Candidate: REGEN-COV2 (formerly REGN-COV2)
Type: Antibody “cocktail” therapy combination consisting of casirivimab (formerly REGN10933) and imdevimab (formerly REGN10987). Both are neutralizing monoclonal antibodies designed to bind non-competitively to the receptor binding domain of SARS-CoV-2’s spike protein by targeting non-overlapping epitopes.
Status: Emergency Use Authorization granted November 21, 2020: The FDA on November 21 granted an emergency use authorization (EUA) to REGEN-COV2 (formerly REGN-COV2) as a treatment for adults and youths ages 12 years and older with mild-to-moderate COVID-19. Before patients can be treated with REGEN-COV2 under the EUA, they must weigh at least 40 kilograms (about 88 pounds) and be deemed at high risk for progressing to severe COVID-19 and/or hospitalization. That high-risk category includes adults who are ages 65 or older, or who have chronic medical conditions.
The EUA recommended a dose of 2.4 g, lower than the 8 g dose taken by President Donald Trump when he began his treatment regimen for COVID-19 with REGEN-COV2 in October. The dosage was changed this fall after data from a clinical trial in ambulatory patients found no significant difference in efficacy between the doses. The 2.4 g (2,400 mg) dose consists of 1.2 g (1,200 mg) of casirivimab and 1.2 g of imdevimab, administered as a single intravenous infusion.
Regeneron said it expects to have REGEN-COV2 treatment doses ready for approximately 80,000 patients by the end of November, rising to approximately 200,000 by the first week of January, and approximately 300,000 patients total by the end of January 2021.
On October 30, Regeneron said it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing REGEN-COV2 in hospitalized adult patients with COVID-19.
In pausing enrollment of the sickest patients, Regeneron said it was following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment.
Regeneron said October 28 that REGEN-COV2 significantly reduced viral load and medical visits in a second group of 524 participants in the Phase II/III portion (NCT04425629) of an adaptive Phase I/II/III trial evaluating the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in ambulatory adult patients with COVID-19.
The new data showed that the average daily reduction in viral load through day 7 in patients with “high” viral load (defined as greater than107 copies/mL) was 0.68 log10 copies/mL greater with REGEN-COV2 compared to placebo. That reduction increased to 1.08 log greater with REGEN-COV2 treatment by day 5—an outcome that Regeneron said corresponded to REGEN-COV2 patients having on average a greater than 10-fold reduction in viral load vs. placebo.
In the overall patient group that began the study with detectable virus, the average daily reduction in viral load through day 7 was 0.36 log10 copies/mL greater with REGEN-COV2 compared to placebo.
Those findings confirmed earlier positive data on viral load and medical visits announced by the company in September from the first 275 patients dosed in the randomized, double-blind trial, which has an estimated enrollment of 2,104 participants. Patients in the trial were randomized 1:1:1 to receive a one-time infusion of 8 grams of REGEN-COV2 (high dose), 2.4 grams of REGEN-COV2 (low dose) or placebo.
However, the company is reviewing a possible change to dosages in the study after finding no significant difference in efficacy between REGEN-COV2’s low dose of 2.4 g, and its high dose of 8 g.
At the American Society of Human Genetics (ASHG) 2020 Virtual Meeting, held October 27-30, geneticists from Regeneron Genetics Center identified three novel loci and three genes contributing to susceptibility of SARS-CoV-2 infection and severity in COVID-19 outcomes. For susceptibility, gene burden tests identified genes GPS2, METTL7B, and PLPPR3—with a fourth gene, GPS2 and three novel loci identified among hospitalized cases: A locus enriched in individuals of African ancestry on 1p31.1, 16q24.3, and 22q21.1. Researchers said they conducted the largest trans-ancestry exome sequencing study of COVID-19 to date in 579,799 individuals, with a larger set of 868,021 individuals with imputed data, across six studies and four ancestries.
Researchers from Regeneron and two partner institutions on October 9 published a study in Science showing that REGEN-COV-2 reduced virus load in lower and upper airways and decreased virus induced pathological sequalae when administered prophylactically or therapeutically in rhesus macaques. The study also showed that administration in hamsters limited weight loss and decreased lung titers and evidence of pneumonia in the lungs: “Our data provide evidence that REGN-COV2 based therapy may offer clinical benefit in both prevention and treatment settings of COVID-19 disease, where it is currently being evaluated.”
On October 7, Regeneron said it will seek emergency use authorization (EUA) from the FDA for REGEN-COV2, a week after reporting positive but preliminary results for the first 275 ambulatory adult patients treated with the antibody cocktail in an adaptive Phase I/II/III trial. Regeneron said REGEN-COV2 rapidly reduced viral load as well as time to alleviate symptoms in non-hospitalized patients with COVID-19, and also reduced medical visits for patients. The ongoing, randomized, double-blind trial measures the effect of adding REGEN-COV2 to standard-of-care, compared to adding placebo to standard-of-care.
“The greatest treatment benefit was in patients who had not mounted their own effective immune response, suggesting that REGN-COV2 could provide a therapeutic substitute for the naturally-occurring immune response. These patients were less likely to clear the virus on their own, and were at greater risk for prolonged symptoms,” stated George D. Yancopoulos, MD, PhD, Regeneron’s president and chief scientific officer.
The previous weekend, REGEN-COV2 generated global headlines when President Donald Trump began treatment for COVID-19 with the antibody cocktail. “He received a single 8 g dose” of REGEN-COV2, Trump’s physician, Sean P. Conley, DO, FACEP, wrote in a letter made public by the White House on October 2.
REGEN-COV2 could generate $6 billion in annual sales in 2021, Morningstar analyst Karen Andersen projected on September 1, based on a 60% probability of approval. But Andersen—one of GEN’s “ Ten Life Science Analysts to Watch in 2020”—added that the firm also expects sales for the antibody cocktail and other COVID-19 drugs and vaccines to rapidly decline soon after: “We expect most US adults will be vaccinated in the first half of 2021.”
Regeneron and Roche said August 19 they will partner on developing and manufacturing REGEN-COV2, through a collaboration whose value was not disclosed. Regeneron agreed to distribute REGEN-COV2 in the U.S., while Roche agreed to oversee distribution in the rest of the world. The collaboration is expected to increase supply of REGEN-COV2 to at least three and a half times the current capacity, with the potential for even further expansion, the companies said.
Regeneron and Roche also agreed to dedicate an unspecified manufacturing capacity to REGEN-COV2 each year; the companies have already begun the process of transferring technology for the antibody cocktail. Each company will foot its own distribution expenses in their designated territories, while both companies agreed to jointly fund and execute ongoing and additional global trials.
Roche will be primarily responsible for securing ex- U.S. regulatory approvals following the initial European Medicines Agency (EMA) approval, as well as conducting any additional studies specifically required for approval by regulators outside the U.S., where Regeneron will work to secure regulatory approvals.
A team of Regeneron researchers on August 3 posted a preprint study in bioRxiv reporting that REGEN-COV2 proved effective when administered prophylactically or therapeutically in two animal models, one of mild disease in rhesus macaques and one of severe disease in golden hamsters. REGEN-COV2 showed reduced viral load in the upper and lower airways, reduced virus induced pathology in the rhesus macaque model, and limited weight loss in the hamster model.
“REGN-COV2 can almost completely block establishment of virus infection; this pattern was observed across all measurements in both nasopharyngeal swabs and bronchoalveolar lavage fluid compared to placebo animals, demonstrating that mAbs administered prophylactically can greatly reduce viral load in both upper and lower airways,” the researchers wrote. “Our results provide evidence of the therapeutic potential of this antibody cocktail.”
Three days later in an investor note, Canaccord Genuity analyst John Newman, PhD, observed: “REGN-COV2 is unique in that it has the potential for treatment as well as preventative therapy for COVID-19, making it a strong therapeutic choice.”
Regeneron Pharmaceuticals in July was awarded a $450 million contract from the Biomedical Advanced Research and Development Authority (BARDA) toward manufacturing and supplying REGEN-COV2. BARDA awarded the funding through its involvement in Operation Warp Speed, through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
Regeneron’s funding agreement with BARDA covered a fixed number of bulk lots expected to be completed in the fall of 2020, as well as fill/finish and storage activities. Regeneron said today that should it win FDA emergency use authorization (EUA) or product approval, the U.S. government has committed to making doses from these lots available to Americans at no cost, and to overseeing their distribution.
The company also disclosed that its clinical program for REGEN-COV2 is now assessing multiple dosages in order to establish the exact number of potential treatment doses (estimated range of 70,000 to 300,000) or prevention doses (estimated range of 420,000 to 1.3 million) available from these lots in total.
On July 6, Regeneron said it was advancing REGEN-COV2 into Phase III trials. Regeneron is partnering with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to conduct what is being planned as a 2,000-patient Phase III trial (NCT04452318) designed to assess REGEN-COV2’s ability to prevent infection among uninfected people who have had close exposure to a COVID-19 patient, such as a patient’s housemate.
Regeneron also advanced REGEN-COV2 into the Phase II/III portion of two adaptive Phase I/II/III trials designed to evaluate the antibody cocktail’s ability to treat hospitalized and non-hospitalized patients with COVID-19. One Phase II/III study (NCT04426695) is designed to assess the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in hospitalized adult patients with COVID-19, with an estimated enrollment of 1,860 participants. The other study (NCT04425629) will evaluate the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in ambulatory adult patients with COVID-19, with an estimated enrollment of 1,054 participants.
The decision to enter Phase III followed Regeneron generating a positive review from the Independent Data Monitoring Committee overseeing the company’s Phase I safety study, following an evaluation of data from an initial cohort of 30 hospitalized and non-hospitalized patients with COVID-19.
In June, Regeneron launched clinical trials of REGEN-COV2, disclosing plans for a clinical program consisting of four separate study populations: Hospitalized COVID-19 patients; non-hospitalized symptomatic COVID-19 patients; uninfected people in groups that are at high-risk of exposure, such as healthcare workers or first responders; and uninfected people with close exposure to a COVID-19 patient, such as the patient’s housemate.
Regeneron said REGN10933 and REGN10987 (since renamed casirivimab and imdevimab) were the two most potent, non-competing and virus-neutralizing antibodies selected from thousands produced through Regeneron’s monoclonal antibody discovery platform VelocImmune®, part of the company’s VelociSuite™ technologies. The company has said it has produced two distinct antibody cocktails, an initial cocktail and a backup.
Addressing analysts on Regeneron’s quarterly conference call in April, founder, president, and CEO Leonard S. Schleifer, MD, PhD, said “it is possible” that the antibody cocktail may be available to patients by the end of summer or this fall.
On the same call, George D. Yancopoulos, MD, PhD, Regeneron co-founder, President, and Chief Scientific Officer, added that Regeneron is committing its Industrial Operations and Product Supply manufacturing facility in Rensselaer, NY toward manufacturing the antibody cocktail, “which on its own could supply hundreds of thousands, if not over the course of time, maybe even on the order of a million or so doses per month.”
Regeneron launched clinical studies for the cocktail in about half the nine-month company record set when the company developed its antibody cocktail for Ebola. The Ebola cocktail, REGN-EB3, is under FDA priority review, with a target action date of October 25, based on successful results from the Phase III PALM clinical trial conducted in the Congo.
Regeneron has also said it is developing the combination of REGN3048 and REGN3051 as a COVID-19 treatment. The combination completed a 48-patient Phase I trial in MERS-CoV last year (NCT03301090). In February, BARDA said it was expanding upon an earlier partnership agreement with Regeneron to develop “multiple monoclonal antibodies that, individually or in combination, could be used to treat new treatments.”
On April 1, New York Gov. Andrew M. Cuomo announced that Regeneron created 500,000 test kits for State use at no charge. The first batch of test kits was delivered to the State on March 30, and the State will receive an ongoing delivery of 25,000 kits per day, Cuomo said.
COVID-19: 300 Candidates and Counting
To navigate through the >300 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: