05/03/2020
This is an amazing update on COVID-19 by Dr. Jennifer Greenhall.
My Friday COVID-19 update—5/1/20:
1. Interesting drug news this week:
Remdesivir received a lot of overblown press this week. Yes, it seemed to help patients recover more quickly (11 vs. 15 days) in an NIAID study though it did not change mortality, which was the original outcome to gauge success. In previous, less well-controlled studies, it has shown no effect. The FDA granted it an emergency use authorization, which allows for use of “unapproved” products in a time of emergency (basically bypassing the long, traditional FDA review), but it means you can more easily receive it outside of a clinical trial. Again, as a nucleoside analog that may inhibit viral replication, it’s much more likely to help if given early in an infection, which means we need to ramp up testing for this to be most effective. Unfortunately, the FDA recommended it only be used in severe hospitalized patients requiring breathing support or “with an SpO2, a measure of blood oxygenation, that is less than 94%.” This is completely asinine and makes me want to bang my head against the wall. IT SHOULD WORK BETTER EARLY, AT THE FIRST SIGN OF INFECTION, IF IT WORKS AT ALL. Whatever little effect it might have, when given late in infection as in these studies, it is not going to make a huge dent in COVID-19.
Great study: I am very excited about a paper in the journal Nature that was released on Thursday. The scientists analyzed the function of all of the proteins of SARS-CoV-2, tried to determine which human proteins and pathways they interacted with, and then tested current drugs, drugs in clinical trials and preclinical compounds to see how they affected the levels of virus and cell toxicity in vitro. They identified 69 promising compounds and investigated 47 of them in addition to others. The drugs largely fell into two categories: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Most of these drugs appear to be 10-100x more potent than remdesivir in vitro. Among them are antihistamines (cloperastine, clemastine), progesterone (may explain why females fare better and is being investigated at Cedars-Sinai), the antipsychotic haloperidol, the antimalarials hydroxychloroquine (HCQ) and chloroquine, and an anti-cancer experimental preclinical compound PB28. Animal testing has begun with PB28, which is an exciting drug because it is 20x more potent than HCQ and at therapeutic levels will be much less likely to cause heart rhythm side effects (less binding to hERG heart receptors). The drugs I mentioned affect the Sigma1 and Sigma2 receptors, which may be involved in a cell’s stress response, ion transport and/or lipid remodeling, which may be important for making viral membranes. These molecules appear to exert their antiviral effect during viral replication, before viral egress from the cell, which puts a hole in the theory that zinc is required for HCQ to work, though of course both Zinc and liposomal vitamin C may help bolster the immune response.
One important finding is that the cough suppressant dextromethorphan actually showed pro-viral activity and should likely be avoided during COVID-19 illness (DHEA and pregnenolone may function this way too based on the mechanism). Also, quercetin, one of my favorite supplements that helps with allergies, and my usual antihistamine, loratadine, did not show antiviral activity against SARS-CoV-2.
Miscellaneous Drug News:
Pepcid (famotidine) may target a SARS-CoV-2 viral enzyme. Doctors found that Chinese peasants died half as often as the wealthy, with the consistent difference being that the peasants were taking the cheaper Pepcid instead of the more expensive Prilosec.
Complement C3 inhibitor, AMY-101: Amyndas Pharmaceuticals provided its compstatin, AMY-101, to treat its first case of COVID-19 with severe ARDS, and the patient improved greatly. It’s just a case study, but complement has been shown to be heavily involved in cytokine storm, thromboinflammation and organ damage due to SARS-CoV-2. Apellis Pharmaceuticals supposedly plans to perform a clinical trial with their complement C3 inhibitors (APL-2, APL-9). I’m looking forward to the results of this trial since I think these drugs may really help with the cytokine storm and excessive clotting in COVID-19.
There are many other therapies in development, but these were the most interesting studies from the week. I believe we can get a handle on this pandemic if we can quickly develop therapies to treat the disease since a vaccine will likely take much longer.
2. Vaccine prospects:
Oxford University: Having already worked on a MERS vaccine, they had a jumpstart. Their Covid-19 vaccine protected six rhesus macaque monkey exposed to heavy quantities of the virus, with all still healthy after four weeks, The vaccine will be tested on more than 6,000 people by the end of May. If the trials go well and regulators grant emergency approval, they may have a few million doses of their vaccine available by September.
Peking Union Medical College in Beijing: Using a vaccine comprised of chemically inactivated particles of SARS-CoV-2, eight monkeys were exposed to the virus, four given a high vaccine dose and four at lower doses. The monkeys receiving a high dose had no detectable virus in their throat or lungs seven days after exposure. Ones receiving lower doses “showed some signs of coronavirus infection — but their levels of virus were much lower than in exposed animals that received no vaccine.” In April, the company developing the vaccine received approval to start human safety trials.
The ethics of sp*eding up vaccine development:
Safe vaccines usually take many years to develop. Performing a human-challenge trial that would intentionally expose vaccine recipients to the virus is one idea being debated to expedite this process. Normally, vaccines are given to study participants to see if less people acquire the virus naturally in the group of patients given the vaccine vs. placebo. It’s considered unethical to intentionally expose patients to the virus to test a vaccine’s efficacy. However, the conventional Phase III testing takes a very long time to complete. Many are against the idea of performing a human-challenge trial with SARS-CoV-2 since we don’t know the long-term complications and don’t have great treatments, and since infections are still climbing rapidly in many locations where a conventional trial might reveal a vaccine’s efficacy quickly. However, if we start to contain the virus, the timeline could be quite long. In the end, I expect they will do human-challenge trials, especially if these early trials fail, but they will do so under very controlled conditions with young, healthy volunteers with the best medical care available to minimize risk. We’ll see how this plays out, and remember, less than 10% of vaccine trials succeed.
To administer vaccines, it would be great if we were ahead of the game this time. We need to scale up NOW the manufacturing of vials, syringes, rubber stoppers, plungers and other medical products required to deliver a vaccine so we don’t repeat the same problem we’re still having with access to testing.
3. Clotting and wondering about long-term effects:
The clotting that’s been reported in COVID-19 seems like it could be caused by a diffuse vasculitis possibly due to the virus attacking ACE-2 on the endothelium (lining) of blood vessels. Some young people have suffered severe acute clots resulting in strokes or limb amputations. I’m also worried that if the damaged vessels develop tiny scars, it may increase the risk of cardiovascular disease. We just don’t know the subtle long-term consequences of COVID-19. For example, the te**is was the organ with the second-highest level of virus (after the lung). Could it affect male fertility? We need to keep in mind that COVID-19 may cause long-term consequences.
4. Opening up:
WEAR A MASK! It’s the cheapest, easiest way to fight COVID-19 and get our economy going again and is a sign that you’re a concerned and caring citizen. The majority of people transmit the virus without symptoms. In most parts of the country, 97% of people have NOT been infected. Unless you want the rest of the country to have a high death-rate like NYC, you still need to wear a mask, social distance and stay home when possible. A study showed that “if 60% of people wear masks that are 60% effective, that’s enough to control the epidemic.” DIY masks can work, though do your research since some are better than others. Also, once you start going out again, even if wearing a mask, I would avoid public restrooms. SARS-CoV-2 can be present in stool and when toilets are flushed they can aerosolize the virus which can stay in the air for a few hours. Even a perfectly fitted N-95 mask only protects a person from inhaling 95% of airborne particles. “Given the cost (~nothing) and the benefit (huge), mandating them is a no-brainer.”
5. 1st US Dog with COVID-19:
A dog caught COVID-19 from his family, three of whom were sick with the disease. He had mild symptoms that lasted a few days (sluggish, sneezing, breathing heavily, lack of appetite). Though there’s no “evidence” we can catch it from our animals, the CDC recommends isolating them from any sick family members and from interacting with people outside the home. I have a hard time believing we cannot contract the disease from them. There is no evidence, but we’re giving the virus to the animals. I don’t see why we can’t contract it from them. I’m going to postpone our vet appointments and grooming for a little longer. As many are probably aware, it was shown that cats, lions, and tigers can acquire the virus from us and pass it on to other felines.
6. We still need more PPE, more and better tests--both diagnostic with a quick turnaround and serological, more CPAPs, and more access to disinfecting agents. Testing needs to increase until only about 3% of tests are positive on at least a state-wide basis (no state is this low yet). CA is currently around 8.5%. Many others are much higher. To get control of this disease as restrictions are relaxed, we also need to ramp up tracing, and it needs to be efficient and quick.
Please stay safe. Wear a mask when out. Protect health care workers who are ~11% of known COVID-19 cases and will suffer even more if this outbreak continues. Be a good citizen and protect the vulnerable by simply wearing a mask.
