President Trump has already received multiple treatments since his COVID-19 diagnosis last week. His treatment began with a leading drug candidate, Regeneron Pharmaceuticals’ two-antibody combination or “cocktail,” REGN-COV2. Within days, his medical team announced that the antiviral remdesivir, from Gilead Sciences, was added to the interventions given to the president. The treatment regimen, which incorporated dexamethasone on Sunday—a steroid typically reserved for serious or more advanced COVID-19 cases—has been rolled out both aggressively and quickly.
Referring to the antibody treatment and remdesivir, Peter Hotez, MD, PhD, professor of pediatrics and molecular virology and microbiology at Baylor College of Medicine, noted that the speed is a factor that makes sense to him. He tweeted over the weekend that “watch and wait” [is] not an option. He added that in order to maximize the effectiveness of these two interventions, you have to “do it now or not at all.” Hotez added that despite “limited experimental data in humans” for the antibody cocktail, the evidence so far shows how it reduces viral load and shows some evidence of improved clinical outcome.
Over the weekend, Trump and his physician, Sean P. Conley, DO, FACEP, sought to reassure Americans that the president was on the mend. Conley initially said Saturday that Trump would stay at Walter Reed National Military Medical Center for an indefinite period. But on Sunday, Brian Thomas Garibaldi, MD, director of the Johns Hopkins Biocontainment Unit, who is consulting with doctors treating Trump, raised hopes of a relatively short hospital stay for the president.
Whether these treatments will diminish the president’s battle with COVID-19 remains unknown and a source of unending speculation.
Despite the questions that remain regarding this situation, these two treatments have been making their way through the required safety and regulatory hurdles. Indeed, they are two of 19 “front runners” among more than 300 COVID-19 drug and vaccine candidates on GEN’s COVID-19 Drug & Vaccine Tracker. Below are some questions and answers about REGN-COV2 and remdesivir.
REGN-COV2 (Regeneron Pharmaceuticals)
Regeneron calls its antibody cocktail REGN-COV2, a combination of two monoclonal antibodies, REGN10933 and REGN10987, that are designed to both treat people with COVID-19 and to prevent SARS-CoV-2 infection.
How is the antibody cocktail designed to work?
Both antibodies are designed to bind non-competitively to the receptor-binding domain (RBD) of SARS-CoV-2’s spike protein. According to a paper published August 21 in Science, REGN10933 targets the spike-like loop region on one edge of the ACE2 interface. The fragment antigen-binding region of REGN10933 binds the RBD from the top, where it collides with ACE2, while REGN10987 only binds to the front or the lower left side of the RBD, away from REGN10933, and has little to no overlap with the ACE2 binding site.
How did Regeneron choose these two antibodies for its cocktail?
REGN10933 and REGN10987 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. Regeneron has said it has produced two distinct antibody cocktails, an initial cocktail and a backup.
How far advanced is REGN-COV2 in the clinic?
REGN-COV2 began its first clinical trial in June , a month later advanced to Phase III, and is now under study in four late-stage clinical trials estimated to recruit at least a combined 11,074 participants:
- The Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in hospitalized adult patients with COVID-19, with an estimated enrollment of 2,970 participants.
- Another 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, with an estimated enrollment of 2,104 participants.
- A portion of the 15,000-patient open-label, Phase III RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial (NCT04381936) that is examining the effectiveness of the cocktail plus standard of care in at least 2,000 hospitalized COVID-19 patients to be chosen at random in the U.K., and comparing that to another 2,000 patients who already receive standard of care alone.
- A Phase III trial (NCT04452318) designed to assess REGN-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. The trial has an estimated enrollment of 2,000 participants.
How much of the antibody cocktail did Trump receive?
“He received a single 8 g dose” of REGN-COV2, Conley wrote in a letter made public by the White House on Friday.
What have clinical trials shown about the 8 g dose of REGN-COV2?
The 8 g dose was the higher of two doses studied in a Phase I/II/III trial of REGN-COV2. The 8 g dose showed better results than the 2.4 g low dose and placebo, according to initial data from the first 275 patients Regeneron released on September 29.
In that trial, approximately 45% of patients were seropositive, 41% were seronegative, and 14% were categorized as “other” due to unclear or unknown serology status. Among seronegative patients, the mean time-weighted-average change from baseline nasopharyngeal viral load through Day 7 was more among patients receiving the 8 g dose (0.60 log10 copies/mL greater reduction compared to placebo) than the 2.4 g dose (0.51 log10 copies/mL greater reduction). Among all patients, those taking the 8 g dose showed a viral load reduction compared to placebo of 0.51 log10 copies/mL, vs. 0.23 log10 copies/mL for 2.4 g dose patients.
How long has Regeneron been developing an antibody cocktail against SARS-CoV-2?
At least since the Biomedical Advanced Research and Development Authority (BARDA) said in February 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.” Initially, Regeneron considered another combination, REGN3048 and REGN3051, which completed a 48-patient Phase I trial in MERS-CoV last year (NCT03301090).
In April, George D. Yancopoulos, MD, PhD, Regeneron co-founder, president, and CSO, said the company had committed 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.”
Remdesivir (Veklury®, DESREM™, or GS-5734; Gilead Sciences)
“An important treatment for hospitalized coronavirus patients,” President Donald Trump said May 1 in announcing FDA emergency use authorization (EUA) for Gilead Sciences’ COVID-19 antiviral drug candidate remdesivir on May 1. “People that are not doing well, people that are sick, people that have this horrible plague that’s set into our country and that we’re getting rid of. And we’re going to be having some really incredible results,” Trump predicted. Five months later, Trump is one of those patients hoping for those really incredible results.
Remdesivir is a broad-spectrum antiviral adenosine nucleotide prodrug initially developed to treat Ebola. Last year, remdesivir and a second experimental Ebola treatment were dropped from a clinical trial because they were “much less effective at preventing death” as other candidates.
How is remdesivir designed to work?
A monophosphoramidate prodrug of a C-adenosine nucleoside analogue, remdesivir is designed to distribute into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA.
According to Gilead, Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity.
How far advanced is remdesivir in the clinic?
Remdesivir began its first COVID-19 clinical trial in February in Wuhan, China, a day after Chinese researchers recommended that the antiviral drug candidate remdesivir be assessed in humans as a potential treatment for SARS-CoV-2. Remdesivir advanced to Phase III in July, and is now under study in nine late-stage trials that have recruited more than 13,500 patients:
- A Phase III randomized, double-blind, placebo-controlled trial (NCT04501952) designed to assess remdesivir’s safety and efficacy in reducing the rate of hospitalization or death in outpatients with early-stage COVID-19, set to enroll up to 1,230 participants.
- The Phase III Adaptive COVID-19 Treatment Trial 1 (ACTT-1; NCT04280705), an adaptive, randomized, double-blind, placebo-controlled trial sponsored by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to evaluate the safety and efficacy of remdesivir and other novel therapeutic agents in hospitalized adults diagnosed with COVID-19. 1,062 participants are enrolled.
- The Phase III Adaptive COVID-19 Treatment Trial 2 (ACTT-2; NCT04401579), a NIAID-sponsored trial similar to ACTT-1 except that it is comparing the combination of remdesivir and Eli Lilly’s Olumiant® (baricitinib) to remdesivir alone in hospitalized adults. 1,034 participants are enrolled.
- The Phase III Adaptive COVID-19 Treatment Trial 3 (ACTT-3; NCT04492475), another NIAID-sponsored trial similar to ACTT-1 and ACTT-2, but comparing the combination of interferon beta-1a and remdesivir to remdesivir alone in hospitalized adults. The trial has an estimated enrollment of up to 1,034 participants.
- A Phase III randomized trial (SIMPLE; NCT04292730) evaluating the safety and antiviral activity of five-day and 10-day remdesivir regimens compared to standard of care in hospitalized patients with moderate COVID-19. The trial has an actual enrollment of 1,113 participants.
- A Phase III randomized trial (SIMPLE-Severe; NCT04292899) assessing the safety and antiviral activity of five-day and 10-day remdesivir regimens compared to standard of care in hospitalized participants with severe COVID-19. The trial has an actual enrollment of 4,891 participants.
- The Phase III DisCoVeRy trial (2020-000936-23 and NCT04315948), sponsored by the French Institut National de la Santé et de la Recherche Médicale (INSERM). The multi-center, adaptive, randomized, open trial is comparing remdesivir to AbbVie’s Kaletra, Merck KGaA’s Rebif (interferon-beta-1a), and Sanofi’s Plaquenil (hydroxychloroquine) in hospitalized adults with COVID-19. DisCoVeRy has an estimated enrollment of 3,100 participants.
- The Phase III World Health Organization Solidarity Trial comparing remdesivir and AbbVie’s Kaletra® (lopinavir/ritonavir) plus interferon beta-1a to standard of care in hospitalized patients with COVID-19. The trial has recruited more than 10,000 participants in 27 countries. In July, the WHO halted Solidarity’s study of hydroxychloroquine and Kaletra alone after interim results showed they did not reduce mortality.
- The Phase II/III CARAVAN trial (NCT04431453), a single-arm, open-label study evaluating the safety, tolerability, and pharmacokinetics (PK) of remdesivir in pediatric participants aged 0 days to < 18 years with COVID-19. The trial has an estimated enrollment of 52 participants.
How much remdesivir did Trump receive?
Trump is receiving a five-day course of remdesivir, Conley told reporters Saturday. Remdesivir is typically given in treatment courses of five or 10 days. Patients are dosed intravenously at 200 mg on day 1 followed by 100 mg the other days.
What have clinical trials shown about the five-day course of remdesivir?
In August, Gilead researchers published in JAMA data from the Phase III SIMPLE trial (NCT04292730) showing that of 584 patients hospitalized with moderate COVID-19, 197 who were randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with the 200 who received standard care at 11 days after the start of treatment. The 199 patients randomized to a five-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance, researchers concluded.
In July, Gilead presented additional data from the Phase III SIMPLE-Severe trial showing that remdesivir was associated with an improvement in clinical recovery and a 62% reduction in the risk of mortality compared with standard of care—a finding that Gilead acknowledged requires confirmation in prospective clinical trials. The mortality rate for patients treated with remdesivir was 7.6% at Day 14, compared with 12.5% among patients receiving standard of care.
SIMPLE-Severe was a comparative analysis of 312 patients treated in the trial with remdesivir and a real-world retrospective cohort of 818 patients with severe COVID-19 who received standard of care. A total 74.4% of remdesivir-treated patients recovered by Day 14, vs. 59.0% of standard of care patients.
And in May, Gilead researchers published a study in The New England Journal of Medicine with preliminary findings from the ACTT trial suggesting that a 10-day course of remdesivir was superior to placebo in treating hospitalized patients with COVID-19. The data showed that patients who were treated with remdesivir showed a 31% faster median time to recovery compared with those who received placebo (11 days compared with 15 days). Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo.
Should they win approval, how much in sales are REGN-COV2 and remdesivir expected to generate?
Morningstar analyst Karen Andersen, CFA, projected last month that REGN-COV2 could generate $6 billion in annual sales in 2021, and remdesivir, $3 billion. Last year, Regeneron generated $7.863 billion in total revenues, while Gilead racked up $22.449 billion.
Andersen—one of GEN’s “ Ten Life Science Analysts to Watch in 2020”— added that her firm also expects sales for those and other COVID-19 drugs and vaccines to rapidly decline soon after next year: “We expect most U.S. adults will be vaccinated in the first half of 2021.”
On June 3, Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, projected $2 billion in sales for remdesivir this year, climbing to $7.7 billion by 2022, then ranging between $6 billion and $7 billion each year after. Porges estimated that remdesivir would be priced at $5,000 per course in the United States, $4,000 per course in Europe, and about $2,000 in other markets. Gilead said in June that the five-day treatment course of remdesivir would be priced at $2,340 for governments of developed countries (six vials at $390 per vial), and $3,120 for U.S. private insurance companies (six vials at $520 per vial).
What is the FDA status of remdesivir and REGN-COV2?
Neither drug is approved. Remdesivir received emergency use authorization (EUA) from the FDA on May 1, initially enabling broader use of the antiviral drug through five-day or 10-day treatment in hospitalized patients with severe symptoms of the disease. The FDA on August 28 expanded the EUA to include treating all hospitalized patients with COVID-19. The expanded EUA followed positive results from two Phase III trials: SIMPLE, and the NIH’s NIAID Phase III Adaptive COVID-19 Treatment Trial 1 (ACTT-1; NCT04280705) in hospitalized patients with a range of disease severity.
REGN-COV2 has not received EUA. The FDA allows “expanded access” (also called “compassionate use”) allowing patients with an “immediately life-threatening condition or serious disease or condition” to access investigational drugs, biologics, or medical devices for use outside of clinical trials when no comparable or satisfactory alternative therapy options are available.
Regeneron said it gave Trump REGN-COV2 under a compassionate use: “All we can say is that they asked to be able to use it, and we were happy to oblige,” Regeneron founder, president, and CEO Leonard S. Schleifer, MD, PhD, told The New York Times.
How close is Trump with the CEOs of Regeneron and Gilead?
Regeneron’s Schleifer has known the president casually enough to be called “Lenny” by Trump. Schleifer is a member of Trump National Golf Club in Briarcliff Manor, NY, five miles north of Regeneron’s headquarters in Tarrytown, NY, and listed Trump National as his home golf club on the PGA Tour’s list of amateur participants for this year. Schleifer topped City & State’s 2018 “Westchester Power 50” list of the suburban county’s 50 most influential leaders, but ranked No. 7 a year later when the list was expanded to 100 leaders.
In March, Schleifer and Gilead’s chairman and CEO Daniel O’Day were among biopharma executives who met with Trump on March 2 at the White House to discuss their efforts to develop drugs and vaccines against COVID-19. A month later, O’Day and Schleifer were among 200 leaders in 13 specific industries—two of 27 in the “healthcare” industry—who were appointed to his Great American Economic Revival Industry Groups tasked with “work[ing] together with the White House to chart the path forward toward a future of unparalleled American prosperity.” And on May 1, O’Day joined Trump and Vice President Mike Pence in the Oval Office in announcing the FDA’s EUA for remdesivir.
How much does Washington have invested in REGN-COV2 and remdesivir?
Through “Operation Warp Speed”—the Trump administration’s effort to fund development, manufacturing, and distribution of COVID-19 drugs and vaccines—the federal government has committed to Regeneron up to $617.7 million-plus toward REGN-COV2, the largest award being a $450.3 million award to demonstrate large-scale manufacturing of the antibody cocktail.
Gilead is not a recipient of Operation Warp Speed funding. However, in June, the U.S. Department of Health and Human Services (HHS) agreed with Gilead and distributor AmerisourceBergen to secure approximately 500,000 commercially available treatment courses of remdesivir for use in U.S. hospitals, at $2,340 per course—a total value of $1.17 billion. The courses were furnished to states (based on COVID-19 hospitalization data), as well as U.S. territories, the Department of Defense, the Department of State, the Veterans Health Administration, the NIH, and the Indian Health Service.
Between May 4 and September 30, Gilead also donated approximately 150,000 treatment courses of remdesivir, according to HHS’ Assistant Secretary for Preparedness and Response (ASPR).
What have Regeneron and Gilead said about their manufacturing plans for their treatments?
Regeneron agreed to manufacture and supply up to 300,000 treatment doses available from bulk lots of REGN-COV2 under the $450 million Operation Warp Speed contract it was awarded in July by BARDA. Should the FDA grant an EUA or approve REGN-COV2, BARDA would buy those up-to-300,000 doses for treatment of patients. At the time, Regeneron said it had yet to establish the exact number of potential treatment doses (ranging from 70,000 to 300,000) or prevention doses (420,000 to 1.3 million) available from the bulk lots.
Regeneron executives have anticipated being able to produce up to 250,000 doses per month next year, through an increase in manufacturing capacity enabled under a partnership with Roche announced in August, and whose value has not been disclosed.
In reporting second-quarter results in July, Gilead stated: “We currently expect to have manufactured more than two million remdesivir treatment courses by the end of 2020, and several million more treatment courses in 2021.”
What other antibody treatments could Trump have chosen?
He could have taken Eli Lilly’s LY-CoV555, a neutralizing antibody targeting SARS-CoV-2 and the lead antibody generated through the pharma giant’s collaboration with AbCellera.
In August, Lilly launched the Phase III BLAZE-2 trial, (NCT04497987), which the company is conducting with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), the COVID-19 Prevention Network, and several long-term care facility networks across the country. BLAZE-2 is designed to study the efficacy and safety of LY-CoV555 in up to 2,400 participants—both residents and staff at U.S. nursing homes and assisted living facilities.
Jake Glanville, co-founder and CEO of Distributed Bio, publicly invited Trump to take his company’s antibody cocktail: “We have something that can help the president and his family immediately, as well as an affordable and mass-producible injectable antibody therapy to end the medical crisis in 2021.” Glanville also offered Distributed’s convalescent plasma optimization protocol.
What else has Trump taken for COVID-19 besides REGN-COV2 and remdesivir?
In a letter the White House made public on Friday, Conley wrote that the president was also taking famotidine, a Histamine-2 blocker (H2 blocker) sold over the counter as Pepcid®, Vitamin D, and zinc.
Trump acknowledged in May that he had taken zinc against COVID-19 in combination with hydroxychloroquine, the anti-malarial drug he has promoted along with azithromycin: “All I can tell you is, so far I seem to be okay,” Trump told reporters on May 18.
On Sunday, Conley added that Trump had been given dexamethasone, a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects. Dexamethasone has been tested in hospitalized patients with COVID-19 in the RECOVERY trial, where it was found to have benefits for critically ill patients.
According to preliminary findings shared with the WHO, the treatment was shown to reduce mortality for patients on ventilators by about one third. For patients requiring only oxygen, mortality was cut by about one fifth. The WHO issued guidelines in September recommending use of dexamethasone and other systemic corticosteroids “in patients with severe and critical COVID-19,” and a conditional recommendation not to use those corticosteroids in non-severe COVID-19 patients.
