Remdesivir
Emergency Use Authorization
The FDA approved remdesivir (Veklury, Gilead), on 10/22/2020, for the treatment of hospitalized COVID-19 patients that are 12 and up and weigh at least 40 kg (88.2 lbs). The FDA issued a new EUA for remdesivir for hospitalized children age 12 and older that weigh at least 3.5 kg (7.7 lbs) but less than 40 kg, and in children under age 12 that weigh at least 3.5 kg.
The FDA granted an EUA for the combination of baricitinib (Olumiant. Lilly) plus remdesivir (Veklury, Gilead) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The approval was based on the 29-day, 1,034 patient, Phase III, ACTT 2 trial (NCT04401579), where baricitinib added to remdesivir reduced the time to hospital discharge by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with COVID-19. ACTT 2 was sponsored by NIAID. The largest effect was seen in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation.
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.
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.
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
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 full prescribing information including administration, dosing and recommendation for monitoring and management of remdesivir patients.
In an update, the American College of Physician recommend that remdesivir should not be initiated in hospitalized COVID-19 patients receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) because the infection has likely progressed to the inflammatory stage of the disease. ACP does recommend consideration of remdesivir for five days in hospitalized patients that do not require ventilation or ECMO. Remdesivir may be given for up to ten days 10 days in patients that progress to mechanical ventilation or ECMO and have already started the drug.
Pre-Clinical Studies
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.
The FDA approved remdesivir (Veklury, Gilead), on 10/22/2020, for the treatment of hospitalized COVID-19 patients that are 12 and up and weigh at least 40 kg (88.2 lbs). The FDA issued a new EUA for remdesivir for hospitalized children age 12 and older that weigh at least 3.5 kg (7.7 lbs) but less than 40 kg, and in children under age 12 that weigh at least 3.5 kg.
The FDA granted an EUA for the combination of baricitinib (Olumiant. Lilly) plus remdesivir (Veklury, Gilead) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The approval was based on the 29-day, 1,034 patient, Phase III, ACTT 2 trial (NCT04401579), where baricitinib added to remdesivir reduced the time to hospital discharge by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with COVID-19. ACTT 2 was sponsored by NIAID. The largest effect was seen in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation.
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.
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.
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
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 full prescribing information including administration, dosing and recommendation for monitoring and management of remdesivir patients.
In an update, the American College of Physician recommend that remdesivir should not be initiated in hospitalized COVID-19 patients receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) because the infection has likely progressed to the inflammatory stage of the disease. ACP does recommend consideration of remdesivir for five days in hospitalized patients that do not require ventilation or ECMO. Remdesivir may be given for up to ten days 10 days in patients that progress to mechanical ventilation or ECMO and have already started the drug.
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.
- 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.
- The ACTT-1 investigators provided a final report on the NIAID sponsored study. In the 29-day, 1,062 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) (NCT04280705), patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 10 days compared to 15 days with placebo in patients with severe COVID-19. However, there was not a significant improvement for patients that required a ventilator or ECMO at study entry. At day 15, there was a significant difference in mortality with remdesivir compared to placebo (6.7% vs 11.9%), but the difference was no longer significant at 29 days (11.4% and 15.2%).
- In the NIAID sponsored 29-day, 1,033 patient, Phase III, ACTT 2 trial (NCT04401579), baricitinib added to remdesivir reduced the time to recovery by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with moderate to severe COVID-19. The largest effect was seen in patients receiving high-flow oxygen or non-invasive ventilation (10 vs 18 days)
- Interim results from the WHO sponsored, 11,330 patient, Phase II/III SOLIDARITY trial (NCT04315948), did not find an improvement in hospitalized COVID-19 patients treated with remdesivir, hydroxychloroquine, lopinavir or interferon compared to no drug in mortality, initiation of ventilation or duration of hospital stay. But some analysts did not agree with the study’s findings. A physician reviewer speculated that remdesivir may be more effective when given early in the infection to patients at high risk for progression. An editorialist highlighted the benefit of remdesivir“to change the course of hospitalization in some patients”. A second editorialist pointed out that SOLIDARITY was not designed to measure time to recovery or clinical improvement. An analysis of oropharyngeal specimens from 181 patients that were collected during the Norwegian arm of the WHO Solidarity study did not find a decrease in SARS-CoV-2 viral load with remdesivir or hydroxychloroquine compared to standard of care.
- An unpublished and unedited invitro study that tested the antiviral effects of plitidepsin, ralimetinib and remdesivir on early SARS-CoV-2 and the B.1.1.7 variant found similar activity with both viral strains.
- In a retrospective review of 2,483 consecutive patients with severe COVID-19, 342 patients received remdesivir with 184 also receiving corticosteroids. Treatment with remdesivir resulted in a decrease in time to clinical improvement (5 vs 7 days). Mortality had a non-significant decrease (7.7% vs 14%), which was not affected by use of corticosteroids. The patient population was 80% non-white, compared to 30% to 47% in clinical trials.
- Gilead Sciences discontinued a 28-day, 1,264 patient, Phase III trial evaluating three intravenous infusions of remdesivir to reduce the development of COVID-19 (NCT04501952), related hospitalization or all-cause death in non-hospitalized COVID-19 patients. The trial was discontinued because the standard of care for outpatient COVID-19 had advanced beyond the need for a multi-day treatment that required administration by intravenous infusion, such as the single dose monoclonal antibodies.
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.
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