Regeneron vs. Remdesivir
Segment # 005
Recently in response to the Biden’s Administration’s efforts to ration the use of Regeneron (monoclonal antibody infusions) in an out patient status, Texas Governor Abbott and Florida governor Desantis have sought private supplies to meet demands. Although numerous studies have shown Regeneron which is approved by the FDA in an out patient status to be superior than Remdesivir, the latter is still the go to protocol for patients in hospitals. The data below clearly shows this approach is not supported by the facts. One possible reason is that under the Emergency Use Authorizations drugs can not be administered if an alternative is available. In short Regeneron and Ivermectin could derail the EUA for vaccines.
Difference between Remdesivir and Regeneron?
Definition
Remdesivir is a medication that was designed to help with viral infections such as respiratory syncytial virus, but its use has extended to Covid-19 and other viruses. Regeneron is a company that has made a medication, REGN-COV2 cocktail, composed of antibodies that are designed to attack the coronavirus, Covid-19.
Regeneron
Federal rationing threatens Texas It appears that Biden is trying to punish red states that have not followed either federal masking or vaccinations mandates in the focus on treatments instead of prevention. At the end of this email is info for North Texas for Monoclonal Antibody Infusions. If you are out of state contact: https://infusioncenter.org/patients-monoclonal-antibody-therapies/ and https://covid.infusioncenter.org/
Supply of Regeneron COVID treatment, a key to Abbott's plan
https://www.houstonchronicle.com/politics/texas/article/Federal-rationing-threatens-Texas-supply-of-16467253.php
Accessing a critical COVID-19 therapy could soon be tougher in Texas as the federal government moves to ration the treatment amid the spread of new variants.
The Biden administration is taking over distribution of monoclonal antibodies, returning to the system that had been in place until vaccines became readily available and infections began to plummet this year. It also purchased 1.4 million additional doses.
Third, in her response Ms. Psaki attempts to define distribution “equity” as if Florida and Oklahoma have the same population. Ridiculous in the extreme. Oklahoma has 3.9 million residents and Florida has 22.9 million. The population of Florida is six times as great as Oklahoma… and two months ahead in setting up treatment centers expanding their capacity to use it.
Lastly, the appropriate response to a shortage of the treatment is to increase production of that product, not to ration it.
Florida Seeking Monoclonal Supplies From GlaxoSmithKline
A man enters the Regeneron Clinic at a monoclonal antibody treatment site in Pembroke Pines, Fla., on Aug. 19, 2021. (Chandan Khanna/AFP via Getty Images)
States See Looming Monoclonal Antibody Crunch as Biden Administration Rations Doses
Dr. Aldo Calvo, medical director of family medicine at Broward Health, shows a Regeneron monoclonal antibody infusion bag during a news conference in Fort Lauderdale, Fla, on Aug. 19, 2021.
DeSantis Criticizes Biden Team For ‘Dramatically’ Cutting Florida’s Covid Treatment Supply Amid Nationwide Shortage
https://www.politico.com/news/2021/09/14/biden-covid-antibody-treatments-511825
Biden's team tightens grip on state use of Covid antibody treatments
Yet administration officials have bristled in recent weeks over the southern states’ reliance on expensive treatments paid for by the federal government — even as several governors have attacked Biden over his attempts to boost the vaccination rate and tamp down caseloads.
States such as Tennessee and Alabama that have relied heavily on the drugs are also among those with the lowest levels of vaccination against Covid-19.
“It’s where the surges are,” said Marcus Plescia, chief medical officer of the Association for State and Territorial Health Officials, of the rising demand for monoclonal antibody drugs. “And where they haven’t been successful with the other mitigation efforts.”
The new HHS policy represents a return to the early days of the pandemic response, when the states had few other options for combating Covid-19 and demand was high for any treatment that could help keep people out of the hospital.
Once the Covid-19 vaccines rolled out across the nation and caseloads fell, demand for monoclonal antibody drugs dropped, allowing the government to more freely dole them out as needed.
Yet as Delta fueled a resurgence throughout the Southeast, Republican governors latched onto the treatments as a preferred alternative to reimposing public health restrictions. In Texas, Gov. Greg Abbott has opened a series of antibody infusion centers, even as he’s sought to ban mask requirements in schools.
DeSantis has similarly touted efforts to make the treatment widely available, while downplaying the virus’ threat and criticizing the Biden administration’s support for vaccine mandates and school mask mandates.
“Floridians who are getting this treatment, they’re people who need it,” DeSantis’ spokesperson, Christina Pushaw, said. “We’re proud of this rollout and proud of Gov. DeSantis for leading on it and raising the profile of this treatment throughout the country.”
In the face of that rising demand, the Biden administration has also scrambled to accelerate manufacturing of the drugs; already, the government has upped its overall weekly shipment to 150,000 doses from 100,000.
Even so, it will likely take several weeks to expand the pipeline for the treatments, with state officials saying they expect the new limits to remain in place at through at least October.
“Nobody was really using monoclonal antibodies until a few weeks ago. Then there was just this surge of use,” Plescia said. “There is now clearly a shortage.”
Monoclonal Antibody Infusion Info for North Texas
https://www.curbsideinfusion.com/about-us/sonia-alizzi/
https://medicalcitydoc.com/covid-19/monoclonal-antibody-therapy.dot
https://medicalcitydoc.com/util/documents/2021-Monoclonal-Antibodies-Info-Sheet-a.pdf
https://www.advanceer.com/emergency-care/covid-19-treatment/
To request infusion of monoclonal antibodies and a medical team at your facility, you may call the 24-hour State Infusion Hotline at 1-800- 742- 5990.
https://covid.infusioncenter.org/
Out of state: https://infusioncenter.org/patients-monoclonal-antibody-therapies/
Finally the American Thinker has a piece on Biden and monoclonal antibody infusions worth reading. As a voter on the left you may disagree; however, this is worth the read for you to understand that many of your fellow citizens, friends, family members, or co-workers definitely believe it. That in itself should be concerning.
Is the Biden Administration trying Murder Its Opponents?
Imagine a doctor standing at a patient’s bedside. The patient is deathly ill, and will likely die without the aid of that life-support device resting by his bed.
“Thank God for these devices, and thank God we don’t have any supply issues in getting large quantities of them,” the doctor thinks to himself. He leans over to administer the life-saving treatment but then pauses. “Wait a minute… is this Joe Smith? The same Joe Smith who called me a dirtbag at the country club last month and argued with me about mask mandates in our kids’ school?”
Now, the question. If the doctor wheels the life-saving device out of the room while citing the fact that someone else might need the device in some other hospital at some unknown time in the future, would that be murder?
If the answer to that question is yes, then it is nowhere near approaching hyperbole to suggest that the Biden administration is murdering its opponents by rationing life-saving monoclonal antibody treatments and specifically withholding them from red states due to an apparent grudge.
In fact, the only problem with that assertion is that it implies that Biden is murdering only his opponents.
In Florida, for example, the state was expecting 72,000 treatments, but the Biden administration supplied only a ration of 30,950. As Emerald Robinson of Newsmax reminded Jen Psaki, “half of the people” seeking treatment in South Florida are fully vaccinated.
That’s right. They put their trust in the government, followed the state-approved “science,” and many undoubtedly voted for Biden. None of that matters. Their lives have been weighed in the balance by Biden’s death panel, and will not be saved.
“Maybe [she’s] better off not having the surgery, but taking a pain pill,” Barack Obama told a woman asking whether or not her elderly mother should receive life-sustaining treatment in 2009, back when the notion of “death panels” were still the stuff of right-wing conspiracies. The idea being promoted by Obama, of course, was confirmation that death panels were the goal of the government’s intrusion into healthcare. The value of the old woman’s life was weighed in Obama’s mind, and without knowing her at all, she was deemed unworthy of treatment that could be provided for others whose lives Obama believed to be more valuable.
The Biden administration has taken that cold calculation to new, wickeder heights. Not only is the government rationing care based upon the broad assumptions of one’s human value, but in consideration to the political disposition of the state in which one lives, and in spite of the fact that there appears to be absolutely no apparent need to ration this particular care at all.
Perplexingly, the reason that Florida won’t be getting the treatments that Floridians need from the Biden administration, according to the logic provided by Jen Psaki, is that the state needs the treatments in the first place:
Monoclonal antibodies are life-saving treatments that are used after infection. So, clearly, the way to protect people and save more lives is to get them vaccinated so that they don’t get, uh, the COVID to begin with. But over the last month, given the rise in cases due to the delta variant, and lower number of vaccination rates in some of these states -- like Florida, like Texas -- just seven states are making up 70-percent of the orders. Our supply is not unlimited, and we believe it should be equitable across states across the country.
Read More
“There’ve been no reports of a lack of supply,” Emerald Robinson responded, which is unquestionably a relevant point. We’ve seen COVID outbreaks of cases, hospitalizations, and deaths occur in regional waves in the past. There is ample supply for the immediate need among affected states and time to ramp up supply for potential outbreaks in the future.
But Psaki disagrees. “I think our role,” she goes on, “as the government overseeing the entire country, is to be equitable in how we distribute [the treatments].”
In this exchange, Psaki accomplishes something spectacular, in that she both invokes the Marxist principle of equitable distribution administrated by the government and simultaneously inverts the promises of Marxism.
“From each according to his ability, to each according to his needs!” This is the enduring slogan of Marxism, popularized by Karl Marx in 1875’s Critique of the Gotha Program.
Well, those with the ability have created an ample supply of life-saving monoclonal antibody treatments. Floridians need the treatments while the federal government is hoarding and withholding them as obvious political punishment for noncompliance.
The inconvenient truth is that this is always the end result of Marxism. “Equity” becomes a virtue that supplants liberty, and the government invariably abuses its power in controlling both the means of production and distribution of resources to punish its political enemies.
When Ukrainian farmers opposed Stalin’s agricultural collectivization efforts in 1928, he accused them of a bourgeois sense of nationalism for defying the ruling party. Millions of men, women, and children were sent to collectivist farms in Siberia, and when production stalled, the promises of “to each according to his need” were certainly not afforded to them, as the Soviet government withheld life-saving food and murdered millions in the Holodomor. Food that could have been given to the starving kulaks was instead given to workers in the cities and sold abroad to finance Stalin’s industrialization efforts (which was the “infrastructure spending” of his day).
Florida is not experiencing anything close to the scale of suffering in the Holodomor, thank God. And the unvaccinated are not yet having treatments withheld due to their vaccination status. But it’s hard to imagine how this might be much different if they were. Right now, if you are a vaccinated Floridian who is in a hospital, there is a chance that the Biden administration has decided to withhold life-saving treatment from you as punishment for your neighbors’ refusal to abide by his command to be vaccinated.
This is also a feature of Marxism -- collective, rather than individual, political punishment by the State for noncompliance.
For the Biden administration, there is a dark political victory being sought, which will come at the cost of all these Floridians’ lives.
Killing Floridians by denying them readily available life-saving treatments will cause death tolls to rise in Florida, in spite of cases, hospitalizations, and deaths having been on the wane for weeks. Nothing has vexed the super-smart scientists who were wrong about nearly everything when it came to COVID mitigation as much as Florida has (except, perhaps, Sweden, which they ignore). New Jersey, for example, did everything the government-approved “science” said to do, and it has a per capita death rate that is roughly 30-percent higher than Florida, which did everything the state-approved science said not to do while, incidentally, having the second-oldest population in the country.
Florida is a far-too-visible testament to the fallibility of the federal government’s “experts,” and they haven’t suffered enough for refusing to “follow the science.” And for that, the Biden administration has decided that more Floridians must die. We shouldn’t delude ourselves by believing that there’s anything nobler than that behind all of this.
To comment, you can find the MeWe post for this article here.
Mayo Clinic, inference AI studies find antibody treatment may reduce hospitalization in high-risk COVID cases
The first of the two studies focused on casirivimab-imdevimab, the monoclonal antibody cocktail present in Regenerton’s REGEN-COV. Using nference’s natural language processing AI software, researchers combed through the lab tests, clinical notes and electronic health records of nearly 1,400 high-risk Mayo Clinic patients with mild to moderate cases of COVID, half of whom were given the antibody treatment.
The analysis found that throughout the four weeks after receiving treatment, the patients who received the antibody infusions were hospitalized at increasingly lower rates than those in the control group. After two weeks, only 1.3% of patients treated with antibodies had been hospitalized, compared to 3.3% of the control group. By the four-week mark, that gap had further widened between the two groups, with hospitalization rates of 1.6% and 4.8%, respectively.
The second study used nference’s AI to examine the effects of bamlanivimab, another monoclonal antibody that is no longer authorized to be administered on its own—after the FDA revoked its EUA in April—but may still be used to treat COVID when combined with etesevimab.
That analysis compared the results of bamlanivimab treatment in 2,335 high-risk COVID patients with those of an untreated control group of the same size. Once again, all-cause hospitalization rates were shown to be significantly lower in the antibody-treated group, clocking in between 1.4 and two percentage points lower than those in the control group after two, three and four weeks.
The researchers also studied ICU admission rates for both groups. The AI analysis found that while the control group’s rate hovered around 1% at each interval, the antibody group’s average admission rate maxed out at 0.56% after four weeks.
“While trials with small cohorts led to the authorization of casirivimab-imdevimab treatment for COVID-19 with monoclonal antibodies, clinical data has been needed to prove its effectiveness,” said AJ Venkatakrishnan, Ph.D., nference’s vice president of scientific research and the co-author of both studies. “These two papers are the latest evidence of how our platform and our scientists are able to provide the real-world evidence necessary to accelerate research and development of important drugs.”
The antibody studies are the latest additions to nference and Mayo Clinic’s growing list of joint research projects, with the bulk of this year’s focusing on COVID-19.
In June, for example, the partners performed a similar AI analysis on the health records related to nearly 133,000 doses of the three FDA-authorized coronavirus vaccines from Pfizer-BioNTech, Moderna and Johnson & Johnson. The study found no significant link between any of the vaccines and cerebral venous sinus thrombosis, a rare condition that causes blood clots in the brain and that was the cause of the 10-day pause on the J&J vaccine in April.
The following month, nference and Mayo Clinic published another study outlining links between certain pre-existing conditions and COVID complications. By analyzing the clinical notes of more than 1,800 Mayo Clinic patients hospitalized due to the coronavirus, the researchers were able to draw definitive lines between 21 risk factors—led by hypertension—and potential complications, including pleural effusion, cardiac arrhythmia, anemia and more.
COVID Infusion Therapy Effective At Reducing Severity Of Disease — If You Get It Soon Enough
Monoclonal antibody therapy to lessen the severity of COVID’s delta strain may be the only drug at this time on which vaxxers and anti-vaxxers can agree.
Some anti-vaccination advocates are counting on being able to get the therapy if they contract COVID, while people who are vaccinated but still get the virus turn to it to lessen the effects of the disease.
Antibodies are proteins made by the immune system to clear infections. For viruses such as COVID-19, these proteins are critical to stopping the infection.
But the bottom line is that the therapy does not work unless it is given in the first 10 days of COVID symptoms. Symptoms include fever, chills, loss of taste or smell and muscle aches. A complete list can be found on the CDC website.
“The problem is that our immune system takes two to three weeks to make good antibodies,” said UAB professor Dr. Turner Overton.
Monoclonal antibodies are supplemental manmade antibodies that can be administered early in the course of the infection. The antibodies rapidly bind and kill the COVID virus and reduce the risk of hospitalization by 70% in high-risk unvaccinated people.
“It is incredibly effective if given early enough,” Overton added.
Note: It cannot be stressed enough that these treatments must be started early to be effective. Studies showing these being employed after day 10 are useless.
Remedesivir
If you are following the vaccine battles, you are probably well aware of remdesivir which came on scene last year heartily endorsed by Fauci as the next big thing for treatments against COVID. You might recall one of the selling points was the ability for remdesivir to shorten your hospital stay by three days.. normally 13 days to around 11. Since all the media coverage was being placed on vaccines, at the time this did not seem to be a very big deal. Now that many countries are dealing with breakthrough cases the vaccinated people are paying more attention to who is living and dying in the hospital. Traditionally patients have been sent home after their positive test until they get worse and then they are admitted to hospitals where they get remdesivir, steroids, and antibiotics as they present symptoms of pneumonia. Understand as you will note below, Europe won’t use remdesivir, Gilead has lowered their economic projections for selling remdesivir, and it still is the standard of care in the US. You might get the feeling it’s all about the money and the FDA, NIH, and the White House could care less about us.
So don’t believe me.. check out the studies on remdesivir.. this is hardly the wonder drug Fauci described… and it hardly has become a lifesaver in the battle against COVID.
I don’t like talking head experts that tell me what to do and what to think. I prefer someone to show the way to find the data that guides me on what to do. The more I dig the more convinced I am that we have lost many people needlessly. But we still have options and that is certainly worth something… Stay well.
World's top intensive care body advises against Remdesivir for sickest COVID patients
BRUSSELS (Reuters) - Antiviral remdesivir should not be used as a routine treatment for COVID-19 patients in critical care wards, the head of one of the world's top bodies representing intensive care doctors said, in a blow to the drug developed by U.S. firm Gilead GILD.O.
FILE PHOTO: An ampule of Gilead Sciences' COVID-19 antiviral remdesivir is pictured during a news conference at the University Hospital Eppendorf (UKE) in Hamburg, Germany, April 8, 2020. Ulrich Perrey/Pool via REUTERS
Remdesivir, also known as Veklury, and steroid dexamethasone are the only drugs authorised to treat COVID-19 patients across the world. But the largest study on remdesivir’s efficacy, run by the World Health Organization (WHO), showed on Oct. 15 it had little or no impact, contradicting previous trials.
In light of the new interim data from the WHO’s Solidarity trial “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, said in an interview with Reuters.
Kesecioglu said the recommendation would be discussed in a scientific paper on COVID therapies that ESICM is preparing with the Society of Critical Care Medicine, another intensive care body, expected to be published by January.
The first version of the paper, released in March, said there was not enough information to recommend the use of remdesivir and other antivirals in critically ill COVID-19 patients.
Gilead, which has questioned the WHO’s findings, said in an emailed statement: “We are confident that doctors on the front lines recognise the clinical benefit of Veklury based on robust evidence from multiple randomized, controlled studies.”
ESICM represents thousands of anaesthesiologists, respiratory physicians, nurses and other critical care professionals in more than 120 countries.
While doctors and hospitals are not obliged to follow its advice, its recommendation could curb the use of remdesivir.
At the end of October, Gilead cut its 2020 revenue forecast, citing lower-than-expected demand and difficulty in predicting sales of remdesivir.
WIDELY USED
The drug remains, however, widely used in hospitals. It is authorised or approved for use in more than 50 countries and was one of the medicines administered to U.S. President Donald Trump when he tested positive for coronavirus in October.
The European Union signed a 1-billion-euro ($1.2 billion)deal with Gilead for 500,000 courses of remdesivir at 2,070 euros each, days before the Solidarity results.
The deal does not oblige European countries to buy remdesivir, but governments decided to place large orders even after the Solidarity results, with Germany buying a big stock in November, saying the drug was useful, especially early in the course of the disease.
Kesecioglu said there was not enough data available about when remdesivir might be effective or for which patients, leading to the decision to discourage its routine use in intensive care.
This means doctors should use remdesivir only occasionally, and not as a standard treatment for COVID-19 patients.
Because of remdesivir’s unclear benefits, the critical care department at the University Medical Center of Utrecht in the Netherlands, where Kesecioglu works, has not used it to treat COVID-19 patients, he said.
POSSIBLE SIDE-EFFECTS
Ten months into the pandemic, a debate continues to rage in the medical industry about which drugs are best to treat hospitalised COVID-19 patients.
Remdesivir has potential side-effects on the kidneys, according to data shared by Gilead with the European Medicines Agency, which is assessing its possible toxicity.
Arnaud Hot, head of medicine at Edouard Herriot hospital in Lyon, France, told Reuters that some patients at his hospital had experienced kidney injury and so it was no longer using remdesivir, except in rare cases.
Kesecioglu said convalescent plasma, which is also experimentally administered to some COVID-19 patients despite not having been approved, was also not recommended by ESICM for routine intensive care use, as its benefits were unclear.
He added the potential side-effects of convalescent plasma - the liquid part of blood extracted from COVID-19 patients - were also not clear
In contrast, Kesecioglu said dexamethasone was recommended for use in hospitalised patients because there was sufficient information on its efficacy.
Published online 2020 May 22. doi: 10.7573/dic.2020-4-14
PMCID: PMC7250494
PMID: 32547625
The Journey of Remdesivir: from Ebola to COVID-19
Joe Pardo, PharmD,1 Ashutosh M Shukla, MD,2,3 Gajapathiraju Chamarthi, MD,3 and Asmita Gupte, MD2,3
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250494/
At day 28, mortality rates were: remdesivir (53.1%), ZMapp (49.7%), MAb114 (35.1%), and REGN-EB3 (33.5%). For remdesivir, 85 and 29% of patients with high- and low-viral loads at baseline died, respectively.
In summary, despite potent in vitro activity against EBOV and unprecedented success in animal models of EVD, the journey of remdesivir for human EVD culminated in disappointing results…… SARS-CoV-2 RNA loads were not reduced with remdesivir compared to placebo. The trial was halted before target enrollment was reached as the COVID-19 outbreak subsided in the study region. As such, the statistical power was reduced from a planned 80 to 58%, and the study remained inconclusive.
Remdesivir: A beacon of hope from Ebola virus disease to COVID-19
Ali Nili, Abolfazl Farbod, Afarin Neishabouri, Mohammad Mozafarihashjin, Soheil Tavakolpour, Hamidreza Mahmoudi,
First published: 30 July 2020
https://doi.org/10.1002/rmv.2133
https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2133
Based on these studies, it seems that remdesivir could be an effective and probably safe treatment option for Covid-19. However, more randomized controlled studies are required….. Despite the introduction of different therapeutic approaches along with efforts for the development of an effective vaccine against Covid-19, no medication has received Food and Drug Administration (FDA) approval yet. However, remdesivir was granted an emergency use authorization (EUA) for Covid-19 on 1 May 2020.17 Meanwhile, several RCTs are currently being conducted to evaluate the benefits and side effects of remdesivir in patients infected by SARS-CoV-2.
The evidence regarding the efficacy of remdesivir in viral infections is somewhat controversial. Following signals of the efficacy of remdesivir in a rhesus monkey model of EVD in 2016, hopes for overcoming this disease flourished.1 Indeed, a 12-day administration of remdesivir showed significant suppression of Ebola virus and Marburg virus replication, followed by amelioration of the disease.1 This report suggested the potential broad-spectrum antiviral activity of remdesivir, not only for Ebola virus but also for other RNA viruses, and indicated it was ready to enter human studies. In 2019, an RCT including 681 patients with EVD demonstrated that remdesivir and Zmapp (triple monoclonal antibody cocktail) did not have any mortality benefit in comparison to the two other treatment arms, MAb114 (single monoclonal antibody) and REGN-EB3 (cocktail of three monoclonal antibodies). In fact, the mortality rate at 28 days in the remdesivir group (53.1%) was significantly higher than that of the REGN-EB3 and MAb114 groups (33.5% and 35.1%, respectively), and slightly higher than that of the Zmapp group (control group; 49.3%). Moreover, this study indicated that remdesivir exhibited a favorable safety profile in the human population.4….. This history of remdesivir in its relatively short life since its introduction and lack of adequate human clinical trials raises hopes for its efficacy in new emerging viruses.
CLINICAL EVIDENCE FOR REMDESIVIR EFFICACY FOR COVID-19 TREATMENT
Initially, remdesivir was administered for compassionate-use in Covid-19 patients. Evidence of possible efficacy first emerged from two case reports that showed satisfactory results from relatively late treatment with intravenous (IV) remdesivir due to the worsening clinical status of the patient. The first case who had a history of traveling to Wuhan was a 35-year-old man, diagnosed in Washington State on 19 January 2020. Remdesivir was initiated on day 11, and improvement was seen on the next day. It should be noted that the patient received other treatments, including nasal high-flow oxygen, cefepime, ibuprofen, guaifenesin, and vancomycin, which make interpretation of remdesivir efficacy more difficult.58 In the other case, who was a Covid-19 patient with ventilatory support, successful extubation occurred 60 hours after remdesivir initiation on day 13 post-symptom onset.59 In addition, successful treatment of a critically ill pregnant woman with Covid-19 by combination of convalescent plasma and remdesivir signaled some positive therapeutic effects, possibly related to remdesivir.60
Following the compassionate-use program for remdesivir in Covid-19 patients, Grein et al61 reported 68% clinical improvement in 53 severe Covid-19 patients in a retrospective study. Included patients were given a 10-day course of remdesivir; clinical improvement, which was defined as at least two points decreasing on the modified ordinal scale, was achieved in 20 of 34 (57%) patients receiving invasive ventilation, and 17 of 19 (89%) patients who were under noninvasive ventilation care. The observed clinical improvement rate in the invasive ventilation group was significantly lower than that of the noninvasive ventilation group at any particular time of the study. This finding was consistent with those observed in other studies of severe and critical Covid-19 patients.62-65 In addition, the study reported the hospital discharge and mortality rates as 23.5% and 17.6%, respectively, in patients who were ventilated compared with 89.5% and 5.2% in those who did not receive invasive ventilation care at a median follow-up of 18 days since the first dose of remdesivir was administered. Their results have shown a surprisingly lower mortality rate (17.6%) in the patients who received invasive mechanical ventilation as compared with the 65.7% proportion reported in the Wuhan cohort study.56 It is worth noting that all the above studies were observational studies without control groups. Moreover, different combination therapies and lack of clear inclusion and exclusion criteria might affect the validity of these studies as compared with the RCTs.
Another recently published randomized, double-blind, placebo-controlled trial, which was conducted from 6 February to 20 March 2020, reported a statistically non-significant benefit in terms of the primary outcome in Covid-19 patients treated with remdesivir vs placebo.18 The study was carried out in 10 hospitals of Wuhan, China, to determine the safety and efficacy of remdesivir in severe Covid-19 patients, who were within their first 12 days of disease onset. The remdesivir group achieved clinical improvement, defined similarly as the Grein et al study, at a median of 21 days vs 23 days in the placebo group.61 Although the duration of invasive ventilation was shorter, and the mortality rate was higher in the remdesivir group, both differences were found to be insignificant between the two study arms. During the treatment period, results of the viral load, measured by quantitative reverse transcriptase-polymerase chain reaction and based on upper and lower respiratory tract specimens, were not significantly different between the two groups. However, capability of remdesivir to make the SARS-CoV-2 undetectable in nasopharyngeal and nasal swab samplings was shown in two Italian studies, with a time to negativity of 12 and 3 days, respectively.65, 66 Of note, although the Wuhan RCT did not show any significant difference between the remdesivir and placebo group, some serious concerns regarding the methodology and study design had been suggested, such as an insufficient sample size and several baseline differences between the two groups, which may have affected the final results.67
The first and most rigorous clinical trial in the United States started on 21 February 2020 by the National Institute of Allergy and Infectious Diseases (NIAID). The study (NCT04280705) sought to evaluate the efficacy and safety of remdesivir in adult patients with a confirmed diagnosis of Covid-19 through a randomized, double-blind, multicenter, placebo-controlled design. So far, a total of 1063 participants have been assigned to the remdesivir or placebo groups. Participants in the treatment arm were initially started with 200 mg IV remdesivir once, daily, on day1, followed by 100 mg/IV/daily on days 2 to 10. On April 27, an independent data and safety monitoring board (DSMB) announced the initial results of their interim analysis to the study team.68 Two main findings were shared with the public on the NIAID website; the DSMB found a 31% faster time to recovery in the remdesivir group patients than those who received placebo (median: 11 vs 15; P < 0.001). In this study, recovery was defined as discharge from the hospital or reaching normal activity. The mortality rate in the remdesivir group was 8.0%, which was numerically but not significantly lower than the 11.6% mortality rate in the placebo group (P = 0.059). More data from the study have not been published yet (11 May 2020). On May 22, the preliminary report of first stage of the study was officially released.69
On April 29, Gilead Sciences, Inc. reported the primary results of an open-label, phase 3 RCT, which had been conducted over 181 medical centers in 15 countries (NCT04292899).70 The efficacy and safety of two regimens of remdesivir on 6000 severe Covid-19 patients were evaluated in this RCT to reach the optimal remdesivir dose. According to the seven-point scale,71 clinical improvement was defined as at least a two-point improvement compared with baseline. Results of the initial phase of the study with 397 participants with a 1:1 allocation ratio showed similar effectiveness of 5-day and 10-day dosing regimens (200 mg IV remdesivir once daily on the first day, followed by 100 mg/IV/daily for 4 or 9 days). The results suggest that decreasing the duration of remdesivir treatment does not have a significant impact on patient outcome. More precisely, 65% of patients who were treated with a 5-day dosing regimen achieved clinical improvement at day 14 compared with 54% in the 10-day treatment group. Numerically, 5-day remdesivir therapy has been associated with a one-day shorter time to clinical improvement (a median of 11 days in the 10-day group vs 10 days in the 5-day group). More patients in the 5-day treatment group achieved clinical recovery and discharge compared with the 10-day treatment group. Moreover, those using the 5-day regimen had a better survival rate on day 14 than those on the 10-day regimen.72 Lack of a control group treated with placebo in this study makes the interpretation about the remdesivir treatment benefits difficult (Figure 2).
“Characteristics of ongoing Remdesivir clinical trials in Covid-19 patients. It provides the study start date and anticipated end date in addition to number of locations where the trials are conducted”
Although findings related to remdesivir studies in the past few weeks, of which most were sponsored by Gilead Sciences, have rendered researchers and physicians more optimistic, longer follow up durations in a higher number of patients and high protocol adherence are required for proper adjudication.
SAFETY CONCERNS AND REPORTED SIDE-EFFECTS
Remdesivir is a relatively new medication, and there is a lack of necessary data about its safety. Based on the previous experiences of remdesivir in the treatment of MERS and EVD, it is considered to have a relatively good safety profile.4, 20 In an RCT, comparing the effectiveness of four therapeutics for EVD among 725 patients, those in the remdesivir group (n = 175) received 200 mg/IV on day 1 as the loading dose, followed by 100 mg/IV/daily for the next 9 to 13 days.4 The patients who were treated with remdesivir did not experience any serious adverse event (SAE) related to remdesivir, except for one who experienced hypotension and finally died due to cardiac arrest despite remdesivir discontinuation.4 Site causality assessment deemed this SAE as definitely related to remdesivir, while the pharmacovigilance working group adjudicated the SAE to be possibly related to remdesivir. Eight other SAEs occurred in the remdesivir group (urinary tract infection, brain edema, diabetic hyperosmolar coma, sepsis, stroke, cerebral malaria, diabetes mellitus, pyogenic arthritis in shoulder region) of which none were attributed to remdesivir by the two adjudication committees.
An increasing number of surveys focusing on remdesivir's safety profile is being made available. The compassionate use study of 53 Covid-19 patients, who were injected with 200 mg IV remdesivir on the first day and 100 mg/IV/daily for the remaining 9 days, has outlined increased hepatic enzymes (23%), diarrhea (9%), rash (8%), renal impairment (8%), and hypotension (8%) as the most common side effects. Twelve patients (23%) experienced SAEs in this study, the most frequent being multiple organ dysfunction syndrome, septic shock, acute kidney injury (AKI), and hypotension that were only experienced by patients intubated at baseline.61 In another study of 35 Covid-19 patients, hypertransaminasemia (43%), AKI (23%), increased total bilirubin level (20%), and rash (6%) were observed after treatment with remdesivir-containing regimens.65 In the recently published RCT, with 155 patients, the most common adverse events (AEs) in the remdesivir group were reported as constipation (14%), hypoalbuminemia (13%), hypokalemia (12%), anemia (12%), thrombocytopenia (10%), and increased total bilirubin (10%) at the same dose as previously mentioned for 10 days.18 Although no new safety concerns were identified and the proportion of patients experiencing SAEs was lower in the remdesivir group compared with the placebo group [28/155 (18%) vs 20/78 (26%)], a higher proportion of patients in the remdesivir group had to discontinue its use due to SAEs compared with the placebo group [18/155 (12%) vs 4/78 (5%)]. No deaths in this RCT were attributed to the use of remdesivir by trial adjudicators. According to the Gilead preliminary results from the Phase 3 investigational trial on April 29, remdesivir appears to be tolerated well, whereas nausea was reported in 20/200 (10%) in the 5-day regimen and in 17/197 (8.6%) in the 10-day regimen groups; acute respiratory failure was also reported in 12/200 (6%) and 21/197 (10.7%) in the 5-day and 10-day regimen groups, respectively.70 Another study reported skin rashes as the only cutaneous adverse event of remdesivir.73 Considering the myriad of signs and symptoms of Covid-19 (including hepatotoxicity), assigning all these reported AEs and SAEs to remdesivir is controversial. Furthermore, the preliminary report of first stage of the NIAID study showed 114 adverse events among 541 Covid-19 patients, who recieved IV remdesivir for 10 days.69 The reported side effects are provided in Table 1.
TABLE 1. The most common adverse events of remdesivir reported in previous or ongoing studies
Concern Virus Number of Events/ total treated-patients (%)
a The administration of 200 mg intravenous remdesivir in the first day following 100 mg of remdesivir up to 10 days.
b The administration of 200 mg intravenous remdesivir in the first day followed by a maintenance dose of 100 mg for 9 to 13 days.
c The administration of 200 mg intravenous remdesivir in the first day following 100 mg of remdesivir up to 5 days.
In addition, there is also lack of data about the possible side-effects and safety of remdesivir in specific sub-populations, such as children, patients with a specific underlying disease (including but not limited to active malignancy, immunosuppression, cardiac disorder, chronic liver and kidney disease, morbid obesity, chronic respiratory disease), and pregnant and breastfeeding patients.74, 75
7 ACTIVE CLINICAL TRIALS
In the literature review for studies of Covid-19 and remdesivir, some small uncontrolled studies and a few registered and controlled studies are available. In view of the efficacy and safety of remdesivir, we searched for ongoing trials and studies submitted to the ClinicalTrials.gov, EU Clinical Trials Register, UMIN Clinical Trials, ANZCTR, CHICTR, and ISRCTN registries up to 11 May 2020 by using the keyword “remdesivir.” We found 12 studies that are currently underway to assess the efficacy and/or safety of remdesivir as a treatment agent in Covid-19; seven clinical trials, three o bservational studies, and two expanded access studies. Details of these studies are presented in Table 2. Among the seven identified RCTs, all are designed to be multicenter, six are in phase 3, and one is in phase 2. For most trials, the anticipated number of recruited participants is more than 1000. Following the preliminary and partial study results showing possible signals of efficacy of remdesivir for treatment of Covid-19, some studies are emerging for the assessment of the possible efficacy of adding anti-inflammatory drugs (Figure 2). On 8 May 2020, NIH announced a new trial for evaluating the efficacy and safety of remdesivir combined with baricitinib, a JAK inhibitor (developed by Eli Lilly and Company), in the treatment of Covid-19 with ARDS. The first arm will receive a 10-day remdesivir course plus 4 mg oral baricitinib for up to 14 days, and the second will be treated with remdesivir plus placebo. The study is a double-blind RCT conducted at approximately 100 medical centers.76
Apr 30, 2020,01:36pm EDT|3,498 views
Urging Caution On Remdesivir
There is palpable excitement today among many regarding the potential of remdesivir to help patients with severe Covid-19 recover. Many are saying there is clear cut evidence that it works, based on a news release issued yesterday by the National Institutes of Health (NIH). Yet, an equally important study about remdesivir was published the same day in the Lancet, with markedly different results and noticeably less attention paid.
According to the NIH, preliminary data analysis from a randomized, controlled trial involving 1063 patients showed that patients who received remdesivir had a 31% faster time to recovery than those who received the placebo. It also suggested — but didn’t statistically prove — that there was a survival benefit to the drug, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group.
Vials of the drug Remdesivir at a press conference In Germany at the start of a new study with the ... [+]
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The Lancet article describes results from a randomized, double-blind, placebo-controlled trial involving 237 patients at ten hospitals in Hubei Province, China. That study found that patients who received remdesivir did not recover any faster than patients given the placebo. They also found that the 28-day mortality was similar between the two groups, with 22 patients (14%) who died in the remdesivir group versus 10 (13%) in the placebo group.
In such a time of despair, it is no wonder that we cling to the more positive results from the NIH trial and all but ignore the news from China. But our hope is premature and may be misplaced. The NIH has not released any comprehensive data from their trial, nor were their findings made public or peer reviewed before the public announcement.
While I have enormous respect for the Institutes and their leaders, releasing the preliminary news without sharing the data behind it is highly irresponsible. We have, unfortunately, already seen what unfounded trust in an unproven medical solution can do, with the death of a man in Arizona who ingested chloroquine from his fish tank in the hopes that it would protect him from Covid-19.
Remdesivir is not a drug without risk.The peer reviewed study out of China showed that 18 patients (12%) had to discontinue remdesivir because of adverse or serious adverse events. These adverse and potentially life-threatening events included gastrointestinal issues and liver function abnormalities — side effects that we have known about for a while already.
It is impossible to know with certainty why the NIH released unpublished preliminary results without accompanying comprehensive data on the same day that a definitive peer reviewed paper with disappointing results was being published. It is possible that they are aware of a credible beacon of hope and they wanted providers and patients alike to know. It is also possible that the decision was done for economic, geopolitical, or political reasons.
But we should not allow hope, nor politics, nor economics to cloud our vision. Viruses do not care much for any of them. If we are to have drugs and vaccines to control this pandemic, we must keep an open mind regarding what works. But we must be equally open to what doesn’t and not base policy or actions on undocumented assertions that may put all of us more at risk than necessary.
