Remdesivir
Emergency Use Authorization
The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. In August, 2020 the FDA expanded the emergency use authorization for remdesivir to include treatment of any hospitalized adult or pediatric patients with suspected or laboratory-confirmed COVID-19, irrespective of their severity of disease. The expansion was based on evidence demonstrating a benefit in patients with mild-to-moderate disease.
HHS signed an Agreement with Gilead for 500,000 treatment courses of remdesivir on 6/29/2020. This represents 100% of July production, 90% of August production and 90% of September production. The U.S. The Department of Health and Human Services (HHS) will control distribution through AmerisourceBergen and hospitals will pay no more than WAC for the drug. The government will tell the AmerisourceBergen how many vials can be shipped to a state. The department of health in each state will direct the wholesaler to deliver doses to the hospitals with the highest number of inpatient COVID-19 cases. Allocations will be determined by data entered on COVID-19 cases or suspected cases into the HHS TeleTracking portal. The initial supply from the Federal Stockpile of 5 million doses were exhausted at the end of June 2020, so hospitals will begin paying for remdesivir in July. HHS will stop managing distribution of remdesivir at the end of September, when supplies are expected to stabilize.
ICER revised its preliminary pricing review for remdesivir on 6/24/2020. ICER has provided two pricing estimates. One is a cost recovery pricing estimate, based on a review of the cost of producing the final finished product and estimated development costs. ICER estimated a cost recovery price of $1,600 for a 10-day course of treatment. Using a threshold price of $50,000 per incremental quality-adjusted life year (and equal value of a life-year gained) and the benefits seen in the Adaptive COVID-19 Treatment Trial (ACTT), ICER estimated a cost-effective price of $4,580 to 5,080 for a 10-day course of remdesivir. ICER also estimated the effect that dexamethasone would contribute and estimated a lower cost-effectiveness price of $2,520 to $2,800 based on non-peer reviewed data from the RECOVERY trial.
Gilead has set AWP for remdesivir (Veklury) at $520 per vial or $3,120 for five days of treatment. This is the price for private insurance patients in the U.S. The U.S. government price for Medicaid and military hospitals is $390 per vial or $2,340 for a five-day course of treatment. This is also the price for developed countries. Pricing for remdesivir is more aligned with estimates from ICER that take into account the potential effect of dexamethasone. Gilead has entered into agreements with generic manufacturers to make the drug available at a substantially lower cost to developing countries, where healthcare resources, infrastructure and economics are lower.
A Fact Sheet for Heath Care Providers that reviews the treatment criteria, dosing, administration and monitoring of the patients receiving the drug is available from the FDA. A Patient Fact Sheet is also available and must be offered to patients.
The FDA defines severe COVID-19 as patients with low blood oxygen (SpO2 of 94% or less) that require supplemental oxygen with or without a mechanical ventilator or ECMO. The drug is approved to be administered in hospitalized patients.
Remdesivir has been used to treat 1,700 patients through expanded access, compassionate use and clinical trials. Gilead has 1.5 million doses of remdesivir available and will donate the supply to treat patients at no cost through expanded access, compassionate use and clinical trials. It is estimated the supply would be enough to treat 140,000 patients. Gilead is ramping up manufacturing and plans to have a drug supply large enough to treat 500,000 patients by the end of October and 1,000,000 by the end of 2020, with larger amounts available in 2021 if needed.
The European Medical Agency (EMA) released recommendations on use of remdesivir through compassionate use programs in Europe. The recommendations include a summary of dosing, administration, monitoring, and management of patients receiving remdesivir. The EMA is reviewing clinical data for remdesivir with the possibility of accelerated approval.
Dosing and Administration
Remdesivir does not have full FDA authorization and is only approved for use under the EUA for the patients described below. NIH has provided recommendations on the use of remdesivir for the treatment of COVID-19.
All patients should have an eGFR determined and liver panel drawn before dosing
Adult patients and pediatric patients weighing ≥ 40 kg requiring a ventilator or ECMO should receive 200 mg on the first day, then 100 mg for 9 more days (total of 10 days).
Pediatric patients that weigh 3.5 kg to < 40 kg are dosed at 5 mg/kg on the first day then 2.5 mg/kg IV for subsequent doses.
Please see the Health Care Provider Fact Sheet for full prescribing information including administration, dosing and recommendation for monitoring and management of remdesivir patients.
Pre-Clinical Studies
Gilead originally developed remdesivir as a treatment for Ebola, but discontinued development when the drug failed the PALM trial. In the 681 patient, Phase II/III PALM Trial, mortality was 33.5% after treatment with REGN-EB3, 35.1% after MAb114, and 53.1% with remdesivir compared to 49.7% with porgaviximab (ZMapp) in patients infected with the Ebola virus.
In vitro data suggests that remdesivir has activity against COVID-19 in levels achievable with a 500 mg dose. A study funded by Johnson and Johnson found that darunavir did not demonstrate in vitro antiviral activity against a clinical isolate of SARS-CoV-2, but remdesivir showed potent antiviral activity supporting the results found in the earlier study. An unreviewed, unedited article described an animal trial sponsored by Gilead and NIH, where early treatment with remdesivir reduced pulmonary disease and viral titers in rhesus macaques.
Clinical Experience
Many small studies may have design flaws, inaccurate or incomplete descriptions of results or missing information. Some published trials are small and have not adequately controlled for confounders, so the true effect of the intervention is not clear. Most often the problem involves several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug is not given until 1-2 weeks after the patient develops symptoms, which may be too late to have a full effect.
In a 28-day, 237 patient, Phase III, Chinese trial, treatment with remdesivir for ten days was not associated with a clinical benefit compared to placebo (non-significant 20 days vs 23 days) in hospitalized patients with severe COVID-19 infection (NCT04257656). Due to a decrease in patients with COVID-19 infections in China, enrollment was suspended after 237 patients entered the study instead of the target of 450 patients, which reduced the statistical power from 80% to 58%. The researchers noted they “could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters". Confounders in this study included 54% of the patients in the remdesivir group receiving the drug more than 10-days after developing symptoms compared to 40% of placebo patients. Almost 30% of remdesivir patients received interferon and/or lopinavir–ritonavir. While use of lopinavir–ritonavir was similar in both groups, 38% of patients received interferon. The placebo group was 65% male compared to 56% in the remdesivir group. These differences could have been due to the final population not reaching the target total.
Results were published from the first 397 patients enrolled in a 6,000 patient, Phase III trial (NCT04292899), which found no difference in efficacy, measured on a seven-point scale that runs from death to not hospitalized, between a 5-day course of remdesivir and a 10-day course in hospitalized patients with severe COVID-19. The data suggested that earlier treatment was more efficacious than later treatment. An accompanying editorial recommended that 5-day treatment be given priority due to the limited supply of the drug.
In an 11-day, 584 patient, Phase III, open-label trial (NCT04292730), patients treated with a 5-day course of remdesivir were more likely to have at least a 2-point improvement on a seven-point scale that runs from death to not hospitalized compared to placebo (70% vs 61%) in hospitalized patients with moderate COVID-19. A 10-day course of remdesivir did not differ from placebo (65% vs 61%), although most patients did not receive a full 10-days of treatment. Patients in the standard of care group were more likely to receive lopinavir-ritonavir, corticosteroids, hydroxychloroquine/chloroquine, azithromycin or tocilizumab.
In the 29-day, 1,059 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) trial (NCT04280705), where patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 11 days compared to 15 days with placebo in patients with severe COVID-19. There was a non-significant difference in the mortality rate of 8% with remdesivir compared to 11.6% with placebo.
Expanded Access and Compassionate Use
The World Health Organization is evaluating remdesivir, chloroquine, hydroxychloroquine and lopinavir-ritonavir with and without interferon-beta versus supportive care in the SOLIDARITY COVID-19 trial and comparing remdesivir and hydroxychloroquine in the WHO NOR trial (NCT04321616). The trials have an adaptive design, so that other drugs can be added at a later time. A French trial, DisCoVeRy (NCT04315948) is being set up with the same parameters.
Gilead is evaluating remdesivir administered as an inhalation in a Phase I study in healthy volunteers and hopes to initiate a COVID-19 patient trial in August 2020, with this formulation.
Chinese researchers were evaluating remdesivir in the placebo controlled Phase III COVID-19 trials in patients with mild-to-moderate infections (NCT04252664). Recruitment for the trial was slowed due to a requirement that patients had not been treated with another therapy within 30-days before entering the trial and a decrease in available patients. Many patients have already self-treated based on information they found on the Internet. The mild-to-moderate infection study was suspended on 4/10/2020 with 308 patients enrolled. The mild-to-moderate trial is estimated to be completed on 4/27/2020. Gilead has stated it is up to the Chinese researchers on when the trial data will be presented or published.
The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. In August, 2020 the FDA expanded the emergency use authorization for remdesivir to include treatment of any hospitalized adult or pediatric patients with suspected or laboratory-confirmed COVID-19, irrespective of their severity of disease. The expansion was based on evidence demonstrating a benefit in patients with mild-to-moderate disease.
HHS signed an Agreement with Gilead for 500,000 treatment courses of remdesivir on 6/29/2020. This represents 100% of July production, 90% of August production and 90% of September production. The U.S. The Department of Health and Human Services (HHS) will control distribution through AmerisourceBergen and hospitals will pay no more than WAC for the drug. The government will tell the AmerisourceBergen how many vials can be shipped to a state. The department of health in each state will direct the wholesaler to deliver doses to the hospitals with the highest number of inpatient COVID-19 cases. Allocations will be determined by data entered on COVID-19 cases or suspected cases into the HHS TeleTracking portal. The initial supply from the Federal Stockpile of 5 million doses were exhausted at the end of June 2020, so hospitals will begin paying for remdesivir in July. HHS will stop managing distribution of remdesivir at the end of September, when supplies are expected to stabilize.
ICER revised its preliminary pricing review for remdesivir on 6/24/2020. ICER has provided two pricing estimates. One is a cost recovery pricing estimate, based on a review of the cost of producing the final finished product and estimated development costs. ICER estimated a cost recovery price of $1,600 for a 10-day course of treatment. Using a threshold price of $50,000 per incremental quality-adjusted life year (and equal value of a life-year gained) and the benefits seen in the Adaptive COVID-19 Treatment Trial (ACTT), ICER estimated a cost-effective price of $4,580 to 5,080 for a 10-day course of remdesivir. ICER also estimated the effect that dexamethasone would contribute and estimated a lower cost-effectiveness price of $2,520 to $2,800 based on non-peer reviewed data from the RECOVERY trial.
Gilead has set AWP for remdesivir (Veklury) at $520 per vial or $3,120 for five days of treatment. This is the price for private insurance patients in the U.S. The U.S. government price for Medicaid and military hospitals is $390 per vial or $2,340 for a five-day course of treatment. This is also the price for developed countries. Pricing for remdesivir is more aligned with estimates from ICER that take into account the potential effect of dexamethasone. Gilead has entered into agreements with generic manufacturers to make the drug available at a substantially lower cost to developing countries, where healthcare resources, infrastructure and economics are lower.
A Fact Sheet for Heath Care Providers that reviews the treatment criteria, dosing, administration and monitoring of the patients receiving the drug is available from the FDA. A Patient Fact Sheet is also available and must be offered to patients.
The FDA defines severe COVID-19 as patients with low blood oxygen (SpO2 of 94% or less) that require supplemental oxygen with or without a mechanical ventilator or ECMO. The drug is approved to be administered in hospitalized patients.
Remdesivir has been used to treat 1,700 patients through expanded access, compassionate use and clinical trials. Gilead has 1.5 million doses of remdesivir available and will donate the supply to treat patients at no cost through expanded access, compassionate use and clinical trials. It is estimated the supply would be enough to treat 140,000 patients. Gilead is ramping up manufacturing and plans to have a drug supply large enough to treat 500,000 patients by the end of October and 1,000,000 by the end of 2020, with larger amounts available in 2021 if needed.
The European Medical Agency (EMA) released recommendations on use of remdesivir through compassionate use programs in Europe. The recommendations include a summary of dosing, administration, monitoring, and management of patients receiving remdesivir. The EMA is reviewing clinical data for remdesivir with the possibility of accelerated approval.
Dosing and Administration
Remdesivir does not have full FDA authorization and is only approved for use under the EUA for the patients described below. NIH has provided recommendations on the use of remdesivir for the treatment of COVID-19.
All patients should have an eGFR determined and liver panel drawn before dosing
- Remdesivir is not recommended in adult and pediatric patients (>28 days old) with eGFR less than 30 mL/min or in full-term neonates (≥7 days to ≤28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk.
- It is not known if dosage adjustment is needed in patients with hepatic impairment and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk.
- Reconstitute remdesivir for injection lyophilized powder with 19 mL of Sterile Water for Injection and dilute in 0.9% saline prior to administration.
- Dilute remdesivir injection concentrated solution in 0.9% saline prior to administration.
- Prepare solution for infusion on same day as administration.
- After infusion is complete, flush with at least 30 mL of 0.9% saline.
- Discard any remaining reconstituted remdesivir lyophilized powder, reconstituted solution or diluted solution.
Adult patients and pediatric patients weighing ≥ 40 kg requiring a ventilator or ECMO should receive 200 mg on the first day, then 100 mg for 9 more days (total of 10 days).
Pediatric patients that weigh 3.5 kg to < 40 kg are dosed at 5 mg/kg on the first day then 2.5 mg/kg IV for subsequent doses.
Please see the Health Care Provider Fact Sheet for full prescribing information including administration, dosing and recommendation for monitoring and management of remdesivir patients.
Pre-Clinical Studies
Gilead originally developed remdesivir as a treatment for Ebola, but discontinued development when the drug failed the PALM trial. In the 681 patient, Phase II/III PALM Trial, mortality was 33.5% after treatment with REGN-EB3, 35.1% after MAb114, and 53.1% with remdesivir compared to 49.7% with porgaviximab (ZMapp) in patients infected with the Ebola virus.
In vitro data suggests that remdesivir has activity against COVID-19 in levels achievable with a 500 mg dose. A study funded by Johnson and Johnson found that darunavir did not demonstrate in vitro antiviral activity against a clinical isolate of SARS-CoV-2, but remdesivir showed potent antiviral activity supporting the results found in the earlier study. An unreviewed, unedited article described an animal trial sponsored by Gilead and NIH, where early treatment with remdesivir reduced pulmonary disease and viral titers in rhesus macaques.
Clinical Experience
Many small studies may have design flaws, inaccurate or incomplete descriptions of results or missing information. Some published trials are small and have not adequately controlled for confounders, so the true effect of the intervention is not clear. Most often the problem involves several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug is not given until 1-2 weeks after the patient develops symptoms, which may be too late to have a full effect.
In a 28-day, 237 patient, Phase III, Chinese trial, treatment with remdesivir for ten days was not associated with a clinical benefit compared to placebo (non-significant 20 days vs 23 days) in hospitalized patients with severe COVID-19 infection (NCT04257656). Due to a decrease in patients with COVID-19 infections in China, enrollment was suspended after 237 patients entered the study instead of the target of 450 patients, which reduced the statistical power from 80% to 58%. The researchers noted they “could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters". Confounders in this study included 54% of the patients in the remdesivir group receiving the drug more than 10-days after developing symptoms compared to 40% of placebo patients. Almost 30% of remdesivir patients received interferon and/or lopinavir–ritonavir. While use of lopinavir–ritonavir was similar in both groups, 38% of patients received interferon. The placebo group was 65% male compared to 56% in the remdesivir group. These differences could have been due to the final population not reaching the target total.
Results were published from the first 397 patients enrolled in a 6,000 patient, Phase III trial (NCT04292899), which found no difference in efficacy, measured on a seven-point scale that runs from death to not hospitalized, between a 5-day course of remdesivir and a 10-day course in hospitalized patients with severe COVID-19. The data suggested that earlier treatment was more efficacious than later treatment. An accompanying editorial recommended that 5-day treatment be given priority due to the limited supply of the drug.
In an 11-day, 584 patient, Phase III, open-label trial (NCT04292730), patients treated with a 5-day course of remdesivir were more likely to have at least a 2-point improvement on a seven-point scale that runs from death to not hospitalized compared to placebo (70% vs 61%) in hospitalized patients with moderate COVID-19. A 10-day course of remdesivir did not differ from placebo (65% vs 61%), although most patients did not receive a full 10-days of treatment. Patients in the standard of care group were more likely to receive lopinavir-ritonavir, corticosteroids, hydroxychloroquine/chloroquine, azithromycin or tocilizumab.
In the 29-day, 1,059 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) trial (NCT04280705), where patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 11 days compared to 15 days with placebo in patients with severe COVID-19. There was a non-significant difference in the mortality rate of 8% with remdesivir compared to 11.6% with placebo.
Expanded Access and Compassionate Use
- Gilead implemented an expanded access program in late March for severe COVID-19 patients, over 18, requiring ventilation through NCT04323761. Please see the web description for inclusion and exclusion criteria. Contact: Gilead Clinical Study Information Center, 1-833-445-3230, GileadClinicalTrials@gilead.com It is recommended that patients be enrolled in a clinical trial if possible. In two of the U.S. trials, all patients receive remdesivir with the comparison being a five-day versus 10-day course.
- Gilead has a compassionate use program for pregnant women and children under 18 years of age with confirmed COVID-19 and severe manifestations of disease. The request must be made through the web site. The online form requires information to justify the need for remdesivir.
- Gilead has a special expanded access program for patients treated at U.S. military hospitals though NCT04302766.
The World Health Organization is evaluating remdesivir, chloroquine, hydroxychloroquine and lopinavir-ritonavir with and without interferon-beta versus supportive care in the SOLIDARITY COVID-19 trial and comparing remdesivir and hydroxychloroquine in the WHO NOR trial (NCT04321616). The trials have an adaptive design, so that other drugs can be added at a later time. A French trial, DisCoVeRy (NCT04315948) is being set up with the same parameters.
Gilead is evaluating remdesivir administered as an inhalation in a Phase I study in healthy volunteers and hopes to initiate a COVID-19 patient trial in August 2020, with this formulation.
Chinese researchers were evaluating remdesivir in the placebo controlled Phase III COVID-19 trials in patients with mild-to-moderate infections (NCT04252664). Recruitment for the trial was slowed due to a requirement that patients had not been treated with another therapy within 30-days before entering the trial and a decrease in available patients. Many patients have already self-treated based on information they found on the Internet. The mild-to-moderate infection study was suspended on 4/10/2020 with 308 patients enrolled. The mild-to-moderate trial is estimated to be completed on 4/27/2020. Gilead has stated it is up to the Chinese researchers on when the trial data will be presented or published.
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