Wuhan #coronavirus and CoVid-19—Rumination #8

Guest post by Rud Istvan

There are as of today (5/1/2020) several newish developments enabling further skeptical comparisons to ‘climate science’. These involve post #4 on two possible therapies (remdesivir and the chloroquines), and post #7 on ivermectin. The bottom line is yet more contradictions and speculations, all reported without full disclosure. This post pulls a new overview together from public sources and from previous comments to other posts.

Remdesivir

Two initial clinical trials have been reported. The first was done in China using remdesivir synthesized there without regard to Gilead’s patent, and after China filed for a patent using remdesivir to treat CoViD-19. The second was done in the US by Gilead and reported midweek. The results contradict each other, sort of like modeled ECS versus observed ECS in climate science.

The China study was reported apparently inadvertently by WHO early this week, and later disappeared by them. 158 symptomatic patients were given remdesivir compared to 79 symptomatic controls. WHO reported remdesivir was “not associated with differences in time to clinical improvement” and the trial was terminated early after significant side effects emerged in 12% of the treatment arm. The Financial Times of London commented that the China trial was a flop. Dr. Fauci never mentions it, although he must be aware of it.

The Gilead study Dr. Fauci is touting as a success the past couple of days–even a as possible new CoViD-19 “standard of care”. A patented money maker for Gilead, helped by NIH. Maybe, maybe not. The actual trial results are not yet available, only Fauci’s enthusiastic take on them.

Chloroquines

There have been three reported ‘trials’.

Brazil is trialing chloroquine phosphate in high and low dose arms. Chloroquine phosphate is known to have more cardiac side effects (arrhythmias) than hydroxychloroquine. It has a narrower therapeutic window. It was the fish tank cleaner that killed a man in Arizona and sickened his wife when they self-administered overdoses. The high dose arm was discontinued when the inevitable side effects emerged. This was proclaimed a failure by the media, when in reality the low dose arm continues with no result yet reported.

The VA did a retrospective study on elderly vets and concluded hydroxychloroquine did not work. The press loudly proclaimed the VA failure this week, condemning President Trumpt for having mentioned the drug after France’s Dr Raoult and New York’s Dr. Zelenko reported success. The VA study was designed to fail. We now know from NYC that about 85% of ventilated over 65s die. That was the ONLY group the VA evaluated retrospectively. And, Dr. Zelenko said the key was hydroxychloroquine plus zinc. The VA did not add supplemental zinc. Dr. Fauci noted the VA failure without noting the bias and the flaw. Neither Fauci nor pharma want HCQ to succeed because there is little money in an off patent inexpensive therapy.

The third true clinical trial is a joint effort of U. Minnesota and McGill. It is well designed with three arms in two cohorts testing two endpoints. Arm 1 is control. Arm 2 is hydroxychloroquine. Arm 3 is hydroxychloroquine plus zinc. Cohort one is people known to have been exposed to Wuhan coronavirus, but not yet symptomatic. The endpoint is progression to symptoms or not, a test of prophylaxis potential. The other cohort is symptomatics. The endpoint is recovery or progression to serious/critical, a test of CoViD-19 therapeutic value.

The media are not covering this study, but McGill put out some good news this week in Canada. Based on results to date, they are modifying the original statistical design by curtailing the number of enrollees, with the goal of a preliminary result by end of May rather than July. This can only mean they are seeing some statistically meaningful positive results. Else, they would continue with the original design to get the originally planned statistical answers.

Repurposing other old drugs

This was the theme illustrated by R#7 Ivermectin. Yesterday (4/30/2020) there was a long illustrated article in The conversation.com by Nevin Krogan of UCSF, discussing a longer paper on the same topic that also appeared yesterday in the prestigious journal Nature.

Krogan reports that his team worked tirelessly for two months to map in silico ALL the possible Wuhan/human protein/proteins interactions. Using this computer model ‘map’, they then tested in silico (more computer models based on chemical mechanism of action–MOA) ~2000 drugs approved for other uses. They identified 69 candidates that might affect a mapped protein interaction either therapeutically or detrimentally. They have now tested 47 in vitro and found a few promising therapeutics and one definite detrimental.

Seemingly big rigorous science news reported in Nature! Except it really isn’t as good as it sounds once the issues are understood, which are unpacked below. MBH98’s hockey stick seemed rigorous until Steve McIntyre showed it wasn’t.

PMC2373733 discusses ‘libraries’ of protein structure. The full structures of about 15000 proteins are known, but many are non-human. This has taken decades because of the complexities of protein folding. The ‘outside’ counts for biology, the ‘inside’ usually doesn’t. PMC4419399 discusses the more common protein fragment libraries. These are typically less than 100 amino acids long, and ‘outsides’. For example, they are used to build DNA or RNA oligomers for ‘gene chips’, or for the new Wuhan coronavirus RNA tests. Building an incomplete and uncertain in silico Wuhan/ human protein interaction ‘map’ is certainly possible in two months using existing libraries. It cannot be complete, and the interactions are only modeled.

Comparing known drug MOAs to this interaction map is also possible in silico. All FDA approved drugs must have an experimentally proven MOA. Although aspirin predates the FDA, its MOA is now known many decades after first used. Aspirin irreversibly inhibits cyclooxygenase (COX-1), thus suppressing signaling for prostaglandins and thromboxanes, thus reducing pain and inflammation. If Wuhan had a protein section resembling COX-1, aspirin might be a therapy.

Testing 47 of the 69 in silico candidates in vitro is possible also. In fact, it is almost criminal that Fauci’s NIH has not already done so with HCQ alone, and plus zinc. Epithelial cells of the African green monkey are a traditional in vitro method for respiratory disease. These were infected with Wuhan in petri dishes and then half were dosed with test drugs (the remainder were controls). Of the 47 drugs identified in silico, 8 appear therapeutic, one is detrimental, and the rest have no impact. That 38 out of 47 (80%) had NO interaction shows how uncertain the UCSF in silico model methodology actually is.

So there may be 8 new drug candidates against CoViD-19 reported in Nature yesterday. Two work via the same MOA as the combination of HCQ plus zinc, by inhibiting the RNA polymerase from assembling new virions. Six supposedly inhibit the ‘sigmaR1 and sigmaR2’ portion of the S spike protein, a “new” therapeutic modality—except it isn’t, since the Conversation article ends by noting that HCQ also binds these, except ‘less efficiently’, thus providing the MOA for HCQ alone. I cannot tell for sure from the articles, but this is probably just the S2 neutralizing antibody target renamed. S1 binds the virion to the ACE2 receptor. S2 enables the virion to pass thru the cell wall into the cell to unpack its RNA and begin replication. Blocking either is neutralizing.

The intent of the rushed Nature article is to get the 8 into CoViD-19 clinical trials and then EUA (temporary Emergency Use Authorization) approval. Two of the 8 are cancer chemotherapies. One of those, zotatifin, is apparently intentionally misrepresented in both the Conversation and Nature. It is only in clinical stage 2A dose ranging, far from a normal post phase 3 FDA approval. The company that is developing it as a new cancer therapy is already touting the Nature article just a day later. It turns out that one of the Nature paper authors is ALSO the company founder. What a Mann like coincidence. I therefore did not bother to track down the rest of the ‘repurposed’ Wuhan drug candidates.