COVID19 update, June 2, 2020: Remdesivir Phase 3 trial results

A short post today, as the day job is keeping me busy. 

 

(1) Today the results of the Phase 3 remdesivir trial were released. (I previously discussed its mechanism of action here: in brief, it’s a nucleoside analog that interferes with viral RNA copying by acting as an “imposter letter” in the RNA genetic code and causing further copying to break off.)

Again, as with prior trials, we see that it’s not a “magic bullet” drug, but clearly has a therapeutic advantage  in patients with moderate disease (signs of pneumonia, but don’t yet need oxygen). The trial used almost 600 patients, divided into three roughly equal groups: (a) standard of care (SOC) + 5-day remdesivir; (b) SOC + 10-day remdesivir; (c) SOC only (control group). In the table below, percentages are given in parentheses:UntitledImage

The “ordinal scale” is an ad hoc 7-point scale ranging from hospital discharge on one end to death on the other end. In the 5-day regimen (which I read between the lines uses twice the dose for half the time), about 10% more patients see an improvement, and 8% fewer patients see a worsening from baseline than with SOC. No patients on the 5-day regime died (compared to four with SOC), but we are in “statistics of small numbers” territory.

As for drug side effects (“AE”), there are about 6% more than with standard care, but actually fewer serious side effects.

Additional Phase 3 trials in severe and moderate disease are in progress in various countries. The drug is currently approved in Japan and under FDA emergency authorization in the US.

 

(2) A few videos:

A 60 Minutes Australia documentary on the Chinese cover-up (see also my earlier post about Fang Fang’s “Wuhan Diary”)

In this video, Dr. Seheult talks about masks and about a database for vaccine clinical trials.

 

 

ADDENDUM: Israeli-developed “disinfection tunnel” sprays harmless disinfectant aerosol generated electrolytically from water and salt

COVID19 update, May 11, 2020: hydroxychloroquine bummer; breakthrough in understanding of the severe disease

Two major updates today, one a bummer, one confirmation of an insight at the cellular level.

(1) The first large-scale clinical trial with hydroxychloroquine, at NY Presbyterian, was just published in the New England Journal of Medicine. http://www.nejm.org/doi/10.1056/NEJMoa2012410 Dr. John Campbell comments at length on YouTube, and as is his wont, strenuously avoids politicking. https://www.youtube.com/watch?v=1XCP1WzOY6M

Watch the whole video. But in a nutshell: there is no statistically significant difference in outcomes between the hydroxychloroquine and control arms of the study. This is a major bummer, as many medical professionals (and not just President Trump) had high hopes based on initial positive reports and several plausible mechanisms.

As Dr. Campbell says, it sounded plausible enough at the time they were desperate for something, anything they could repurpose. Especially given the known immunomodulatory effects (cf. use in arthritis, lupus) and as it became increasingly clear people were getting killed by their own immune systems going amok rather than directly by the virus. Besides, it worked in the test tube against the old SARS.

More’s the pity, since it was something they could use off the shelf and didn’t cost an arm and a leg. So far, Remdesivir is the only thing that’s passed the double-blind test [it got FDA approval right after]— and that’s (a) only an incremental therapeutic benefit, no magic bullet; (b) a proprietary drug that Gilead themselves will have to license to other companies because they simply can’t manufacture enough. (Hoffmann-LaRoche probably can.)

(2) Now for the major insight (hat tip: Mrs. Arbel). Haaretz English Edition [*] has a write-up in popular language (archived copy here http://archive.is/g6qaL ) of a paper from the Weizmann Institute that just came out in the prestigious journal CELL. https://doi.org/10.1016/j.cell.2020.05.006

This paper helps rationalize at the level of single cells what has become increasingly clear on an empirical, “macro” level: that COVID19 is really two diseases in one. The first stage is a unpleasant but not life-threatening viral disease — and about 80% of patients on average (fewer for older patients, but over 95% of young patients) just get better on their own, and that’s the end of it. The remainder, who proceed to the second stage, get a massive immune overreaction (“cytokine storm”, CS) that becomes life-threatening (and kills a nontrivial percentage of patients). I have linked the videos by Drs. Hansen and Seheult (both pulmonologists) about the clinical picture in previous updates; postmortem, several German and Swiss pathologists have shared the results of many autopsies. , where severe blood clotting secondary to CS was seen over and over, causing organ failures and strokes as well as ultimately death by heart attack or pulmonary embolism.
Now a paper from the Weizmann Institute, by the team of Prof. Ido Amit at the Department of Immunology, offers a glimpse at what goes on at the cellular level.

In the study, which [also involved] research assistants Amir Giladi and Pierre Bost, researchers used state-of-the-art genomic technologies which included a method known as single-cell genomics, an area developed and led by Prof. Amit. […] By obtaining a picture of the cell at a given moment, one can compare the differences between the activity of cells invaded by the coronavirus in severely and lightly affected individuals. Researchers can see which cells and genes are activated and which cells are silenced, thus learning about changes in inter-cellular communication and about cells that are activated by the virus in areas where it is active.

The key question of what differentiates biological processes and the actions of the immune system in severely ill COVID-19 patients as opposed to those who are slightly ill has been occupying researchers and physicians since the virus was first detected.
In the lungs of seriously ill patients, [Amit and coworkers] found that macrophages – cells that normally assist in ridding the lungs of infection, viruses and microbes – are replaced by cells that exacerbate the illness. The researchers also found that in seriously ill patients, the coronavirus neutralizes the immune system’s T-cells, which also fight infections, thereby allowing other viruses that are present in the body to inflict their damage. […] The researchers behind the study hope that a deeper understanding of the factors leading to a patient’s deterioration will help find weak spots in the chain of reactions initiated by the virus in severe cases, paving the way for effective treatments that would prevent or significantly curtail the impact of the disease.

The pattern of the disease among people who are hit hard is quite clear: After a week of mild symptoms, there is a rapid and sharp deterioration in their condition, characterized by hyperactivity of the immune system called a cytokine storm. This hyperactivity leads to serious damage to a patient’s health, often leading to a collapse of multiple systems, including the heart, liver and kidneys. In the lungs, the disease is characterized by damage to macrophage cells, whose role is to clear the lungs of infections.

The study analyzed hundreds of thousands of cells that were taken from the lung fluid of seriously ill patients, slightly ill patients and healthy people. The researchers discovered which types of cells are invaded by the virus and learned about its pathway. They found that the virus usually attacks epithelial cells, which in the lungs are responsible for respiration by enabling transport of oxygen from the air to the blood. “Due to the infection, the whole immune environment of the lungs undergoes a total transformation” explains Amit.

The study showed that in patients who are severely hit by the virus, there is a dramatic effect on the immune system as compared to patients who are only slightly affected. In the former, macrophages in the lung tissue are replaced by other immune system cells. “We found that they are replaced by monocytes, blood cells which accelerate a cytokine storm. They are recruited from the circulation as part of the overreaction of the immune system,” explains Amit.

The researchers found an enhanced presence of polypeptide cytokines called IL-6 and IL-8 in seriously ill patients. These cytokines are usually released by the monocytes, serving to either augment or suppress inflammation according to need. In this case, they facilitate inflammation. “The cytokine storm produced by the virus prevents the immune system in these patients from launching adaptive processes which are required for mounting an appropriate immune response,” says Amit. “In other studies we’re involved in, together with researchers from China and Italy, we see enhanced cytokine levels in the blood of severely ill patients before any pathological signs are evident.”

Another change that accompanies the cytokine storm involves the activity of T-cells. “In contrast to patients with light symptoms, seriously ill patients have T-cells that are neutralized and inactive,” says Amit. The researchers found that this dramatic change causes indirect damage, such as infection by other viruses which the immune system had previously managed to repulse.

I’d been wondering for a while for how many people who died of COVID19, secondary opportunistic infections (by viruses or drug-resistant “hospital bacteria”) were the proximate cause of death, or a contributory one, even if the root cause was still COVID19.

The researchers are now developing clinical studies that will use treatments to protect macrophages, with the hope that they will be able to prevent a deterioration in patients who are mildly impacted by the virus.

More than that: this may give another impetus to treatments that combine immunomodulators with anticoagulants (to combat the severe thromboses that appear to be a common by-product of the severe disease).