A University-inspired, and Very Successful, Drug Development Effort
From Bob Dorr, UA Cancer Center Professor (retired)
Interesting story about the development of Merck’s antiviral drug, molnupiravir. It was originally synthesized in 2014 at a drug discovery spinoff of Emory University, Drug Innovation Venture Emory (DRIVE). The goal was to develop a drug to treat Venezuelan equine encephalitis virus for the US Defense Department. DRIVE showed the drug was active against a variety of viruses including influenza, chikengunya, Ebola and various corona viruses. DRIVE then licensed the drug to Miami-based Ridgeback Biotherapeutics, which planned to develop the drug as a therapeutic for influenza. Molnupiravir is actually a prodrug that is metabolized to the active form, a ribonucleoside analog of N-4 hydroxycytidine-5’-triphosphate. That “active form” is a tautomer (exists in two chemical forms) that alternates between an analog or “mimic” of cytidine and uridine, which are basic building blocks of RNA. When the virus tries to copy itself, the drug, in one of the two mimic forms, is incorporated into the viral RNA by the virus’ RNA polymersase. Incidentally, that viral RNA polymerase is distinctly different from mammalian polymerases, so there is complete specificity for effecting viral RNA and not mammalian RNA. The virus is destroyed when the drug causes so many improper uridine and cytidine mutations in the growing RNA strand that viral reproduction is halted. The massive number of viral mutations caused by the drug has also been also called lethal mutagenesis, or error catastrophe. Merck, which was partnering with Ridgeback, decided in Sept of 2020 to do a phase II/III trial in patients hospitalized with COVID-2. For the phase III portion of that trial Merck chose non-hospitalized patients with a positive COVID-2 test, and at least one well-defined risk factor, like extreme age, obesity, or diabetes. Of interest, they genotyped the subjects’ COVID-2 specimens and 80% were a so-called COVID-2 “variant”, mostly Delta, Mu and Gamma. The trial aimed to enroll 1500 subjects in a one-to-one randomization to either molnupiravir (two capsules twice a day for 5 days), or placebo capsules on the same schedule. The trial was halted at 745 patients accrued by the independent safety monitoring committee. That was because there was already a statistically-significant difference in the two study arms, hugely favoring the molnupiravir arm. There was a 14% hospitalization rate on the placebo arm compared to 7% on molnupiravir, a 50% reduction in hospitalization. More importantly, there were 8 deaths on the placebo and none on molnupiravir. Side effects were not problematic and there were actually more subjects stopping therapy due to perceived side effects on the placebo than on molnupiravir. Dr Marty Makary (Johns Hopkins) has an editorial in October 7th WSJ advocating for the FDA to grant Emergency Use Authorization (EUA) to potentially completely stop the death rate from COVID-2 infections. The “downside” has been the view that approving molnupiravir would increase or validate resistance to getting vaccinated. But Dr. Makary argues that should be subordinated to reducing hospitalization and especially deaths from ongoing COVID-2 infections. Anyway, I thought it was an interesting story of a university-inspired, and very successful, drug development effort.