GlaxoSmithKline (GSK) and Vir Biotechnology have applied to the FDA seeking emergency use authorization (EUA) for VIR-7831 as an early treatment for COVID-19 in adults and adolescents, citing data that their dual-action monoclonal antibody candidate showed efficacy against SARS-CoV-2—and maintains activity against several of its variants as well.

The companies are seeking the EUA for VIR-7831, also called GSK4182136, to treat patients aged 12 and older weighing at least 40 kg (88 pounds) with mild-to-moderate COVID-19 who are at risk for progression to hospitalization or death.

GSK and Vir are basing their EUA submission on an interim analysis of positive results from 583 patients enrolled in their Phase III COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial—Intent to Care Early) study (NCT04545060). The trial evaluated VIR-7831 as monotherapy for the early treatment of COVID-19 in adults at high risk of hospitalization.

The interim analysis, whose results were first announced by the companies on March 10 in a press release, showed an 85% reduction in hospitalization or death in patients receiving VIR-7831 as monotherapy compared to placebo, the primary endpoint of the trial.

As a result, GSK and Vir said, the trial’s Independent Data Monitoring Committee (IDMC) recommended the study stop enrolling patients due to evidence of “profound” efficacy.

Data from the COMET-ICE trial will also form the basis for the companies’ eventual Biologics License Application (BLA) submission to the FDA, Vir and GSK said, with other regulatory submissions to come elsewhere in the world.

“GSK and Vir will continue discussions with the European Medicines Agency (EMA) and other global regulators to make VIR-7831 available to patients with COVID-19 as soon as possible,” the companies added.

Activity vs. three variants

Also on March 10, GSK and Vir posted in vitro data on bioRxiv showing that VIR-7831 and VIR-7832, another COVID-19 antibody being developed by the companies, showed activity against three SARS-CoV-2 variants that have alarmed public health officials worldwide in recent weeks, including the U.K. variant B.1.1.7, the South African variant B.1.351, and the Brazilian variant P.1.

The companies tested the neutralization capacity of VIR-7831 and VIR-7832 against the three variants of SARS-CoV-2 in a VeroE6 cell-based live virus system. VIR-7831 scored best in testing with 12 substitutions in the Spike sequence against the Brazilian variant, showing a reduction in susceptibility of 0.35-fold. The 12 substitutions were D138Y, D614G, E484K, H655Y, K417T, L18F, N501Y, P26S, R190S, T1027I, T20N, and V1176F.

VIR-7831 showed a reduction in susceptibility of 0.60-fold against the South African variant following testing with nine substitutions—L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G, and A701V.

However, VIR-7831 achieved its lowest score against the U.K. variant, with a reduction in susceptibility of 2.3-fold following testing with 10 Spike sequence substitutions—H69-, V70-, Y144-, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H.

“Based on additional soon-to-be-published preclinical data, VIR-7831 also appears to maintain activity against the California variant,” GSK and Vir stated Friday in an announcement of their EUA application.

VIR-7832 showed slightly further reduced susceptibility against all three variants with the same substitutions as made for VIR-7831, from 0.42-fold against P.1, to 0.72-fold against B.1.351, to 2.5-fold against B.1.1.7.

“That VIR-7831 and VIR-7832 retain activity against the B.1.1.7, B.1.351, and P.1 spike proteins in 277 pseudotyped virus assays is a key finding at this stage of the pandemic,” the researchers concluded in the preprint, whose corresponding author was Christy M. Hebner, vice president virology, and COO of research with Vir Biotechnology.

Support for hypothesis

GSK and Vir said their findings against the variants supported their hypothesis gleaned from earlier preclinical data suggesting that VIR-7831 targeted a highly conserved epitope of the spike protein, which may make it more difficult for resistance to develop.

COMET-ICE is one of four “COMET” trials comprising the companies’ clinical development program for VIR-7831. The other three:

  • COMET-PEAK (NCT04779879): An ongoing Phase II trial with two parts: to compare the safety and viral kinetics of 500 mg intramuscularly (IM) administered VIR-7831 to 500 mg intravenously administered VIR-7831 among low-risk adults with mild to moderate COVID-19 and to evaluate the similarity in pharmacokinetics between VIR-7831 manufactured by different processes.
  • COMET-TAIL: A Phase III trial expected to begin in the second quarter in high-risk adults to assess whether IM-administered VIR-7831 can reduce hospitalization or death due to COVID-19.
  • COMET-STAR: A Phase III trial expected to begin in the second quarter in uninfected adults at high risk to determine whether IM-administered VIR-7831 can prevent symptomatic infection.

VIR-7831 is also under study with Eli Lilly’s FDA emergency use-authorized COVID-19 antibody bamlanivimab (LY-CoV555) in low-risk adults with mild to moderate COVID-19, as part of an expansion of the ongoing, 700-participant Phase II BLAZE-4 trial (NCT04634409).

On Wednesday, the U.S. government halted distribution of bamlanivimab as a monotherapy, citing a sustained increase in variants of SARS-CoV-2 that are resistant to the monotherapy—but continues to distribute bamlanivimab in combination with etesevimab (LY-CoV16 or JS-16), another Lilly antibody. The combination won FDA authorization for emergency use last month.

VIR-7831, which incorporates Xencor’s Xtend™ Fc technology, is designed to bind to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1, indicating that the epitope is highly conserved, which according to the companies may make it more difficult for resistance to develop.

VIR-7831 and -7832—which is engineered to potentially enhance virus-specific T cell function—are among 21 “Front Runner” candidates among the more than 300 COVID-19 therapeutics under study in GEN’s “COVID-19 Drug & Vaccine Candidate Tracker.”