Guest post by Rud Istvan,
In the 3/19 Wuhan virus briefing with the FDA, team Trump made much of the possibilities for two therapeutic candidates, chloroquine and remdesivir. Having now done informed basic research on both, I found their stories intrinsically interesting, while enabling an early assessment of their chances of success. Hence this hopeful guest post.
Wuhan coronavirus is an enveloped positive sense single strand RNA virus, meaning its core genetic RNA code is just one long chain coding directly for several proteins, surrounded first by a protective viral protein capsid coat, and then a lipid membrane ‘envelope’ from which project so called “E” (for envelope) and “S” (for spike) proteins. The S protein is what the virus uses to bind to and then invade the lung’s epithelial cells in order to hijack those cell’s reproductive machinery to make copies of itself using its RNA polymerase, itself encoded in about 2/3 of the core viral genetics. The newly assembled virions that then bud out to infect new cells also eventually kill the infected epithelial cell. Covid 19 disease is caused both by the death of those cells and the immune system’s eventual response to the infection.
The S spikes are also the reason this virus class is named corona, because the spikes make it look under SEM like the virus is wearing a crown.
These are actually two closely related anti-malarials, hydroxychloroquine (the small French trial) and chloroquine phosphate (the larger Chinese trial). Both were developed in the 1950’s, and interestingly the main use now is to treat rheumatoid arthritis rather than malaria (which evolved resistance).
The discovery that certain classes of anti-malarials also affect rheumatoid arthritis (RA) was made quite by accident in 1951 by an asute doctor treating malaria in an RA patient. The problem then was the side effects of chronic RA use made them unacceptable for RA. The chloroquines were developed expressly as ‘milder’ side effect anti-malarials, and in the mid to late 1950’s there were a number of papers (I reviewed several for this post) reporting good RA safety and efficacy leading to global approvals for that indication.
The mechanism of chloroquine action on RA has long been well known. It increases a cell’s lysosomal pH. (Lysosomes are membrane bound cellular organelles [think tiny balloons inside the cell floating at a lower pH in the higher pH cytosol] containing about 50 enzymes, discovered and named in 1955.) This in turn changes their ‘leaked’ enzyme balance into the cytosol, which then inhibits the cell’s RA tissue antigen signaling, which in turn reduces the immune system’s attack on the RA tissue, slowing (but usually not stopping) progression of RA tissue damage.
The reason the Chinese and then the French thought to use chloroquine against Wuhan coronavirus is this same mechanism of action, albeit with different sequelae. The viral S protein binds to the epithelial cell wall’s angiotensin-converting enzyme 2 (ACE2) receptor. Raising lysosomal pH changes (via indirect enzymatic action) the ‘shape’ of ACE2 enough that the S protein cannot bind to it, thus preventing cell infection. Chloroquine changes the cell ‘lock’ so the viral ‘key’ doesn’t work. Does not undo damage from infected cells, nor prevent an infected person from shedding existing viable virus, but does stop the spread in an infected person’s body—a promising therapeutic for those testing positive.
Since safety is well known (the main side affect is retinopathy [vision problems] in 25% of patients over 50 that resolves [slowly] after discontinuation), the main FDA legal issue (FDCA Act of 1906 as amended) issue is to determine dosing and duration for this new indication. But for starters, the standard RA 250mg once a day generic cheap pill should suffice for emergency use authorization (EUA). As a ‘Big Pharma’ goodwill gesture, today (3/19) Bayer announced it donated 3 million 250mg chloroquine phosphate pills to the US to get started.
This is a novel antiviral from Gilead that has a somewhat checkered past. It was originally developed for Ebola, where in African trials a few years ago it was shown reasonably safe but not very effective. It did, however, show efficacy against SARS and MERS in vitro. And, importantly, the NEJM reported a positive case outcome in Seattle patient zero under a compassionate use exception. The patient had visited Wuhan, returned to Seattle, began displaying symptoms, and was hospitalized on symptom day 3. By symptom day 8 X-ray showed clear lower respiratory tract viral pneumonia (diagnostic ‘ground glass’) and supplemental oxygen was started. Patient worsened, and intravenous antibiotics were started day 9. Patient worsened (proving viral pneumonia), so attending physicians consulted with FDA then had Gilead rush the experimental drug by air, with intravenous treatment starting day 10. Patient improved in 24 hours, was saved, and has since been discharged. For those interested, there is this NEJM case report providing a very hopeful proof of principle.
The reason Gilead tested it against SARS and MERS even though those two episodes died out naturally has to do with Remdesivir’s novel mechanism of action. The ‘drug’ is just an analog of the amino acid adenosine, one of the 20 amino acid (only, in all life on Earth, proving a common genetic ancestor) building blocks the viral polymerase uses to ‘assemble’ new copies of the viral RNA genetic code. The polymerase does not recognize the small difference between adenosine and the analog. Flood an infected cell with enough remdesivir molecules, and the polymerase will eventually grab one and add it to the ‘building’ RNA copy. Remdesivir is enough different that the polymerase is then blocked from adding any more amino acids to the RNA chain, so viral replication halts. Neat very basic molecular genetics provided at a basic science 101 level.
What Gilead scientists recognized was that the RNA code for Ebola RNA polymerase was very similar to SARS and MERS RNA polymerase, hence the in vitro testing. And when the Chinese first published the roughly 30,000 base RNA code for Wuhan coronavirus in January, it was evident immediately that it was another good RNA polymerase match, so they started immediate in vitro testing once viral samples were in hand.
Aside from price (Gilead is infamous for its Hep C cure that ‘only’ costs about $100,000 per treated patient), and scaled up availability (none yet, same issue that killed my 3 of 4 EUA for a persistent hand sanitizer in the 2009 swine flu pandemic), there are questions about dosing and treatment timing. There is some thought that remdesivir may not be useful past symptom day 10 or 11, typically when a patient worsens to need an ICU ventilator. The concern logic is simple. Remdesivir blocks virion replication in an infected cell, but not its spread to newly infected cells by virions from previously infected cells. So basically a quantity/quality argument saying eventually blocking further spread when you already need a ventilator for viral pneumonia is futile. Those clinical questions are why China is conducting a double blind (drug/placebo) trial on ~790 patients in Beijing and Gilead is conducting an unblinded smaller trial in the US, starting in Nebraska with Diamond Princess patients. The first results from both will be available sometime in April.
Neither chloroquine nor remdesivir are just luck. The rapidity of their development against Wuhan virus reflects the enormously powerful insights that molecular genetics and molecular biology and their associated tools (sequencing, PCR, oligomer synthesis, protein structure) now bring to science and medicine. To echo the contrasts to climate science in my first post on Wuhan, this is as if we actually had now the computational power to avoid parameterization in climate models. Climatologists do not, but virologists do.
Chloroquine probably works, as AW previously posted. It would solve this pandemic’s key issue, progression to viral pneumonia requiring ICU ventilation. New York’s Governor Cuomo said yesterday that he has been told that without ‘bending the curve’ based on Italy, New York will require 27000 ventilators in a few weeks when the state only has 3000. Invoking the Defense Procurement Act cannot solve that mismatch in time without a ‘bent curve’ achieved via social distancing, frequent hand washing, and avoiding touching the mouth, nose, and eyes. All three are difficult but not impossible. Ambassador Dr. Birx is pretty clear about the dire consequences of Millennials ignoring these basic common sense recommendations during Spring Break this week in Florida. Here in ground zero Fort Lauderdale, our public beaches are closed, and the closure is policed.
But chloroquine still has the same Wuhan issue illustrated by its previous use for malaria–evolving resistance. RNA viruses like Wuhan coronavirus mutate rapidly (explained in my first post on this topic). The most conserved protein is necessarily the RNA polymerase. We know this from influenza, where it is the hemagglutinin and neuraminidase envelope proteins (equivalent to Wuhan S) that mutate so the annual vaccine is never ‘right’. Chloroquine may well be effective now, but if Wuhan coronavirus becomes endemic (now likely given its spread in Africa and Southeast Asia), then it is not a long-term solution like a vaccine. But it will probably buy the precious time to get a vaccine.
Remdesivir may be a longer-term therapeutic solution, because it tricks the conserved RNA polymerase. But its cost and efficacy remain to be determined.