Thread by @rplenge

Drug development is like lasagna: If you are really hungry now, take a lasagna out of the fridge; if you anticipate being hungry later, make a lasagna from scratch. A thread on drug repurposing for SARS-CoV-2 / COVID-19, with emphasis on anti-inflammatories.

It is useful to think of approved medicines available now to test in COVID-19 patients (lasagna in the fridge) vs those that need to be developed (lasagna from scratch). Here is a good overview on drug development in COVID-19 @kakape @sciencemagazine

science.sciencemag.org/content/367/64…

First, it is important to understand when in the viral lifecycle and disease pathogenesis a drug may act: before infection (eg, vaccines), early in infxn (eg, direct-acting anti-virals, anti-inflammatories), late in disease (eg, anti-inflammatories to treat cytokine storm).

Second, it is important to understand the medicine’s mechanism of action. If designed uniquely against the virus, this will likely require new drug development (lasagna from scratch). Examples include vaccines, passive immune therapy, and direct-acting antivirals.

Vaccines work at the very beginning to prevent infection. As vaccines need to be tailored to the virus itself, vaccines are not candidates for drug repurposing and will not be further discussed here. There is exciting progress with mRNA vaccines.

Passive immunotherapy (i.e., antibodies that bind to and neutralize virus) may be used prophylactically in high-risk individuals to prevent infection or early in the infection process to prevent viral replication and spread. Exciting progress.

jamanetwork.com/journals/jama/…

Direct-acting antivirals (i.e., bind to viral proteins to inhibit function) prevent viral replication and spread early in infection. While most antivirals need to be tailored to the virus, some (e.g., remdesivir) may be repurposed. Also lots of progress.

nature.com/articles/d4158…

Back to repurposing…if a medicine’s MoA is not unique to SARS-CoV-2, then it is more likely to be suitable for repurposing. Examples include indirect-acting antivirals and anti-inflammatories.

There are >10 approved “anti-inflammatory” medicines in ongoing clinical trials: hydroxychloroquine, anti-IL6R/anti-IL6, anti-TNF, anti-IL1R/anti-IL1, JAK inhibitors, S1P1R modulators, corticosteroids, anti-IFN gamma, anti-VEGF, anti-C5, colchicine.

clinicaltrials.gov/ct2/results?co…

Anti-inflammatories work in two ways: (1) dampen a maladaptive immune response to prevent a patient from progressing from mild/moderate to severe disease requiring ICU care, and (2) treat cytokine storm in severe patients.

thelancet.com/journals/lance…

Early intervention with anti-inflammatories could be key: this a sizable portion of patients and also represents an important inflection point in patient care: preventing the progression to critical disease requiring ICU care (where capacity is limited).

Treating cytokine storm is also important.

thelancet.com/journals/lance…

Unfortunately, we know little about the maladaptive immune response in SARS-CoV-2 / COVID-19.

Fortunately, new reports appear daily.

medrxiv.org/content/10.110…

Two final points about repurposing approved meds for COVID-19: (1) clinical trials must be practical, given the challenges that health care providers face; and (2) drug supply must be available to meet demands in the event of a positive study.

Real-world data will be important to establish inclusion criteria and measure clinical outcomes. A robust informatics system to mine EMR data will be critical. @zakkohane @atulbutte

Finally, I borrowed the lasagna analogy from an excellent story by @lisamjarvis @cenmag on repurposing remdesivir. She attributes the quote to Sina Bavari (USAMRIID). Credit (or blame!) goes to them.

cen.acs.org/content/cen/ar…