The pharma side of COVID-19 and what family of drugs might show promise.

Charles Corfield, President & CEO, nVoq Healthcare Leave a Comment

Charles Corfield, nVoq’s CEO, shares his thoughts this week into the pharma side of COVID-19 and what family of drugs might show promise. This is our third installment of Charles’ thoughts on COVID-19 and, for fans, a mention of Monty Python.
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Charles Corfield, President & CEO, nVoq

On the statistical front my eye was drawn to a couple of papers this week, but first a couple of observations about the pharma world. The first observation is that we have thousands of compounds that have been used for years or are in various stages of clinical trial; the second observation is that the overwhelming majority of compounds that appear promising in the lab don’t work in the (much more) complicated environment of the human body. The second observation tells you that you need to screen a lot of compounds in order to have a decent chance of finding one that works. In the last few weeks, I have seen a few papers that have tackled this question by using computers to screen drug databases for molecules which would bind to critical components used by the virus to enter cells and replicate.

There is a group that has figured out how to test 12,000 compounds in cells which have been programmed to express ACE2 and TMPRSS2 (the keys which the virus uses to gain entry to host cells). In short order they have been able to identify a number of compounds, which (in the environment of a cell culture) suppress infection by the virus. Also, I might add, confirm that this really is a needle-in-a-haystack problem because most of the 12,000 compounds don’t do anything. Even with hindsight, some of the candidates that came to the fore were probably not on the tip of anyone’s tongue. It is encouraging to see that a mass screening of existing compounds is even possible.

And, lastly, to something which is more speculative. I have begun to wonder if a big piece of the COVID-19 puzzle has been sitting under our noses (so to speak) since the very beginning, but we have mis framed our perspective. In the earliest days of the epidemic, Chinese physicians noted inter-a-lot-of-alia, that d-dimer levels were elevated. Doctors measure d-dimer levels when they want to rule-in/out blood clots. It was a puzzle because the patients didn’t have any obvious embolisms (btw: that is no longer the case, doctors are reporting a few patients with sizeable clots, but they are not sure if it is a statistical fluke or something real). Radiologists noted that patients had ground glass opacities in the lungs which they usually associate with viral pneumonias. Patients described how they were breathing fine one moment and the next they were gasping. ER doctors have been puzzled by happy hypoxics sitting in bed fiddling with their cell phones, yet their O2 saturation numbers are those of an ex-Norwegian-Blue-parrot (apologies to Monty Python).

Other doctors have commented on the extreme levels of inflammatory signaling (cytokines and friends) they see in the severest patients, which has led to the phrase “cytokine storm” and interest in therapies which tamp down the immune system’s (apparent) overreaction. Cytokine storms make me think of toxic shock and sepsis where the rise in inflammatory signaling triggers a coagulatory cascade and your blood turns from free-flowing liquid to sludge and that is the end of you – this is called “disseminated intravascular coagulation”, aka “DIC”. Suppose what is going on in our COVID-19 patients is a more localized DIC in parts of their lungs? In other words, the viral infection reaches a point where it triggers clotting in the capillaries. The clotting will happen within minutes, which is consistent with the patient’s experience of breathing fine one moment and gasping the next. It too would appear as a ground glass opacity in x-rays. When patients have undesirable clotting you think “anticoagulant”, so I searched for “sars-cov-2 and heparin” and hit pay dirt. A pre-print has just been submitted by doctors from Brazil who noted rapid improvement in a couple of dozen patients to whom they administered heparin. I would not treat this as any form of “proof”, but it would be motivation to conduct a controlled prospective study to see if their findings can be replicated in a way that would support clinical adoption (and not necessarily with heparin, there are other anti-coagulants which may be better). A team in Japan has registered a clinical trial for Nafamostat, because it blocks TMPRSS2 (transmembrane proteases serine 2), which the virus depends on to gain entry into host cells. However, Nafamostat is also an anti-coagulant, so their trial may turn out to be important for more than the original reason. If anti-coagulation therapy turns out to be a viable tool in the management of COVID-19, then we may find another use for the bottle of aspirin in our medicine cabinets – the doc/nurse tells us to take one before we head to the ER...

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