American biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD) has announced the topline results of the phase 3 SIMPLE clinical trial evaluating the use of the pharmacologic antiviral agent Remdesivir for the treatment of the Coronavirus Disease COVID-19. The study is one of two phase 3 human trials of Remdesivir initiated by Gilead in March of 2020.
The randomized, multicenter, open-label trials sought to assess whether intravenously administered Remdesivir can safely treat COVID-19, the disease caused by the severe acute respiratory syndrome 2 coronavirus (SARS-2-CoV), a virus thought to have originated in Wuhan, China, possibly following transmission from illegally trafficked pangolins.
- Remdesivir Receives Emergency Use Authorization for the Treatment of COVID-19 from the FDA
- Gilead Announces Completion of Phase 3 SIMPLE Clinical Trial of Remdesivir in Patients with Severe COVID-19
- Data Expected from Phase 3 Trial Sponsored by the NIAID
- Clinical Outcomes of Remdesivir Compassionate Use Published in The New England Journal of Medicine
- Details of the Phase 3 SIMPLE Studies
- In Vitro Data Indicating the Efficacy of Remdesivir for Controlling SARS-CoV-2 Infection
Remdesivir Receives Emergency Use Authorization for the Treatment of COVID-19 from the FDA
On May 1st, 2020, Gilead announced that the United States Food and Drug Administration (FDA) has granted emergency use authorization (EUA) to remdesivir for the treatment of COVID-19. While the move is temporary and not a substitute for the normal approval process including processing of Gilead’s Investigational New Drug application, it will enable the use of the drug at additional hospitals across the nation and facilitate the distribution of limited drug to patients with the greatest need for treatment.
Chairman and CEO of Gilead Dr. Daniel O’Day stated, “This EUA opens the way for us to provide emergency use of remdesivir to more patients with severe symptoms of COVID-19. We will continue to work with partners across the globe to increase our supply of remdesivir while advancing our ongoing clinical trials to supplement our understanding of the drug’s profile. We are working to meet the needs of patients, their families and healthcare workers around the world with the greatest sense of urgency and responsibility.”
The EUA follows the completion of a phase 3 human trial evaluating the safety and optimal treatment duration of remdesivir therapy in patients with severe COVID-19. Additional ongoing clinical trials of the drug will further influence decision making regarding the use and regulation of remdesivir.
Gilead has donated 1.5 million individual doses of remdesivir that will be provided “at no cost” to treat COVID-19 patients. The company intends to manufacture 500,000 treatment courses by October of 2020, 1 million treatment courses by December of 2020, and “millions more in 2021, if required.”
Gilead Announces Completion of Phase 3 SIMPLE Clinical Trial of Remdesivir in Patients with Severe COVID-19
On April 29th, 2020, Gilead announced the results from the open-label phase 3 SIMPLE trial that evaluated 5- and 10-day dosing schedules of remdesivir in patients with severe cases of COVID-19. The study showed that patients receiving the 5-day course of the antiviral drug achieved a “similar improvement in clinical status” to those that were treated over 10 days. “No new safety signals” or increased incidence of adverse events were identified among the patients in either cohort.
Chief Scientific Officer of Gilead Dr. Merdad Parsey, MD, PhD, stated, “Unlike traditional drug development, we are attempting to evaluate an investigational agent alongside an evolving global pandemic. Multiple concurrent studies are helping inform whether remdesivir is a safe and effective treatment for COVID-19 and how to best utilize the drug. These study results complement data from the placebo-controlled study of remdesivir conducted by the National Institute for Allergy and Infectious Diseases and help to determine the optimal duration of treatment with remdesivir.”
“The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with our current supply of remdesivir. This is particularly important in the setting of a pandemic, to help hospitals and healthcare workers treat more patients in urgent need of care,” Dr. Parsey continued.
At the time of enrollment in the trial, patients had evidence of pneumonia and lowered oxygen levels but did not require mechanical ventilation. Participants were regarded as having recovered clinically if they were discharged from the hospital or no longer needed “oxygen support” or “medical care.”
Among patients treated with Remdesivir for 5 or 10 days, 50 percent experienced clinical improvement in 10 or 11 days, respectively. By day 14, over half of the patients in either treatment group were discharged from the hospital (5-day: 60.0%, n=120/200 vs.10-day: 52.3% n=103/197; p=0.14), and at two weeks post-treatment, 64.5 percent (n=129/200) and 53.8 percent (n=106/197) of patients in the 5-day and 10-day cohorts, respectively, had achieved clinical recovery.
The study found that patients treated earlier with remdesivir, within 10 days after the onset of symptoms, were more likely to have better clinical outcomes than those treated later. By Day 14 after the initiation of treatment, 62 percent of patients administered the medication “early” were eligible for discharge from the hospital, while only 49 percent of patients that received the drug “late” were able to be discharged.
One of the lead study investigators Dr. Aruna Subramanian, MD, stated, “These data are encouraging as they indicate that patients who received a shorter, 5-day course of remdesivir experienced similar clinical improvement as patients who received a 10-day treatment course. While additional data are still needed, these results help to bring a clearer understanding of how treatment with remdesivir may be optimized, if proven safe and effective.”
In general, the drug was well-tolerated among patients in both the 5-day and 10-day treatment cohorts. Nausea (5-day: 10.0%, n=20/200 vs. 10-day: 8.6%, n=17/197) and acute respiratory failure (5-day: 6.0%, n=12/200 vs. 10-day: 10.7%, n= 21/197) were the most common adverse events. 7.3 percent (n=28/385) of patients experienced liver enzyme (ALT) elevations of Grade 3 or higher and 3.0 percent (n=12/397) needed to discontinue use of remdesivir due to elevated liver tests.
The trial found that clinical outcomes varied geographically and had an overall mortality rate was 7 percent (n=23/320), clinical improvement rate of 64 percent (n=205/320), and hospital discharge rate of 61 percent (n=196/320) at Day 14 among both treatment cohorts.
Data Expected from Phase 3 Trial Sponsored by the NIAID
A phase 3 clinical trial of Remdesivir sponsored by the National Institute of Allergy and Infectious Diseases has met its primary endpoint and is expected to be discussed in detail at an upcoming briefing.
Clinical Outcomes of Remdesivir Compassionate Use Published in The New England Journal of Medicine
The outcomes of 53 patients with severe cases of COVID-19 administered Remdesivir through Gilead’s compassionate use program were published in The New England Journal of Medicine in April 2020. At the time of administration, approximately two-thirds (34/53) of the patients were receiving mechanical ventilation. During follow-up, 36 experienced an “improvement in oxygen support class,” 17 were extubated, and 25 were discharged from the hospital.
According to lead author of the publication Dr. Jonathan Grein, MD, “Currently there is no proven treatment for COVID-19. We cannot draw definitive conclusions from these data, but the observations from this group of hospitalized patients who received remdesivir are hopeful. We look forward to the results of controlled clinical trials to potentially validate these findings.”
Dr. Merdad Parsey, MD, PhD, stated, “While the outcomes observed in this compassionate use analysis are encouraging, the data are limited. Gilead has multiple clinical trials underway for remdesivir with initial data expected in the coming weeks. Our goal is to add to the growing body of evidence as quickly as possible to more fully evaluate the potential of remdesivir and, if appropriate, support broader use of this investigational drug.”
Details of the Phase 3 SIMPLE Studies
The phase 3 clinical trials of remdesivir currently sponsored by Gilead, known as the SIMPLE studies, have primarily enrolled patients in Asian countries but incorporated medical centers worldwide. Data from the trials will accompany that of current trials already evaluating Remdesivir for the treatment of COVID-19, two of which are being conducted by the China-Japan Friendship Hospital in China’s Hubei Province, and another in the United States under the guidance of the National Institute of Allergy and Infectious Diseases (NIAID).
According to their press release, Gilead has “donated drug and provided scientific input” for these clinical trials. The Chinese trials are expected to be completed in April 2020.
The Gilead trials were initiated after the company filed an investigational new drug (IND) application for the use of remdesivir in the treatment of COVID-19. After rapid review, the IND application was accepted by the US Food and Drug Administration (FDA) and Gilead has since moved forwards with the clinical trials.
Merdad Parsey, MD, PhD, stated, “Gilead’s primary focus is on rapidly determining the safety and efficacy of remdesivir as a potential treatment for COVID-19, and this complementary array of studies helps to give us a more expansive breadth of data globally on the drug’s profile in a short amount of time.
The speed with which remdesivir has moved into clinical development for this coronavirus reflects the pressing need for treatment options and the shared commitment of industry, governments, global health organizations and healthcare providers to respond to this public health threat with the highest urgency.”
In total, Gilead’s phase 3 trials are expected to enroll 1,000 patients. 400 patients severely affected by COVID-19 will receive 5 or 10 days of intravenous remdesivir at a starting dose of 200 mg followed by 100 mg daily until day 5 or 10, based on random assortment into treatment groups at a 1:1 ratio. These patients will receive remdesivir in addition to standard-of-care therapies.
600 patients found to have moderate clinical manifestations of the disease will be treated with five or ten days of intravenous remdesivir in the same arrangement as the 400-patient trial or by standard-of-care therapies alone, with patients randomly assorted into these three treatment groups according to a 1:1:1 ratio.
The primary endpoint of the trials is clinical improvement as measured by a sustained return of fever and oxygen saturation to normal levels [T < 36.6 C armpit, < 37.2 C oral, < 37.8 C rectal; and Sp02 > 94%] for at least 24 hours through Day 14 after the initiation of treatment.
In addition, the phase 3 trials will measure the proportion of patients from each group discharged by Day 14. Gilead may have decided to include evaluate these symptoms given the high incidence of fever and respiratory problems among patients infected by the virus.
While remdesivir has not yet been licensed or approved anywhere globally for the treatment of COVID-19 or other uses, Gilead is providing the drug on a compassionate use basis for the emergency treatment of “qualified patients” not included in their clinical trials. Currently, according to Gilead, remdesivir has “not been demonstrated to be safe or effective for any use.”
However, previous animals models and in vitro studies of remdesivir have shown the drug to have antiviral activity against multiple viral pathogens including the Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) coronaviruses, human coronaviruses in the same family as the SARS-2-CoV.
In Vitro Data Indicating the Efficacy of Remdesivir for Controlling SARS-CoV-2 Infection
A publication in the esteemed scientific journal Cell in February 2020 showed that remdesivir is “highly effective” for controlling SARS-CoV-2 infection in vitro. The researchers evaluated the efficacy of the drug for inhibiting replication of the virus in cells derived from the human liver. Their work also indicated that the dose of the drug required to be effective against the virus could be achieved in non-human primates, an important finding since the drug would not be useful if the necessary dose were not clinically feasible.
Although remdesivir has been studied in people infected by the Ebola virus and in healthy volunteers, Gilead stated, “Individual compassionate use cases are not sufficient to determine the safety and efficacy of remdesivir in treating COVID-19, which can only be determined through prospective clinical trials.”
According to Belgian virologist and physician Dr. Erik de Clerq, who co-discovered the important anti-viral agent Tenofovir, and Dr. Guangdi Li, SARS-CoV-2 treatment strategies are more likely to include existing antiviral agents such as remdesivir instead of novel vaccines or compounds. “No drug or vaccine has yet been approved to treat human coronavirus” and “new interventions are likely to require months to years to develop,” stated Clercq and Li.
Remdesivir, which has a structure similar to the HIV inhibitor Tenofovir, has shown efficacy against the 2019 coronavirus in vitro. The recovery of an infected US patient, who received intravenous infusions of Remdesivir, may be attributable to the drug. In addition to the Gilead studies, two phase 3 trials evaluating the efficacy of intravenous Remdesivir for the treatment of the coronavirus were initiated in February and are anticipated to be completed by April 2020.
SARS-2-CoV, which has spread from China to the United States and other nations around the world, has an incubation period of up to two weeks and may survive for up to 9 days on surfaces at room temperature.
Clercq ED, Li G. (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00016-0