The UK RECOVERY trial investigators recently disclosed that Regeneron’s REGEN-COV, a pair of monoclonal antibodies, actually reduced the risk of death by 20% in patients hospitalized with COVID-19 who failed to sustain their own immune response. According to the company’s press release, this monoclonal antibody cocktail represents the first antibody treatment that improved survival in patients hospitalized with COVID-19. The company will not only share this data with regulatory authorities immediately but will also seek to expand its U.S. EUA to include appropriate hospitalized patients.
TrialSite provides a brief summary breakdown of this most recent information generated by the UK RECOVERY trial. Note that this platform was developed initially using a Sentinel agreement with the U.S. Food and Drug Administration (FDA) during the early days of the pandemic. TrialSite is pleased to report that this company has been one of the more transparent ones meaning when questions were submitted to company spokespersons they were quick to turn around and send answers.
What is the UK RECOVERY trial?
The RECOVERY trial (Randomized Evaluation of COVid-19 thERapY) was conducted by the registered clinical trials units in the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine. The trial was supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit and NIHR Clinical Trials Unit Support Funding.
In the case of the Regeneron product, between September 18, 2020 and May 22, 2021, 9,785 patients hospitalized with COVID-19 were randomly allocated to receive usual care plus REGEN-COV (8,000 mg by intravenous infusion) or usual care alone as part of the RECOVERY trial. Usual care was determined by individual facilities and clinicians, and could include steroids and remdesivir. Follow-up is complete for 99% of participants.
The trial involved many thousands of doctors, nurses, pharmacists, and research administrators at 176 hospitals across the whole of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, the Secure Anonymised Information Linkage at University of Swansea, and the NHS in England, Scotland, Wales and Northern Ireland.
What is REGEN-COV?
REGEN-COV (casirivimab and imdevimab) is a cocktail of two monoclonal antibodies (also known as REGN10933 and REGN10987) that was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19, using Regeneron’s proprietary VelocImmune® and VelociSuite® technologies. The two potent, virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in Science.
Under an EUA, REGEN-COV is available throughout the U.S. – information on availability in your area is available from the Department of Health and Human Services and the National Infusion Center Association. REGEN-COV can be administered by intravenous infusion (as short as 20 minutes) or by subcutaneous injection (four injections), which is an alternative when intravenous infusion is not feasible and would lead to a delay in treatment. It is now authorized as a co-formulated single vial, or in individual vials to be administered together.
In the U.S., REGEN-COV is not authorized for use in patients who are hospitalized due to COVID-19 or require oxygen therapy, or for people currently using chronic oxygen therapy because of an underlying comorbidity who require an increase in baseline oxygen flow rate due to COVID-19.
What the key study findings?
The primary outcome of RECOVERY showed that adding REGEN-COV 8,000 mg to usual care reduced all-cause mortality by 20% in seronegative patients (primary analysis population), compared to usual care alone (24% of patients in the REGEN-COV group died versus 30% in the usual care group by day 28; rate ratio [RR]: 0.80; 95% confidence interval [CI]: 0.70-0.91; p=0.001). When combining the larger seropositive group (as well as those with unknown status) with the seronegative patients, there was no longer a significant effect on 28-day mortality (overall 20% of patients in the REGEN-COV group died, versus 21% in the usual care group; RR: 0.96; 95% CI: 0.86-1.03; p=0.17).
The company was upbeat about the positive results from the largest study investigating any monoclonal antibody treatment patients hospitalized with severe COVID-19. This study’s finding, that by adding the investigational monoclonal antibody named herein to usual care reduced the risk of death by 20% in patients who had not mounted a natural antibody response on their own against SARS-CoV-2, compared to the usual care on its own.
“These results are very exciting. The hope was that by giving a combination of antibodies targeting the SARS-CoV-2 virus we would be able to reduce the worst manifestations of COVID-19,” said Sir Peter Horby, Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, and Joint Chief Investigator for the RECOVERY trial. “There was, however, great uncertainty about the value of antiviral therapies in late-stage COVID-19 disease. It is wonderful to learn that even in advanced COVID-19 disease, targeting the virus can reduce mortality in patients who have failed to mount an antibody response of their own.”
RECOVERY is the first trial large enough to definitively determine whether REGEN-COV reduces mortality in patients hospitalized with severe COVID-19. Previous Phase 3 trials in non-hospitalized COVID-19 patients have shown that REGEN-COV reduced viral levels, shortened the time to resolution of symptoms and significantly reduced the risk of hospitalization or death.
Previous Phase 1/2 Clinical Trials
In a Phase 1/2 trial in hospitalized patients, REGEN-COV also rapidly reduced viral levels, with preliminary evidence suggesting that it lowered the risk of death or receiving mechanical ventilation, with the benefit driven by patients who entered the trial without having mounted a natural antibody response of their own (seronegative); and in the absence of REGEN-COV treatment, seronegative patients had higher mortality rates than patients who had already mounted their own immune response (seropositive).
Based on the above Phase 1/2 data, the independently-run RECOVERY trial prospectively focused on seronegative patients. Similar to the prior trial, patients in RECOVERY who received usual care alone had double the mortality rate at day 28 if they were seronegative (30%) compared to seropositive (15%); approximately one-third of hospitalized patients were seronegative (n=3,153), one-half were seropositive (n=5,272) and one-sixth had unknown serostatus (n=1,360). The mean age of patients for this comparison was 62 years, and more than 90% received corticosteroids across all groups.
Data Gets Stronger
“Definitive Phase 3 trials have now demonstrated that REGEN-COV can alter the course of COVID-19 infection from prevention, to very early infection, all the way through to when patients are on a ventilator in the hospital,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. “We are incredibly grateful to the RECOVERY team, participating investigators and patients for conducting this in-depth analysis, and hope that the results mean that even more patients may soon be able to benefit from this life-saving medicine. We intend to rapidly discuss these results with regulatory authorities, including in the U.S. where we will ask for our EUA to be expanded to include appropriate hospitalized patients.”
Among seronegative patients in the RECOVERY trial, the median duration of hospital stay was 4 days shorter in the REGEN-COV group (13 days versus 17 days), and the proportion of patients discharged alive by day 28 was greater (64% versus 58%; RR: 1.19; 95% CI: 1.08-1.30). Among the seronegative patients not on invasive mechanical ventilation at baseline, the risk of progressing to the composite endpoint of invasive mechanical ventilation or death was lower among the REGEN-COV group than the usual care group (30% versus 37%; RR: 0.83; 95% CI: 0.75-0.92). No such benefits were seen in the overall trial population (combining patients with negative, positive, or unknown serostatus).
“The RECOVERY trial has shown that in patients who had not made their own antibodies against SARS-CoV-2, treating them with REGEN-COV antibodies dramatically reduced their risk of dying or being on a ventilator, and also shortened how many days they remained in the hospital,” said David Weinreich, M.D., Executive Vice President, Global Clinical Development at Regeneron. “The trial was conducted at a time when most patients had not been fully vaccinated. These results provide hope to patients who have a poor immune response to either the vaccine or natural infection, as well as those who are exposed to variants for whom their existing antibodies might be sub-optimal.”
Multiple analyses, including a recent publication in Cell, have shown that REGEN-COV retains potency against the main variants of concern circulating within the U.S.; consequently, REGEN-COV remains available for use in all 50 states. REGEN-COV retains potency against variants including P.1 (first identified in Brazil, now classified by the World Health Organization [WHO] as Gamma), B.1.351 (first identified in South Africa, now classified by the WHO as Beta) and B.1.162.2 (first identified in India, now classified by the WHO as Delta). The combined frequency of the P.1 and B.1.351 variants now exceeds 10% of new COVID-19 diagnoses across eight states (Arizona, California, Florida, Illinois, Indiana, Massachusetts, Oregon, and Washington), and the prevalence of these and other variants continue to be closely monitored.
Today’s data in hospitalized patients follow multiple positive Phase 3 results earlier this year from Regeneron-sponsored trials assessing the ability of REGEN-COV to treat outpatients already infected with SARS-COV-2 (including symptomatic outpatients and recently infected asymptomatic patients), and also to prevent infection in close contacts of infected individuals. REGEN-COV has not been approved by the U.S. Food and Drug Administration (FDA), but is currently authorized in the U.S. under an Emergency Use Authorization (EUA) to treat mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing ≥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. This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.
What’s Next with Regulators?
Regeneron is in discussions with the FDA to expand the current EUA to other populations, including the prevention and hospitalized patient settings. Later this summer, Regeneron expects to submit a full Biologics License Application (BLA) for REGEN-COV.
Why does Regeneron Collaborate with Roche?
Regeneron is collaborating with Roche to increase global supply of REGEN-COV. Regeneron is responsible for development and distribution of the treatment in the U.S., and Roche is primarily responsible for development and distribution outside the U.S. The companies share a commitment to making the antibody cocktail available to COVID-19 patients around the globe and will support access in low- and lower-middle-income countries through drug donations to be made in partnership with public health organizations.
Public Monies go into REGEN-COV Development
The development and manufacturing of REGEN-COV have been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, under OT number: HHSO100201700020C.
Proprietary Drug Development Platform
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved fully human monoclonal antibodies currently available. This includes REGEN‑COV (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb) and Inmazeb™ (atoltivimab, maftivimab.