Covid-19 Dual Therapy Drug Trial Okayed

Scanning electron microscope image showing SARS-CoV-2 viruses, in yellow. (NIAID, NIH)

17 June 2020. A company developing an oral drug that treats both Covid-19 infections and overactive immune system reactions received regulatory approval for a later-stage clinical trial. PTC Therapeutics Inc. in Plainfield, New Jersey says the Food and Drug Administration cleared the company’s request to begin a mid- and late-stage trial of its experimental drug, code-named PTC299.

PTC Therapeutics develops drugs mainly for cancer and rare diseases. With the Covid-19 pandemic, the company began reviewing PTC299, an experimental small-molecule or low-molecular weight cancer drug, as a therapy to treat infections from SARS-CoV-2 viruses, but also the debilitating immune reactions called cytokine storms. These immune reactions are initiated by invading cells deemed dangerous by the host immune system. In most cases, the reaction by macrophages and other immune system cells is controlled and enzymes called cytokines triggered by the immune system do not cause more than mild symptoms. But in some cases, larger volumes of cytokines are released, causing dangerous inflammation in the lungs and other organs, with life-threatening results.

PTC299 inhibits the cellular enzyme dihydroorotate dehydrogenase, or DHODH, that researchers in an independent paper submitted for publication identified as a leading target for Covid-19 therapies. By limiting DHODH activity, says PTC Therapeutics, PTC299 also reduces production of a nucleic acid called pyrimidine that can promote replication of SARS-CoV-2 viruses responsible for Covid-19 infections. At the same time, reduced pyrimidine production can also limit stress-induced cytokine storms.

PTC Therapeutics originally developed PTC299 as a treatment for acute myeloid leukemia for its ability to limit pyrimidine production implicated in blood-related cancer cell development. The company is testing PTC299 in an early-stage clinical trial among adult patients with relapsed or difficult-to-treat acute myeloid leukemia, looking primarily for safety issues, dosage levels, and early evidence of anti-cancer response. Through that trial, the company is establishing a safety profile for the drug independent of the disease. PTC Therapeutics says the drug is being tested in other cancer clinical trials among some 300 patients.

The new clinical trial of PTC299 is a mid- and late-stage study, first enrolling 40 participants, and later a larger group of 340 individuals hospitalized with lung inflammation from Covid-19 infections. Participants will be randomly assigned to receive PTC299 or a placebo, with the study team looking mainly for changes in respiratory functions, but also for safety issues. The company anticipates conducting similar trials in Europe, Brazil, and Australia.

In a company statement, University of Massachusetts virologist Jeremy Luban, whose lab studies viral replication, says “PTC299 is among the most promising potential treatments on the immediate horizon because it potently inhibits SARS-CoV-2 in the lab, it has already been used in people, it is already formulated as a tablet, and it may attenuate the deadly inflammation observed in the most severe cases of Covid-19. Additionally, PTC299 targets a cellular enzyme, as opposed to a viral one, and is therefore less likely to elicit drug-resistant SARS-CoV-2.”

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