Remdesivir

An Oral Remdesivir Analogue for Treatment of COVID-19

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In vaccinated individuals with mild-to-moderate COVID-19, VV116 was associated with faster symptom resolution.

VV116 (mindeudesivir) is an oral remdesivir analogue that blocks SARS-CoV-2 replication by targeting the viral RNA polymerase. In a previously reported phase 3 clinical trial in high-risk patients with COVID-19, VV116 was comparable to nirmatrelvir/ritonavir (Paxlovid) regarding time to clinical recovery (NEJM JW Infect Dis Jan 19 2023 and N Engl J Med 2023; 388:406). Now, investigators in China report results of a placebo-controlled trial in 1347 patients with mild-to-moderate COVID-19 during the Omicron era.

Participants were randomized 1:1 to receive 5 days of VV116 or placebo; about 44% had a risk factor for severe COVID-19. Median age was 35 (only 7% were aged ≥60). Almost all participants (97%) had received COVID-19 vaccination. Median time to sustained symptom resolution was 10.9 days (VV116) versus 12.9 days (placebo), a statistically significant difference. Only one participant —who was in the placebo group — progressed to severe COVID-19; no one died. Participants who received VV116 were more likely to clear the virus by day 5 than those who received placebo.

Comment

Although VV116 has been approved in China, I am not aware that this agent is being reviewed by the FDA. Obeldesivir. opens in new tab, another oral remdesivir analogue, is being evaluated in a phase 3 clinical trial in the U.S. and Japan. If obeldesivir shows clinical benefit, we may have another option for managing COVID-19 in nonhospitalized patients. An advantage of remdesivir analogs over the SARS-CoV-2 protease inhibitors nirmatrelvir/ritonavir (Paxlovid) and ensitrelvir. opens in new tab (currently in phase 3 clinical trials) is that remdesivir has few to no drug interactions.

Coronavirus: Run, Here Come the Experimental Drugs

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As I’ve shown in recent articles (archive here), the virus hunters have fallen far short of proving a coronavirus is causing this “outbreak.” But here come the antiviral drugs.

They’re ordinarily used for other diseases (malaria, HIV) or, in one case, no disease yet (unapproved, unlicensed). But it’s time for “heroic measures.” A better term would be “reckless experimentation.”

Public health officials are expressing a mixture of hope and…vampire-ish worry that the epidemic may not last long enough to properly test the efficacy of the drugs.

LA Times, 2/13/2020, “Doctors fight coronavirus outbreak with drugs that target HIV, malaria and Ebola”:

—Characterizing the remarks of a Harvard professor of medicine, the Times author writes: “The lack of certainty surrounding treatment for coronaviruses is partly due to the boom-and-bust nature of outbreaks — they can spread like wildfire and then disappear… Although that is good for the public’s health, it also means scientists sometimes don’t have the time or the means to thoroughly test a treatment in humans.” Tsk, tsk, what a shame.

Here’s another telling quote from the Times article: “The ramp-up in [drug] research and investments into outbreaks can wreak havoc on private drug companies, especially if the virus disappears at some point, as SARS did, said Dr. Jesse Goodman, a professor of medicine at Georgetown University in Washington, D.C. The federal government helps offset these costs through initiatives…” What do you know about that? The SARS virus “disappeared.” And pity the poor drug companies. Their research was interrupted.

Among the drugs suddenly being used on people diagnosed with the coronavirus: Kaletra (anti-HIV); chloroquine (anti-malaria); remdesivir (unapproved, anti-Ebola).

rxlist.com provides a list of adverse effects of Kaletra:

* diarrhea
* headache
* weakness
* nausea
* vomiting
* stomach upset
* drowsiness
* dizziness
* a bad taste in the mouth
* trouble sleeping
* skin rash
* changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist)

“Tell your doctor if you have serious side effects of Kaletra including”:

* unexplained weight loss
* persistent muscle aches or weakness
* joint pain
* numbness or tingling of the hands/feet/arms/legs
* severe tiredness
* vision changes
* severe or persistent headaches
* signs of infection (such as fever, chills, trouble breathing, cough, non-healing skin sores)
* signs of an overactive thyroid (such as irritability, nervousness, heat intolerance, fast/pounding/irregular heartbeat, bulging eyes, unusual growth in the neck/thyroid known as a goiter)
* signs of a nerve problem known as Guillain-Barre Syndrome (such as difficulty breathing/swallowing/moving your eyes, drooping face, paralysis, slurred speech)
* increased thirst
* increased urination
* confusion
* persistent nausea or vomiting
* stomach or abdominal pain
* yellowing eyes or skin
* dark urine

Chloroquine adverse effects (from Drugs.com)—“Check with your doctor immediately if any of the following side effects occur while taking chloroquine”:

* anxiety
* attempts at killing oneself
* back, leg, or stomach pains
* black, tarry stools
* bleeding gums
* blistering, peeling, or loosening of the skin
* blood in the urine or stools
* blurred or decreased vision
* change in near or distance vision
* chest discomfort or pain
* chills
* cold sweats
* confusion
* continuing ringing or buzzing or other unexplained noise in the ears
* cough
* dark urine
* diarrhea
* difficulty in focusing the eyes
* difficulty with speaking
* difficulty with swallowing
* disturbed color perception
* dizziness
* dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
* double vision
* drooling
* fast, slow, irregular, or pounding heartbeat
* feeling that others are watching you or controlling your behavior
* feeling that others can hear your thoughts
* feeling, seeing, or hearing things that are not there
* fever
* general tiredness and weakness
* halos around lights
* headache
* hearing loss
* inability to move the eyes
* increased blinking or spasms of the eyelid
* joint or muscle pain
* large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
* light-colored stools
* loss of balance control
* lower back or side pain
* muscle trembling, jerking, or stiffness
* muscular pain, tenderness, wasting, or weakness
* night blindness
* nausea
* overbright appearance of lights
* painful or difficult urination
* pale skin
* pinpoint red spots on the skin
* puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
* red skin lesions, often with a purple center
* red, irritated eyes
* restlessness
* shuffling walk
* skin rash, hives, or itching
* sore throat
* sores, ulcers, or white spots on the lips or in the mouth
* sticking out of the tongue
* stiffness of the limbs
* sweating
* swollen or painful glands
* tightness in the chest
* trouble breathing
* tunnel vision
* twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
* uncontrolled movements, especially of the face, neck, and back
* unusual bleeding or bruising
* unusual tiredness or weakness
* upper right abdominal or stomach pain
* vomiting
* yellow eyes and skin

Adverse effects of remdesivir—the drug has not been approved for public use. I find at least one human clinical trial has been done on people “infected by the Ebola virus,” and another clinical trial is underway now. So far, I see no published list of adverse effects—probably because the drug is still in the test phase. Using this drug on “coronavirus patients” would certainly be experimental.

This is what I’m sitting here picturing: A person in Wuhan, who is having respiratory problems, owing to the unprecedented mixture of toxic pollutants in the air of the city, enters a clinic. He is given a chest CT Scan. He’s told he has a lung infection—pneumonia. Because a CT Scan is now absurdly sufficient for a diagnosis of “epidemic coronavirus,” he is given that label. NO test for the purported coronavirus is done. The person is shunted into a treatment room, and a doctor tells him his condition is quite serious, and he will be treated with a drug: chloroquine.

Go back and read the list of adverse effects again.

Suppose this patient tells his doctor he has a relative who lives out in the country, where the air is much better, and he wants to stay with her.

The doctor will, of course, tell the patient this is not possible. The city is locked down. If the patient left Wuhan, he could “spread the virus to others.”

He will be given the drug. What about informed consent? Will the doctor read the patient the complete list of adverse effects? Are you kidding? Wouldn’t that be “counter-productive?”

Mustn’t interrupt the “research” of pharmaceutical companies.

We can only hope and pray the “epidemic” is SAID TO LAST long enough so these benevolent corporations can complete their testing. What else is a pool of human guinea pigs for?

And worry not, the pill kings have their bases covered. When “test subjects” become sicker or die, the kings can simply say, “The coronavirus was responsible.”

It all works out for the best, doesn’t it?

We haven’t even gotten to the coronavirus vaccine yet. The professionals are working hard on cooking one up. When they do, there will be no danger of an interruption in their work, if “the virus disappears.” The vaccine will be injected into healthy people. If and when some of these people keel over, all sorts of reasons can be trotted out: underlying genetic condition; the coronavirus hidden in their cells suddenly activated; undisclosed immune-system deficiency; an unrelated disease; allergic cross-reaction; and, of course, “a rare and unavoidable adverse effect among all the life-saving injections given, at no charge, to the global population…”

I’m looking through mainstream articles. I’m trying to find one that publishes the complete lists of adverse effects of the experimental drugs now being deployed on “coronavirus” patients. Odd. I can’t find one. I wonder what that means. Maybe I should ask a doctor. He would possibly be able to set me straight. Perhaps I should query a public communications pro at a pharmaceutical company. Certainly, he could contact major press outlets and urge them to print the adverse-effect lists, in the interest of full disclosure.

Right?

Right?

Is Remdesivir OK for COVID Patients With Severe Renal Impairment?

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Small trial in hospitalized patients didn’t see any toxic kidney effects

Vials of Remdesivir.

Antiviral remdesivir (Veklury) appeared safe for hospitalized COVID-19 patients with severe kidney dysfunction, according to a secondary analysis of the CATCO trial.

In the analysis of the 59 patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 at study randomization, no increased risk for hospital death was identified among those treated with remdesivir rather than standard of care (40.6% vs 52%, respectively; relative risk [RR] 0.78, 95% CI 0.41-1.49), reported Srinivas Murthy, MD, CM, MHSc, of the University of British Columbia in Vancouver, and colleagues.

This held true in a model that adjusted for sex and baseline eGFR as well (odds ratio [OR] 0.74, 95% CI 0.23-2.40), the group noted in a research letter in JAMA Network Open.

Need for new mechanical ventilation or incidence of any adverse events also trended lower in patients treated with remdesivir:

  • New mechanical ventilation: RR 0.57 (95% CI 0.15-1.80)
  • Adverse event: RR 0.37 (95% CI 0.05-1.33)

Furthermore, total average length of hospital stay wasn’t significantly different between the groups (23.1 days for remdesivir vs 21.6 for standard of care).

In this group of hospitalized patients with severe renal impairment, remdesivir also appeared to be safe for the kidneys, without any additional risk of transaminitis or toxic kidney effects by day 5:

  • Day 5 eGFR: 31.2 mL/min/1.73 m2 for remdesivir vs 20.5 mL/min/1.73 m2
  • Day 5 creatinine: 2.83 mg/dL for remdesivir vs 4.12 mg/dL
  • Day 5 alanine aminotransferase: 40.8 for remdesivir vs 91.9

For patients who didn’t require dialysis at baseline, the need for new dialysis was also no different for those given remdesivir (RR 0.95, 95% CI 0.25-3.56).

“These findings suggest that remdesivir can be safely administered in patients with kidney dysfunction, balancing possible risks and benefits,” Murthy’s group said, while noting the small study population as a limitation.

This is particularly reassuring as remdesivir is not currently recommended for use in patients with severe renal dysfunction, particularly those with an eGFR below 30, “owing to the presence of excipients that may accumulate in kidney dysfunction and worsen kidney or hepatic outcomes,” the researchers wrote.

They added that the “need for assessing kidney function in the absence of clinical suspicion before and during outpatient administration of remdesivir can be questioned.”

Data for the analysis came from the Canadian Treatments for COVID-19 (CATCO) trial that was part of the larger global Solidarity Trial. This trial didn’t impose any kidney-specific exclusion criteria to participation.

Patients randomized to receive open-label remdesivir were administered lyophilized remdesivir, diluted and administered intravenously with a loading dose of 200 mg on the first day, and then followed by daily 100-mg doses for 9 days or until the patient was discharged. The dose of remdesivir was not adjusted for baseline kidney functioning.

Standard of care was delivered in the form of “best-quality supportive care,” the team noted.

Along with the small study population (34 patients in the remdesivir group and 25 in the standard-of-care group), the current analysis was also limited by baseline differences, according to the researchers.

Between the remdesivir and control groups, respectively, baseline differences included median age (74 vs 80 years), male sex (38.2% vs 68%), median frailty score (4 vs 5), need for intensive care (32.4% vs 28%) or oxygen (47.1% vs 56%), as well as median creatinine (2.62 vs 3.88 mg/dL) and eGFR levels (22.7 vs 12.4 mL/min/1.73 m2), among others.

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses

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Background

The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.

Methods

Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.

Findings

Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.

Interpretation

Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

Remdesivir for Patients Hospitalized with COVID-19

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The WHO SOLIDARITY trial shows remdesivir reduces mortality in patients who do not yet require ventilation.

While U.S. guidelines suggest hospitalized patients with severe COVID-19 receive remdesivir, the WHO has a conditional recommendation against its use in this setting. WHO guidelines are based, in part, on preliminary results of the WHO-sponsored SOLIDARITY trial (NEJM JW Infect Dis Feb 2021 and N Engl J Med 2021; 384:497), which did not show a reduction in mortality among hospitalized patients who received remdesivir. Now, final SOLIDARITY results have been published and a more nuanced picture has emerged.

In this open-label trial conducted in 35 countries, 8275 inpatients with COVID-19 were randomly assigned to receive remdesivir or control (no study drug). Overall, mortality was similar in both groups (14.5% [remdesivir] and 15.6% [control]). Among those who already required ventilation, mortality was 42.1% (remdesivir) and 38.6% (control). However, among those who did not require ventilation, mortality was lower in the remdesivir group: 11.9% vs. 13.5% (rate ratio, 0.86; P=0.02). Progression to ventilation also occurred less frequently in the remdesivir group.

COMMENT

Remdesivir is most likely to be beneficial when initiated early in the course of COVID-19. The PINETREE study showed that remdesivir prevents progression to hospitalization in high-risk outpatients with mild-to-moderate COVID-19 (NEJM JW Infect Dis Feb 2022 and N Engl J Med 2022; 386:305). Studies in hospitalized patients find the benefit of remdesivir is most evident in those who have severe COVID-19 but have not yet progressed to requiring ventilation (NEJM JW Infect Dis Dec 2020 and N Engl J Med 2020;383:1813). For patients hospitalized with COVID-19 and requiring oxygen, I prescribe a combination of remdesivir and dexamethasone — and if progression occurs, I add a second immunomodulatory agent (baricitinib or tocilizumab).

CITATIONS

WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: Final results of the WHO Solidarity randomised trial and updated meta-analyses. BMJ 2022 May 2; [e-pub]. (https://doi.org/10.1016/S0140-6736(22)00519-0. opens in new tab)

FDA expands use of remdesivir in patients with COVID-19

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The FDA recently announced it has expanded its approval of Gilead Sciences’ antiviral drug remdesivir — marketed in the U.S. as Veklury — to allow certain outpatients with COVID-19 to receive it.

According to a press release, the FDA expanded the approval of IV remdesivir to include nonhospitalized adults and children aged 12 years and older weighing at least 40 kg (about 88 lbs.) who have mild to moderate COVID-19 and are at high risk for advancement to severe disease, including hospitalization or death.

FDA HQ in Washington
The FDA recently made two decisions that expand access to the COVID-19 treatment remdesivir.
Photo source: Adobe stock.

The FDA said it also updated its emergency use authorization for remdesivir to include children who weigh 3.5 kg to less than 40 kg or children aged less than 12 years who weigh at least 3.5 kg and have tested positive for SARS-CoV-2 via viral testing, are not hospitalized, have mild to moderate disease and are at high risk for progression to severe COVID-19, including hospitalization or death.

Both FDA decisions allow remdesivir to be administered to nonhospitalized, high-risk patients for a total of 3 days, the agency said. Children who are prescribed the drug should receive a weight-adjusted dose, according to the press release.

The expanded approval of remdesivir is based on a randomized controlled trial of 562 nonhospitalized patients with mild to moderate COVID-19 who were at elevated risk for progression to severe disease. Of the 279 patients who received remdesivir, two were hospitalized for COVID-19 compared with 15 of the 283 patients who received placebo (0.7% vs. 5.3%), according to the FDA. No deaths occurred in either group. As Healio previously reported, the trial also showed that an early 3-day course of remdesivir lowered the risk for hospitalization or death by 87%.

The FDA’s “actions bolster the arsenal of therapeutics to treat COVID-19 and respond to the surge of the omicron variant,” Patrizia Cavazzoni, MD, the director of the FDA’s Center for Drug Evaluation and Research, said in the press release. The actions also offer a therapeutic option “outside of a traditional inpatient hospital setting, including at skilled nursing facilities, home health care settings and outpatient facilities such as infusion centers,” she said.

Remdesivir use was previously restricted to patients requiring hospitalization from the disease.

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients

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Abstract

BACKGROUND

Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19–related medically attended visit or death from any cause by day 28.

RESULTS

A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.

CONCLUSIONS

Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo.