Candidate: Remdesivir (GS-5734)
Type: Nucleotide prodrug
2021 Status: Study Concludes ‘No Clinical Benefit’—A European team tof investigators conducting the Phase III DisCoVeRy trial (NCT04315948; EudraCT2020-000936-23)published results from their study September 14 in The Lancet Infectious Diseases, concluding that: “No clinical benefit was seen from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen.” The study showed no significant difference between the 135 of 406 patients treated with Veklury to which serious adverse events (SAE) occurred, and the 130 of 418 SAE control patients randomized to placebo.
DisCoVeRy was an open-label, adaptive, multi-center, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. The trial’s primary endpoint was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes.
Inhaled Formulation Scrapped—Gilead Sciences Chief Medical Officer Merdad Parsey, MD, PhD, told analysts on July 29 that the company has opted not pursue development of an inhaled formulation of Veklury based on results of an initial proof-of-concept study, “suggesting suboptimal lung deposition.”
“To address patient needs in the evolving pandemic, we are continuing our efforts on advancing multiple novel antivirals,” Parsey said during the company’s second-quarter earnings call. “We expect to submit IND filings later this year or early next year for these agents.”
Gilead disclosed that Veklury generated $829 million in Q2 sales—ahead of Wall Street estimates of $675 million, Reuters reported.
Reduced Mortality in Hospitalized Patients—Gilead on June 21 announced positive data from three retrospective studies evaluating real-world treatment of patients hospitalized with COVID-19, presented at the World Microbe Forum (WMF). The analyses showed that in the overall patient populations, patients who received Veklury treatment had significantly lower risk for mortality compared with matched controls. The three real-world data analyses presented at WMF include 98,654 patients hospitalized with COVID-19.
Two retrospective studies observed treatment trends and outcomes in the U.S. from the HealthVerity and Premier Healthcare databases. The HealthVerity analysis showed that 24,856 patients receiving Veklury had a statistically significant 23% lower mortality risk compared with 24,856 control patients, regardless of baseline oxygen requirement. A significantly greater likelihood of discharge by Day 28 was observed in patients completing a full five-day course of Veklury compared with controls—especially in patients with lower oxygen requirements at baseline. The Premier analysis showed that the 28,555 patients who were treated with Veklury had a significantly lower risk of mortality both at Day 14 and at Day 28 compared with the 16,687 patients who did not receive Veklury.
A third analysis compared clinical outcomes in 1,974 patients receiving a 10-day treatment course of Veklury in the extension phase of the global, open-label SIMPLE-Severe study with 1,426 patients receiving standard of care in a real-world retrospective longitudinal cohort study. Treatment with Veklury was associated with a statistically significant 54% lower mortality risk at 28 days versus those not treated with Veklury, regardless of a patient’s baseline oxygen requirements.
Selected for NIH’s ACTIV-3b Trial—Veklury (remdesivir) and NeuroRx’s Zyesami (aviptadil) will be evaluated in the NIH’s Phase III ACTIV-3 Critical Care trial (ACTIV-3b; NCT04843761). ACTIV-3 Critical Care is a master protocol to evaluate the safety and efficacy of drug candidates aimed at improving outcomes for patients with acute respiratory failure related to COVID-19. ACTIV-3 Critical Care allows for sub-studies of different therapeutics to run concurrently. Each sub-study will enroll approximately 640 participants.
For the primary analysis of the trial, participants will be assessed on a six-category ordinal scale 90 days after enrollment, and outcomes will be compared among treatment groups. This scale ranges from recovered and living at home without supplemental oxygen within two weeks of enrollment, to death. Following the assessment at the primary endpoint, participants will receive one additional follow-up at 180 days.
The principal investigator of ACTIV-3 Critical Care is Samuel Brown, MD, of Intermountain Healthcare and the University of Utah, Salt Lake City. ACTIV-3 is supported by two components of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung and Blood Institute (NHLBI), and is part of the NIH Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) public-private partnership.
$1.5B in Q1 Sales—Gilead Sciences on April 29 reported $1.456 billion in first quarter sales for Veklury® (remdesivir), a key reason why the company’s Q1 product sales rose 16% over Q1 2020, to $6.34 billion. A consensus of analysts expected Gilead to report $1.44 billion in Veklury sales, according to FactSet.
Veklury racked up $820 million in U.S. sales, $388 million in Europe, and $248 million in other international sales. However, Veklury’s Q4 sales fell 25% from the $1.938 billion reported for the third quarter of 2020.
On April 12, Gilead said it halted a Phase III Veklury intravenous study in high-risk non-hospitalized patients with COVID-19. “Based on the evolution of the COVID-19 landscape and challenges in enrolling this study, we no longer believe that developing a multiple day IV infusion treatment that requires administration in a healthcare setting addresses an unmet need for non-hospitalized patients,” the company stated.
2020 Status: APPROVED OCTOBER 22—Eight months after it was first tested in human patients at the center of the world’s first COVID-19 outbreak, Veklury® (remdesivir) won the FDA’s first approval of a drug against the virus—but for a smaller population than allowed under its previous emergency use authorization (EUA) from the agency.
Remdesivir—to be marketed in the United States as Veklury®—will be indicated for adults and pediatric patients 12 years of age and older who have forms of COVID-19 serious enough to require hospitalization, and who weigh at least 40 kg (88 pounds).
“Since the beginning of the COVID-19 pandemic, Gilead has worked relentlessly to help find solutions to this global health crisis. It is incredible to be in the position today, less than one year since the earliest case reported of the disease now known as COVID-19, of having an FDA-approved treatment in the United States that is available for all appropriate patients in need,” Gilead chairman and CEO Daniel O’Day said in a statement.
The FDA approval does not extend to children under age 12 who are hospitalized with COVID-19 and who weigh between 3.5 kg (7.7 pounds) and 40 kg (88 pounds) because clinical trials in that subpopulation of patients remain ongoing. Those children remain covered by the EUA first granted to remdesivir on May 1 for use in hospitalized patients with severe COVID-19, and expanded on August 28 to include treating all hospitalized patients with COVID-19.
Researchers working with the World Health Organization (WHO) posted interim results October 15 from the agency’s 11,266-patient Solidarity trial which included Gilead Sciences’ Veklury® (remdesivir) among four antiviral treatments that they said failed to show effectiveness in hospital inpatients with COVID-19—the same day the agency added the antiviral drug to its “prequalified” list, supporting its use by the UN and other global entities.
“Remdesivir, hydroxychloroquine, lopinavir [co-administered with ritonavir] and interferon regimens appeared to have little or no effect on hospitalized COVID-19,” the researchers concluded in a preprint posted in medRxiv. “The unpromising overall findings from the regimens tested suffice to refute early hopes, based on smaller or non-randomized studies, that any will substantially reduce inpatient mortality, initiation of ventilation or hospitalisation duration.”
As a result, “remdesivir is now classified as a drug you should not use routinely in COVID-19 patients,” the President of the European Society of Intensive Care Medicine (ESICM), Jozef Kesecioglu, told Reuters in November.
Solidarity was one of nine late-stage trials recruiting more than 13,500 patients in which Veklury was evaluated. The drug advanced to Phase III in July.
Remdesivir also made history October 15, when it became the 579th medicine or finished pharmaceutical product—and the first COVID-19 therapeutic—to receive prequalified status from the WHO. The WHO prequalifies drugs whose manufacturers have shown the agency that they have the capacity to produce a product of consistent quality in accordance with international standards and WHO/UNFPA-United Nations Population Fund specifications.
Veklury could generate $3 billion in annual sales in 2021, Morningstar analyst Karen Andersen projected on September 1. But Andersen—one of GEN’s “ Ten Life Science Analysts to Watch in 2020”—added that the firm also expects sales for Veklury 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.”
The FDA on August 28 expanded its Emergency Use Authorization (EUA) for Veklury® (remdesivir) to include treating all hospitalized patients with COVID-19, not just those with severe COVID-19 as the original EUA allowed. The expanded EUA followed positive results from the Phase III SIMPLE trial which evaluated Veklury in hospitalized patients with moderate COVID-19 pneumonia (NCT04292730), as well as results from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Phase III Adaptive COVID-19 Treatment Trial 1 (ACTT-1; NCT04280705) in hospitalized patients with a range of disease severity.
Researchers from Gilead and its clinical collaborators reported results from the SIMPLE trial in a study published in JAMA on August 21. They showed that hospitalized patients with moderate COVID-19 who were randomized to a five-day course of Veklury plus standard of care were 65% more likely to have an improvement in clinical status compared with those randomized to standard of care alone. For patients in the 10-day Veklury group, the improvement in clinical status at Day 11 was not statistically significant compared to the standard of care group.
The randomized, open-label SIMPLE trial included 584 patients with moderate COVID-19, of which 197 received a 10-day course of remdesivir, 199 received a 5-day course of remdesivir, and 200 received standard care. Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. The day 11 clinical status distribution measured on a 7-point ordinal scale was significantly better for those randomized to a 5-day course of remdesivir (median length of treatment, 5 days) compared with those randomized to standard care (6 days).
Gilead is also sponsoring a second Phase III SIMPLE trial evaluating Veklury in patients with severe COVID-19, called SIMPLE-Severe (NCT04292899).
Gilead said August 10 it submitted an NDA to the seeking approval to market Veklury—the final tier of the rolling NDA submission that was initiated on April 8. Veklury is available in the U.S. under an Emergency Use Authorization for the treatment of hospitalized patients with severe COVID-19.
The NDA is supported by data from two randomized, open-label, multi-center Phase III trials of Veklury conducted by Gilead; and the Phase III randomized, placebo-controlled study of Veklury conducted by NIAID. According to Gilead, the studies showed that treatment with Veklury led to faster time to recovery compared with placebo, and that a 5-day or 10-day treatment duration led to similar clinical improvement—though no data was included in the announcement.
Three days earlier, Gilead signed a multi-year agreement with Pfizer for remdesivir, through which Pfizer agreed to provide contract manufacturing services at its McPherson, KS, facility to manufacture and supply the COVID-19 treatment, Pfizer said. The value of the agreement was not disclosed. Pfizer is one of multiple external manufacturing organizations working with Gilead to scale up supply of remdesivir.
The NIH said August 6 that its National Institute of Allergy and Infectious Diseases (NIAID) has launched the Adaptive COVID-19 Treatment Trial 3 (ACTT 3; NCT04492475), a Phase III study designed to assess the combination of remdesivir and interferon beta-1a compared to remdesivir alone. ACTT 3 is anticipated to enroll more than 1,000 hospitalized adults with COVID-19 at up to 100 sites in the U.S. and overseas. ACTT 3 participants are being randomly assigned in a 1-to-1 ratio to receive either subcutaneous interferon beta-1a plus remdesivir (combination therapy) or remdesivir alone.
ACTT 3 is also designed to evaluate whether time to recovery is shorter in the combination therapy group compared to the remdesivir-only group. Recovery is defined as the participant being well enough for hospital discharge, meaning the participant either no longer requires supplemental oxygen or ongoing medical care in the hospital, or is no longer hospitalized (with or without some limitation on activities). Recovery is evaluated up until day 29.
Preliminary results are expected in the fall of 2020, the NIH said. A key secondary goal of the ACTT 3 study is to compare patient outcomes at day 15 using an ordinal eight-point scale ranging from fully recovered to death. The trial also will compare other secondary outcome variables between treatment groups, including mortality alone.
Interferon beta-1a is marketed as Rebif® by EMD Serono, the North American biopharmaceutical business of Merck KGaA, Darmstadt, Germany, and is approved in the U.S. and more than 90 other countries for the treatment of multiple sclerosis.
The European Commission said it signed a contract July 28 with Gilead to secure treatment doses of Veklury®, as remdesivir is marketed in Europe, to treat approximately 30,000 patients presenting severe COVID-19 symptoms under a contract valued at €63 million ($75 million), financed through the Commission’s Emergency Support Instrument. The contract will help cover patient needs over the next few months, while ensuring a fair distribution within the EU based on an allocation key and advice from the European Centre for Disease Prevention and Control.
The Commission is also preparing a joint procurement for further supplies of Velkury, which it expects will cover additional needs and supplies from October onward.
Gilead on July 10 announced the presentation of additional data from the Phase III SIMPLE-Severe trial–namely 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. The comparison showed 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.
A total 74.4% of remdesivir-treated patients recovered by Day 14, vs. 59.0% of standard of care patients. 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 assessed the safety and efficacy of 5-day and 10-day dosing durations of remdesivir administered intravenously in hospitalized patients with severe COVID-19. Results were published May 27 in The New England Journal of Medicine. Results are pending from an expansion phase of the study was added to enroll up to 5,600 additional patients, including those on mechanical ventilation.
At the Virtual COVID-19 Conference, being held as part of the 23rd International AIDS Conference, Gilead presented additional data from 229 patients consisting of subgroup analyses, including the race and ethnicity of patients treated in the U.S., and global baseline characteristics associated with improved clinical status, and concomitant use of hydroxychloroquine. In the U.S., rates of clinical improvement at Day 14 were 84% for 43 African American patients, 76% for 17 Hispanic white patients, 67% for 18 Asian patients, 67% for 119 non-Hispanic white patients, and 63% in 32 patients who did not identify with any of those groups.
In patients who received concomitant hydroxychloroquine compared with patients treated with remdesivir alone, Gilead reported rates and likelihood of recovery were lower after 14 days (57% vs. 69%). Patients receiving concomitant hydroxychloroquine did not show increased mortality, but experienced overall higher rates of adverse events in the 14-day analysis window.
Australia’s Department of Health said July 10 that the Therapeutic Goods Administration (TGA) granted provisional approval to remdesivir (to be sold as Veklury) as the nation’s first treatment option for COVID-19. Veklury has received provisional approval for use in adults and adolescent patients with severe COVID-19 symptoms who have been hospitalized. Provisional approval is limited to a maximum of six years, and was based on preliminary clinical data.
Gilead licensee Mylan said on July 6 that remdesivir 100 mg/vial was approved by the Drug Controller General of India (DCGI) for restricted emergency use in India as part of its accelerated approval process to address the COVID-19 pandemic. Remdesivir will be launched as DESREM™ and indicated for the treatment of suspected or laboratory confirmed incidences of COVID-19 in adults and children hospitalized with severe presentations of the disease.
DESREM will be priced at INR 4,800 ($64), more than 80% below the price of the branded version for governments in the developed world, Mylan said. India is one of 127 nations where Mylan is commercializing remdesivir under a global colloaboration agreement of undisclosed value announced in May.
The European Commission on July 3 granted conditional marketing authorization for remdesivir—under the name Veklury®—as a treatment for SARS-CoV-2 infection in patients ages 12 years and older, and weighing at least 40 kg (88 pounds) with pneumonia that requires supplemental oxygen. Veklury is the first drug approved in Europe for treating the virus.
The conditional marketing authorization is initially valid for one year, but can be extended or converted into an unconditional marketing authorization based on submission and assessment of additional confirmatory data. Veklury’s conditional approval will be supported by data from a forthcoming global Phase III trial to be conducted by the NIH’s National Institute of Allergy and Infectious Diseases.
The U.S. Department of Health and Human Services (HHS) said June 29 that it secured more than 500,000 treatment courses of remdesivir for U.S. hospitals through September—all of Gilead’s projected production for July (94,200 treatment courses), 90% of production in August (174,900 treatment courses), and 90% of production in September (232,800 treatment courses), in addition to an allocation for clinical trials. A treatment course of remdesivir averages 6.25 vials.
“President Trump has struck an amazing deal to ensure Americans have access to the first authorized therapeutic for COVID-19,” HHS Secretary Alex Azar II said in a statement. “To the extent possible, we want to ensure that any American patient who needs remdesivir can get it.”
Under an agreement with Gilead, the U.S. Department of Health and Human Services (HHS) and states will continue to manage allocation to hospitals until the end of September.
Also on June 29, Gilead Chairman and CEO Daniel O’Day wrote in an “Open Letter” that the company had set a price for remdesivir: Gilead will charge governments of developed countries of $390 per vial—which equates to $2,340 per patient based on current treatment patterns in which “the vast majority” of patients are expected to receive a five-day treatment course using six vials of remdesivir.
Private U.S. insurers will be charged $520 per vial to account for discounts that government healthcare programs expect, as well as what O’Day called “the way the U.S. system is set up.” “At the level we have priced remdesivir and with government programs in place, along with additional Gilead assistance as needed, we believe all patients will have access,” O’Day asserted.
He also projected that by year’s end, Gilead will have spent more than $1 billion in the development and manufacture of remdesivir.
A week earlier, O’Day wrote in a June 22 “Open Letter” that the company will begin Phase I trials of an inhaled version of remdesivir in healthy volunteers. Screening for volunteers will start the week of June 22, to be followed in August by the launch of the studies. O’Day said an inhaled formulation would be given through a nebulizer, “which could potentially allow for easier administration outside the hospital, at earlier stages of disease.”
On June 17, Gilead said it designed and will soon begin enrollment in the Phase II/III CARAVAN clinical trial (NCT04431453), designed to assess the safety, tolerability, pharmacokinetics, and efficacy of remdesivir in treating approximately 50 pediatric patients with moderate-to-severe COVID-19, ranging from newborns to adolescents. The open-label, single-arm trial will be conducted at more than 30 sites in the U.S. and Europe.
A research team at the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) published a study in Nature on June 9 reporting that in a rhesus macaque model of SARS-CoV-2 infection, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12 hours after the first treatment administration. Remdesivir treatment did not reduce virus shedding from the upper respiratory tract.
“Our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia,” the NIAID researchers concluded.
A day earlier, the European Medicines Agency said June 8 it received Gilead’s application for conditional marketing authorization of remdesivir as a COVID-19 treatment. Because some data has already been assessed during the first cycle of a rolling review that started April 30 and ended May 15. As a result, the EMA said, its risk-benefit assessment of remdesivir will take less time, with an opinion potentially being issued “within weeks.” In parallel, EMA’s Pharmacovigilance Risk Assessment Committee completed its initial assessment of Gilead’s preliminary risk management plan.
Also in June, Gilead reported topline results from the 600-patient initial phase of the second Phase III SIMPLE trial in hospitalized patients with moderate COVID-19 pneumonia. Patients in the 5-day remdesivir treatment group were 65% more likely to have clinical improvement at Day 11 compared with those in the standard of care group. However, that percentage dropped to a non-significant 31% for patients in the 10-day treatment course of remdesivir versus standard of care.
In the study, hospitalized patients with confirmed COVID-19 infection and evidence of pneumonia without reduced oxygen levels were randomized (1:1:1) to receive open-label remdesivir for 5 or 10 days or standard of care alone. The primary endpoint was the clinical status as assessed by a 7-point ordinal score at Day 11, ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death. The secondary study objective was the rate of adverse events in each remdesivir treatment group compared with standard of care.
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 U.S., $4,000 per course in Europe and about $2,000 in other markets. The Institute for Clinical and Economic Review has recommended a price of $4,500 per 10-day treatment course.
The U.K. in May authorized remdesivir as a COVID-19 treatment in selected patients through the Medicines & Healthcare products Regulatory Agency (MHRA)’s Early Access to Medicines Scheme. Remdesivir will be used in adults and adolescents hospitalized with severe COVID-19 infection who meet clinical criteria suggesting that they have the greatest likelihood of benefiting from the drug.
According to the MHRA, remdesivir is indicated for patients with severe disease are those with an SpO2 ≤ 94% on room air or requiring supplemental oxygen, or requiring non-invasive or invasive ventilation or extracorporeal membrane oxygenation (ECMO). The MHRA and the Commission on Human Medicines (CHM) authorized remdesivir based on emerging results of an Active COVID-19 Treatment Trial (ACTT) study, and other studies conducted by Gilead: “The data was sufficient to meet the criteria for an EAMS scientific opinion, and the benefits were determined to outweigh the risks.”
That same day, SunTrust Robinson Humphrey analyst Robyn Karnauskas reported, based on talks with Gilead executives, that they expect to start generating sales in July. While the company has yet to disclose a list price for remdesivir, she estimated Gilead could generate $1.1 billion in revenue just this year and $3.2 billion in 2021, based on the assumption that the price wil be $10,000 a treatment course—more than double the $4,500 “fair value” recommended by ICER. At that price, Gilead could rack up more than $2 billion in sales, according to Piper analyst Tyler van Buren.
Four days earlier, researchers conducting the 1,063-patient, NIAID-sponsored ACTT trial published a study in The New England Journal of Medicine consisting of preliminary findings suggesting that suggest that a 10-day course of remdesivir was superior to placebo in treating hospitalized patients with COVID-19.
The researchers cited data showing 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.
More detailed information about the results, including more comprehensive data, will be available in a forthcoming report, the NIH said.
“The result was statistically significant, but really modest,” NIAID Director Anthony S. Fauci, MD, said May 12 in testimony before the U.S. Senate Committee on Health, Education, Labor & Pensions. “We hope to build on this modest success with combinations of drugs and better drugs.”
Yet those results, the NIAID researchers said, justified the agency’s public release of results April 29: “Given the strength of the results about remdesivir, these findings were deemed to be of immediate importance for the care of patients still participating in the trial as well as for those outside the trial who might benefit from treatment with remdesivir.”
The researchers added: “Benefit was most apparent in patients with a baseline ordinal score of 5 (requiring oxygen), a finding most likely due to the larger sample size in this category.”
A week earlier, Gilead licensed remdesivir to five generic drug makers with operations in India and Pakistan: Cipla, Mylan, Ferozsons Laboratories, Hetero Labs and Jubilant Life Sciences. The five will not pay Gilead royalties until either a second drug is approved, or the pandemic is declared ended.
On May 8, NIAID launched the next iteration of its Adaptive COVID-19 Treatment Trial (ACTT 2) by starting a randomized clinical trial to evaluate the combination of remdesivir and Olumiant® (baricitinib)—licensed to Eli Lilly by Incyte—in hospitalized adults with COVID-19. ACTT 2 closed to enrollment on June 30 after recruiting 1,034 participants at 71 U.S. and international sites.
ACTT 2 is designed to evaluate whether time to recovery is shorter in the combination arm (baricitinib plus remdesivir) compared with remdesivir plus placebo. Recovery is defined as the participant being well enough for hospital discharge, meaning the participant either no longer requires supplemental oxygen or ongoing medical care in the hospital, or is no longer hospitalized (with or without some limitation on activities). Recovery is evaluated up until day 29.
Participants are set to receive a 200mg IV dose of remdesivir, followed by a 100mg once-daily IV dose for the duration of hospitalization up to a 10-day total course of treatment. Baricitinib is being administered as a 4mg oral dose (or crushed and given through a nasogastric tube) up to a 14-day total course of treatment.
Under the name Veklury®, Remdesivir on May 7 received approval from Japan’s Ministry of Health, Labour and Welfare as a treatment for SARS-CoV-2 under an exceptional approval pathway due to the COVID-19 pandemic.
Earlier in May, Gilead said it was in talks with “some of the world’s leading chemical and pharmaceutical manufacturing companies” about manufacturing remdesivir for Europe, Asia, and the developing world through at least 2022 under voluntary licenses. Gilead also said it is negotiating long-term voluntary licenses with several generic drugmakers in India and Pakistan aimed at producing remdesivir for developing countries, and was in active talks with the Medicines Patent Pool to license remdesivir for developing countries.
Additionally, Gilead disclosed “advanced” discussions with UNICEF to deliver remdesivir using its distribution networks.
Remdesivir received emergency use authorization (EUA) from the FDA on May 1, enabling broader use of the antiviral drug through 5-day or 10-day treatment in hospitalized patients with severe symptoms of the disease. The agency conditioned its EUA on remdesivir being administered to hospital inpatients via intravenous infusion, and on the U.S. government, in collaboration with state and local governments, directing the supply and distribution to authorized distributors, or directly to a U.S. government agency, that will distribute to hospitals and other healthcare facilities.
O’Day has committed the company to manufacturing at least 500,000 treatment courses by October—10 times the number of courses available as of April 29, he told Bloomberg News—then doubling that number to 1 million over the following two months.
The FDA acted two days after NIAID released ACTT’s preliminary findings showing remdesivir outperformed placebo, and met its primary outcome of statistically significant improvement in time to recovery by Day 29. The 1,063 hospitalized adult patients participating in the adaptive, randomized, double-blind, placebo-controlled trial, highlighted on CBS’ “60 Minutes”, showed a broad mix of COVID-19 symptoms.
“Although a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept. What it has proven is that a drug can block this virus,” Fauci said during an appearance with President Donald Trump. “This will be the standard of care.” Fauci’s support was among reasons why remdesivir has received a cool reaction from two prominent supporters of President Donald Trump quoted by Politico on May 2.
That same day, The Lancet published results showing that remdesivir failed to show clinical improvement in severely infected patients in a Chinese Phase III trial (NCT04257656). In that study, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, remdesivir had not reduced the presence of SARS-CoV-2 in the bloodstream of 158 patients treated with the antiviral candidate in the 237-patient trial.
The primary endpoint was time to clinical improvement up to day 28. The average time to clinical improvement was 21 days for remdesivir patients, compared with 23 days for placebo patients. “The numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies,” the study authors wrote. Twenty-eight days after treatment, 22 of 158 patients (13.9%) in the remdesivir cohort died, compared to 10 of 78 untreated control patients (12.8%)—a difference the researchers concluded was not statistically significant. A draft version of the Chinese study results was accidentally published April 23 by the World Health Organization (WHO) on its website.
The trial—which was originally supposed to enroll 453 patients—was the second Phase III study of remdesivir in China to end early due to low enrollment. The inability to enroll patients was a consequence of the decrease in COVID-19 cases since the winter, the trial sponsor, China’s Capital Medical University, stated on the study’s page on ClincalTrials.gov: “The epidemic of COVID-19 has been controlled well in China, no eligible patients can be enrolled at present.”
On April 15, Capital Medical University also disclosed on ClincalTrials.gov that enrollment was suspended in a Chinese trial designed to assess remdesivir in patients with mild-to-moderate forms of COVID-19 (NCT04252664). That trial was a randomized, double-blind, placebo-controlled multicenter study intended to evaluate remdesivir’s safety and efficacy in hospitalized adults. The trial’s estimated enrollment was 308 patients.
That same day, Gilead trumpeted a cohort analysis of 53 patients hospitalized with severe complications of COVID-19 who were treated with remdesivir on an individual compassionate use basis. According to the cohort analysis, published in The New England Journal of Medicine, treatment with remdesivir resulted in an improvement in oxygen support class for 36 of the 53 patients (68%) over a median follow-up of 18 days from the first dose. Seventeen of 30 patients on a ventilator were extubated (57%), while 25 of the 53 patients (47%) were discharged from the hospital following treatment with remdesivir.
Remdesivir treatment in severe COVID-19 patients led to rapid recoveries in fever and respiratory symptoms with nearly all patients discharged in less than a week, STAT reported April 16, after obtaining a video discussion by the investigator conducting the Phase III SIMPLE-Severe trial at University of Chicago, one of 169 treatment sites. Gilead responded with a statement emphasizing: “The totality of the data need to be analyzed in order to draw any conclusions from the trial,” while UChicago Medicine stated: “Drawing any conclusions at this point is premature and scientifically unsound.”
Earlier in April, Gilead dramatically increased the patient populations of three Phase III trials of remdesivir—from 400 to 2,400 patients in the severe disease study, from 600 to 1,600 moderate COVID-19 patients in the SEVERE study in moderate COVID-19 patients, and from 440 to 800 COVID-19 patients with a broad mix of symptoms in the NIAID trial. The three are among seven trials assessing remdesivir’s safety and effectiveness, Gilead Chairman and CEO Daniel O’Day stated in an April 11 “open letter.”
A day earlier, researchers published results in The New England Journal of Medicine from a Gilead-funded cohort analysis showing that 36 of 53 severe COVID-19 patients treated with remdesivir (68%) showed an improvement in oxygen support class over a median follow-up of 18 days from the first dose. Seventeen of 30 patients on mechanical ventilation (57%) were extubated, while 25 of all 53 patients studied (47%) were discharged from the hospital following remdesivir treatment.
On April 4, O’Day stated Gilead’s goal of producing more than 500,000 treatment courses by October, and more than 1 million treatment courses by the end of this year. O’Day said the company significantly increased its available supply of remdesivir to 1.5 million individual doses, including finished product ready for distribution as well as investigational medicine in the final stages of production.
“Depending on the optimal duration of treatment, which is something we are studying in clinical trials, this supply could equate to well over 140,000 treatment courses for patients,” O’Day wrote.
On March 25, Gilead requested that the FDA rescind the orphan drug designation the company was granted for remdesivir in COVID, which confers seven years of marketing exclusivity, and said it will waive all benefits that accompany the designation. The company’s action followed criticism by Sen. Bernie Sanders, who accused Gilead of “profiteering” and benefiting from a “corporate giveaway” since the NIH is overseeing a clinical trial of the drug.
Three days earlier, Gilead said it was shifting how it allowed severely ill patients to access remdesivir, from individual compassionate use requests to expanded access programs, citing an “exponential increase” in demand. A 25-year-old New Jersey man was airlifted to the Hospital of the University of Pennsylvania to enter a clinical trial where the drug was being offered, his mother told The New York Times.
Rear Adm. Richard Childs, an assistant surgeon general and lung specialist at the NIH, told The Wall Street Journal in a report published March 13 that remdesivir showed a positive effect on 14 Americans who contracted SARS-CoV-2 aboard the Diamond Princess cruise ship, and received the drug during treatment at Japanese hospitals.
Remdesivir showed “no adverse events” when administered to the first American confirmed to be infected with SARS-CoV-2, members of the Washington State 2019-nCoV Case Investigation Team reported in a case study published in The New England Journal of Medicine.
Among other trials of remdesivir is a large study in France (2020-000936-23), and two Phase III trials in the U.K. assessing remdesivir in patients with moderate to severe COVID-19 at an initial 15 sites.
Remdesivir and chloroquine phosphate were “highly effective in the control of 2019-nCoV infection in vitro,” a team of Chinese researchers reported in a study published February 4 in Cell Research.
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: