Candidate: Sotrovimab (formerly VIR-7831, also known as GSK4182136)
Type: Dual-action SARS-CoV-2 monoclonal antibody based on Vir’s proprietary monoclonal antibody platform technology.
2022 Status: Amended EUA Application for Intramuscular Early Treatment—Vir and GSK said January 13 that they had applied for an amendment to their Emergency Use Authorization (EUA) for sotrovimab to allow use of the monoclonal antibody for early treatment of COVID-19, including intramuscular (IM) administration.
The submission wass based on data from the Phase III COMET-TAIL trial (NCT04913675). The randomized, open-label, non-inferiority study achieved its primary endpoint by showing that 500mg IM administration of sotrovimab in 376 patients was non-inferior and offered similar efficacy to 500 mg IV administration in 378 patients for the early treatment of mild-to-moderate COVID-19 in high-risk, non-hospitalized adults and adolescents. Serious adverse event rates of ≤1% in both arms were seen.
Under the current EUA, sotrovimab can be used for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
2021 Status: In Vitro Activity Retained vs. Omicron—Vir and GSK said December 7 that researchers have posted a preprint on bioRxvix showing that Sotrovimab retained in vitro activity against the Omicron variant of SARS-CoV-2 (B.1.1.529). The preclinical data was generated through pseudo-virus testing of the combined known mutations of the Omicron variant, which included the maximum number of changes (37 mutations) identified to date in the spike protein. The findings built upon initial preclinical data generated through pseudo-virus testing, provided December 2 showing sotrovimab retained in vitro activity against key individual mutations of the Omicron variant, including those found in the binding site of sotrovimab.
Primary Endpoint Met in COMET-3—Vir and GSK on November 12 announced topline data from the randomized, multi-center, open-label Phase III COMET-TAIL trial (NCT04913675) showing that it achieved its primary endpoint by showing that intramuscular (IM) administration of sotrovimab was non-inferior to intravenous (IV) administration for the early treatment of mild-to-moderate COVID-19 in high-risk, non-hospitalized adults and adolescents (12 years of age and older).
COMET-TAIL was designed to evaluate the efficacy, safety and tolerability of sotrovimab delivered via IM administration compared to IV administration in high-risk patients up to seven days after symptom onset. In the IM administration (500mg) arm of the trial, there was a 2.7% rate of progression to hospitalization for more than 24 hours or death through Day 29 of the trial, compared to 1.3% in the IV administration arm (also 500mg).
GSK and Vir added that they remained in “ongoing discussions with the FDA regarding the existing Emergency Use Authorization for sotrovimab.”
Canada Purchases 10,000 Doses—GlaxoSmithKline said October 4 that Canada’s government agreed to buy 10,000 doses of sotrovimab from the company for an undisclosed price, with an option to purchase additional doses next year.
Final Positive Data, NIH Recommendation—GSK and Vir on June 21 said final, confirmatory results from the Phase III COMET-ICE trial (COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early; NCT04545060) showed that sotrovimab significantly reduced the risk of hospitalization or death among high-risk adult outpatients with mild-to-moderate COVID-19. The primary efficacy analysis of all 1,057 patients in the COMET-ICE trial demonstrated a 79% reduction (adjusted relative risk reduction) in hospitalization for more than 24 hours or death due to any cause, by Day 29 compared to placebo, meeting the primary endpoint of the trial.
GSK and Vir also said the NIH has updated its COVID-19 treatment guidelines to recommend sotrovimab for non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk of clinical progression and noted that sotrovimab appears to retain activity against current variants of concern and interest.
SOTROVIMAB GRANTED FDA EUA—The FDA on May 26 granted an Emergency Use Authorization (EUA) for sotrovimab, a single-dose monoclonal antibody, for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
The EUA was granted to sotrovimab based on an interim analysis of efficacy and safety data from the Phase III COMET-ICE trial in high-risk adult outpatients, which was stopped early by an independent data monitoring committee in March 2021 due to evidence of profound clinical efficacy. (See COMET-ICE Interim Analysis, below).
CHMP Issues Positive Opinion—The European Medicines Agency (EMA)’s Committee on Human Medicinal Products (CHMP) on May 21 issued a positive opinion recommending sotrovimab (formerly VIR-7831) for the treatment of adults and adolescents (aged 12 years and over and weighing at least 40 kg) with COVID-19 who do not require oxygen supplementation and who are at risk of progressing to severe COVID-19.
The CHMP opinion came less than a month since the EMA launched a rolling review of data on sotrovimab. GlaxoSmithKline (GSK) and Vir Biotechnology said May 7 that the rolling review was based data from an interim analysis of efficacy and safety data from the Phase III COMET-ICE trial, designed to evaluate VIR-7831 as monotherapy for the early treatment of COVID-19 in adults at high risk of hospitalization.
COMET-ICE Interim Analysis—The interim analysis, based on data from 583 randomized patients, showed an 85% reduction in hospitalizations over 24 hours or deaths in those receiving sotrovimab compared to placebo, the primary endpoint of the trial.
The EMA’s rolling review will continue until enough evidence is available to support a formal marketing authorization application (MAA), GSK and Vir added.
The EMA rolling review comes three weeks after the EMA’s Committee for Human Medicinal Products (CHMP) began a separate review of sotrovimab. CHMP will provide European Union-wide recommendations for national authorities considering early use of the medicine, ahead of an MAA, the companies said April 15.
Also on April 15, GSK and Vir said Australia’s Therapeutic Goods Administration (TGA) granted VIR-7831 a provisional determination, which provides a formal and transparent mechanism for accelerating the registration of promising new medicines with preliminary clinical data. VIR-7831 is the first anti-SARS-CoV-2 monoclonal antibody to receive the designation.
Researchers for Vir and the University of Washington on April 1 published preclinical research in bioRxiv in which VIR-7831 was shown to maintain its neutralizing activity against a mutation in the receptor binding domain (RBD) of SARS-CoV-2, called L452R, found in the California variant (B.1.427/B.1.429). The study also showed that the L452R mutation reduced both the neutralization potency of plasma from vaccinated and convalescent donors and the neutralization activity of 14 RBD-specific and 10 N-terminal domain (NTD)-specific monoclonal antibodies, including three clinical-stage monoclonal antibodies.
Researchers characterized the impact of L452R’s three mutations: S13I and W152C in the NTD and L452R in the RBD. Data from 43 vaccinated donors and nine convalescent donors showed that, in a pseudotyped virus system, the S13I, W152C and L452R mutations reduced the neutralization potency of plasma by three-to-six-fold. In addition, the L452R mutation reduced the neutralization activity of 14 out of 35 RBD-specific mAbs, including three clinical-stage antibodies. Researchers also reported a complete loss of neutralization by all NTD-specific monoclonal antibodies that is mediated by an unconventional escape mechanism. VIR-7831, which targets a non-receptor binding motif epitope, was unaffected by the L452R mutation.
The data has been submitted to a peer-reviewed journal for future print publication, Vir said.
Vir and Eli Lilly said March 29 that Lilly’s bamlanivimab (LY-CoV555) 700 mg co-administered with Vir’s VIR-7831 (also known as GSK4182136) 500 mg showed a 70% relative reduction in persistently high viral load at day 7 compared to placebo, meeting the primary endpoint of the expanded Phase II BLAZE-4 trial (NCT04634409) studying low-risk adult patients with mild to moderate COVID-19.
Vir and Lilly also said the combination of bamlanivimab and VIR-7831 also showed a statistically significant reduction compared to placebo in the key virologic secondary endpoints of mean change from baseline to days 3, 5 and 7 in SARS-CoV-2 viral load. There were no events for the secondary endpoint of COVID-19 related hospitalization or death by day 29 in either study arm. One patient (in the treatment arm) visited the emergency room for COVID-19 related symptoms. No serious adverse events were seen with co-administration of bamlanivimab and VIR-7831.
Vir and GSK said March 10 that they plan to apply for FDA emergency use authorization (EUA) and similar authorizations in other countries for VIR-7831, based on positive results from their Phase III COMET-ICE trial. The trial’s Independent Data Monitoring Committee (IDMC) recommended the study stop enrolling patients due to evidence of “profound” efficacy. The companies cited an interim analysis of data from 583 patients enrolled in the COMET-ICE trial, showing an 85% reduction in hospitalization or death in patients receiving VIR-7831 as monotherapy compared to placebo, the primary endpoint of the trial. VIR-7831 was well tolerated.
The trial remains ongoing and blinded with patients continuing to be followed for 24 weeks. Additional results, including epidemiology and virology data, will be forthcoming once the trial is completed, Vir and GSK said.
COMET-ICE is one of four “COMET” trials comprising the companies’ clinical development program for VIR-7831. The other three:
- COMET-PEAK: 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 and another Vir-developed antibody against COVID-19, VIR-7832, is being evaluated in the Phase Ib/IIa NIH-supported AGILE trial (NCT04746183) in adults with mild to moderate COVID-19. VIR-7832 is the second monoclonal antibody from the Vir-GSK collaboration to be investigated as a potential COVID-19 treatment.
Vir joined Eli Lilly and GlaxoSmithKline (GSK) on January 27 to say that Lilly’s bamlanivimab 700 mg is being studied in combination with Vir/GSK’s VIR-7831 (GSK4182136), 500 mg, in an expansion of the ongoing, 700-participant BLAZE-4 trial, which the companies said marks the first time that monoclonal antibodies from separate companies will be brought together to explore potential outcomes. The neutralizing antibodies bind to different epitopes of the SARS-CoV-2 spike protein.
2020 Status: 2020 Status: Vir and GSK said August 31 that the first patient was dosed last week in the Phase II/III COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early) study, designed to evaluate whether VIR-7831, as a single-dose monoclonal antibody, can prevent hospitalization in patients with mild or moderate forms of COVID-19 who are at high risk of progression to severe disease, such as the elderly or those with pre-existing conditions such as lung or heart disease.
COMET-ICE will consist of a Lead-In phase that will assess the safety and tolerability of a single 500 mg intravenous (IV) infusion of VIR-7831 or placebo over a 14-day period in non-hospitalized patients. It aims to recruit 20 patients across the U.S. The Expansion phase will assess the safety and efficacy of a single IV infusion of VIR-7831 or placebo in approximately 1,300 non-hospitalized participants globally.
The primary efficacy endpoint is the proportion of patients with mild or moderate COVID-19 who worsen, as defined by the need for hospitalization or death, within 29 days of randomization. Initial results from COMET-ICE may be available before the end of 2020, with complete results expected in the first quarter of 2021, Vir and GSK said. Patients could potentially access the antibody treatment as soon as the first half of 2021, the companies added.
Vir and GSK disclosed that the clinical development program for VIR-7831 includes two additional planned trials—one for the treatment of severely ill hospitalized patients and another for the prophylaxis of symptomatic infection.
Vir and GSK said they expect to start a Phase II of another neutralizing monoclonal antibody, VIR-7832, which shares the same characteristics as VIR-7831 but may also function as a therapeutic and/or prophylactic T cell vaccine.
On June 15, Vir disclosed in a regulatory filing that six days earlier, it formalized an exclusive collaboration agreement with GSK to research, develop, and commercialize products for the prevention, treatment and prophylaxis of diseases caused by SARS-CoV-2, and potentially other coronaviruses.
For four years following the agreement’s April 29 effective date, subject to rights granted to WuXi Biologics under agreements with Vir, GSK and Vir will have exclusive research collaborations covering antibody products directed to SARS-CoV-2 or any other coronavirus, as well as functional genomics CRISPR screens for drug discovery and development in connection with SARS-CoV-2 or other coronaviruses.
Vir is primarily responsible for development and clinical manufacturing activities for the antibody program, and for initial development activities directed to a vaccine. GSK will be primarily responsible for commercialization activities for the antibody program (except in connection with sales of antibody products licensed to WuXi in greater China), the later-stage development, manufacturing and commercialization activities for the vaccine program and the development, manufacturing and commercialization activities for the functional genomics program.
The companies agreed to share all development costs, manufacturing costs and costs and expenses for the commercialization of the collaboration products, with Vir bearing 72.5% of such costs for the antibody products, 27.5% of such costs for the vaccine products, and the parties sharing equally all such costs for the functional genomics products.
In April, GSK agreed to make a $250 million equity investment in Vir under an R&D collaboration designed to advance COVID-19 candidates into Phase II clinical trials later this year,. The companies agreed to identify new anti-viral antibodies, and study existing ones, to prevent and treat COVID-19 and future coronaviruses.
GSK and Vir also agreed to research vaccines designed to prevent SARS-CoV-2 and other coronaviruses, as well as combine their expertise in CRISPR screening and artificial intelligence to identify products based on genome-wide CRISPR screening of host targets expressed in connection with exposure to SARS-CoV-2.
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: