcement.
Large-scale genome sequencing could be possible after that, said Rao. Researchers are applying to get this funding to sequence samples on a local basis, and it will be important to tie that to clinical outcomes, said Sethi. However, now when samples are shipped for sequencing analysis of variants, it is not possible to tie them to a specific patient, said Sethi.
AstraZeneca did not respond to a request for comment, and Eli Lilly did not comment before press time.
Manasi Vaidya is a Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.