Some Information About Remdesivir

Short summary

Remdesivir is a moderately potent anti-viral drug. In clinical trials to test safety, the drug appears to be reasonably safe and well-tolerated. The data on whether it can decrease the death rate shows it does not do that. But what the data does appear to show, and this needs to be confirmed, is that the drug significantly shortens the time it takes a person to recover from the infection.

What remains unclear to me are (i) what "recovery" from the infection means, or how it is defined, and (ii) how early in the infection the drug needs to be started for it to have enough time to have a significant beneficial clinical effect. If the drug is started too late in a person's infection, it cannot save them if they are going to die with or without the drug.

Short technical summary

The FDA gave emergency authorization to use Remdesivir to treat the Covid-19 infection. Stories in the news yesterday indicated that some strange things had been going on in the process of authorizing use of the drug. One strange thing was a change in the 'clinical endpoint' for the drug from a reduced death rate to a reduced time to recovery, which went from 15 days to 11 days. That reduction in time to recover was called 'significant'. In drug development, 'significant' almost always means statistical significance of p < 0.05 (p means probability).

The p < 0.05 statistic means that there is a 5% chance the observed efficacy of the drug is a fluke or a false positive. A p < 0.05 value is only a modest showing that the drug is active in whatever clinical test it is analyzed in. It is preferable to hit a p-value of  0.01 or lower to have greater confidence that a drug's observed clinical activity is real.

In vivo: an assay or test in an animal or human

In vitro: an assay or test not in an animal or human, typically in cells growing in tissue culture or in cell extracts or artificial assays for individual enzymes

A February 2020 paper in the journal Cell Research reported basic antiviral activity and in vitro toxicity data for remdesivir. The drug returned values of EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87. That indicated a moderately potent drug with a relatively low toxicity profile in vitro.

The EC50 = 0.77 μM value means that at a concentration of 0.77 micromolar (μM), the drug inhibited viral replication by 50%. The EC50 is the half maximal effective concentration the drug shows in an assay. EC50 = 0.77 μM means that remdesivir is moderately potent in this particular assay. Drugs with an EC50 of 0.1 μM or lower are usually preferred.

The CC50 > 100 μM value refers to the concentration of the drug needed to kill half of the cells used in the assay. It is a general indicator of how toxic the drug is. In this case, the cells used were epithelial cells from monkey kidney. The cell line is called Vero E6 and it was developed in the 1960s. Thus, a drug that is not very toxic will have a high CC50. The lower the CC50, the more toxic the drug is. A CC50 of > 100 μM indicates that remdesivir is moderately toxic for Vero E6. It does not provide detailed information about how toxic remdesivir would be in humans.

Clinical trial experience with remdesivir in humans indicated a fairly low toxicity:

"Intravenous infusions in previously phase I clinical trials have good safety and pharmacokinetic properties. Also, no cytotoxicity, hepatorenal toxicity, or no serious adverse reactions related to metering have been observed in climbing experiments. Subjects were tolerant in studies that repeated 150 mg intravenously daily for 7–14 days. Remdesivir did not show any renal injuries in a multi-dose study."

The selectivity index value, SI > 129.87, is just EC50 ÷ CC50 (0.77 μM ÷ 100 μM). The higher the SI, the better the efficacy vs safety profile for the drug is in the assay used. Since remdesivir is not very water soluble, the CC50 is expressed as > 100 μM instead of = 100 μM. The real selectivity index cannot be evaluated due to the low water solubility for remdesivir, but it is likely to be higher than 130. However, since the SI is for an in vitro assay, it is not nearly as important as the reported toxicity and efficacy data obtained from controlled human clinical trials.

Remdesivir is a ribonucleotide analog that the virus uses to replicate itself and by incorporating the molecule into viral RNA and stopping complete duplication of the viral genome. The similarity of the remdesivir structure to natural ribonucleotides in essence "tricks" the virus polymerase into using it in place of real ribonucleotides that are always present in human, animal and cells of other kinds of self-replicating life, e.g., plants. This is a chemical strategy that has been used against RNA viruses for decades, including the first analog used to treat HIV, AZT (azidothymidine), back in the 1980s.

Remdesivir

Vaccine Risk Shift to Taxpayers

Context

When drug makers ramp up drug or vaccine production before clinical trials and data analyses are complete, it is called “at risk” production. The risk lies in the FDA’s refusal to approve the drug or vaccine on safety and/or efficacy grounds. All drug and vaccine production is usually costly, so the risk tends to be high. Companies tend to hesitate to produce at risk unless they are confident about their safety and efficacy data. The upside of at risk production is that once FDA approval is received, product sales can occur almost immediately after approval. Each day of sales protected by either market exclusivity or patents is precious. Each day can be worth millions in profit to a company.

Risk shift

The Washington Post reports that under a federal government effort, called “Operation Warp Speed”, taxpayers will assume the risk of at risk production of Covid-19 vaccine. That seems like a dumb name. Maybe the president dictated it. It sounds like him. Whatever.

Operation ludicrous speed

The downside is that taxpayers will have to pay the cost of at risk production if the vaccine fails to be sufficiently safe or effective. The upside is that if a vaccine does get FDA marketing approval, it can be at least fairly widely available within a few weeks. The goal of the effort is to have a vaccine publicly available by January of 2021. If that timeline pans out, it would be an amazing research and production achievement in such a short time.

The risk shift to taxpayers illustrates a key aspect of America’s for-profit healthcare system. Namely, it is a for-profit industry. Companies will not take risks that do not pass muster with internal company reviews, even if the risk could save many lives. Taking excessive risk can open a company and its executives up to shareholder lawsuits. Shareholders hold shares to make money, not to make people safe. That is the cold, hard reality of American healthcare. Profit, not service to the public interest, is the overwhelming moral imperative of capitalism.

Incoherent, self-serving drivel from our endlessly blame-shifting Blitherer-in-Chief

Naturally, the president chimed in. WaPo writes:

“President Trump said it is not too optimistic to try to produce roughly 300 million doses of vaccine in eight months, enough for the entire country.

‘No, I’m not overpromising. I don’t know who said it, but whatever the maximum is, whatever you can humanly do, we’re going to have. And we hope we’re going to come up with a good vaccine,’ the president said at the White House.

He added that ‘we’re going to fast-track it like you’ve never seen before, if we come up with a vaccine.’

Asked who is in charge of the effort, Trump said he is. 

‘I think probably, more than anything, I’m in charge. And I’m the one that gets blamed. And I get blamed anyway,’ Trump said.”

“I don’t know who said it.” That pretty much sums up the president’s grasp of things like science, the Covid-19 pandemic and reality in general.

“I think probably, more than anything, I’m in charge.” Probably in charge? Har, har, har! He will claim to be in charge if the effort works. But it will be the fault of Obama, Hillary’s Benghazigate and/or emailgate or something like that if it fails.

Sarcasm: Russia, if you’re listening, please find the missing emails. That is where Covid-19 came from and the vaccine recipe is in there too. Ludicrous speed on that hacking, please.

The fact that the president waited this long to jump to warp speed does mean he will be blamed for the needless delay because the delay was needless and he should be blamed. Why do this now and not three or four months ago? That inexcusable incompetence-driven delay is on the president, not Barak, Hillary, Pelosi, Schumer, the New York Times hidden emails or anything or anyone else.

Even at this very late date, the president clearly does not grasp the scope or gravity of what America is facing right now. He is amazingly clueless.

A sincere wish for the future

Maybe one day, the news won’t be so endlessly bad and idiotic. Maybe one day American politics will return to some reasonable degree of coherence and some reasonable grounding in facts, sound reason and transparent accountability. I do not know when that day will be, but I hope it is very soon.

‘MOST PEOPLE JUST DON’T THINK,’ SAYS SELF-HELP GURU JESSE ELDER AS HE FILMED HIMSELF WALKING GARBERVILLE’S MAIN STREET YESTERDAY

Texas man, Jesse Elder, self-described “Millionaire Mentor, an Improv Philosopher, former MMA fighter turned entrepreneur, and also the author of The Upgraded Life”, rolled through Garberville yesterday, walking and filming himself giving a monologue on critical thinking.

Elder, whose website says “his popular Mind Vitamin videos, online courses, events, and private coaching [teach] others how to create their own success and fulfillment, reclaim their personal freedom, and master their reality,” argues in the video that confusion is key to critical thinking as it allows one to ask the right questions.

With the empty streets of the tiny Southern Humboldt town lit by sunset, the self-help guru explained to viewers that he is traveling through on his way towards Seattle.  Elder is apparently unworried about catching COVID-19. He says he’s “wearing his mask on the inside in the form of a wolverine-like immune system.”

He adds that if anyone is concerned about “catching some sort of thing” from him as he reads “the look of fear on their face,” he alters his trajectory to stay more than six feet away from them.

Video  was filmed in Garberville by Elder and posted on Facebook. Unfortunately, they may make it difficult for some to view.

To view:

https://kymkemp.com/2020/04/29/most-people-just-dont-think-says-self-help-guru-jesse-elder-as-he-filmed-himself-walking-garbervilles-main-street-yesterday/

The Continuing Failure of the Mainstream Media

CONTEXT

Before the 2016 election, the broadcast media gave the president more far air time than other candidates. An estimate the New York Time published in March 2016 was that the free air time was worth about $1.9 billion to the president's campaign.

NPR's failure

NPR's Morning Edition program broadcast a 4-minute segment on how the Trump campaign is raising money for the 2020 elections. It is a fluff piece. It is very supportive of how the president is harvesting cash from the public for his campaign. The segment sounded like an advertisement paid for by the president's re-election campaign.

There was no mention of Biden or his campaign anywhere in today's Morning Edition program.

I found the segment to be highly offensive. I wrote to NPR complaining about supporting the president's re-election without also supporting Biden's election campaign with equal air time and an equal tone of approval.




Questions: Am I overreacting and this piece isn't anything of importance to the president's re-election? Should Biden be given equal airtime for every second that NPR and other broadcast sources give to the president?