A year with COVID-19: The therapeutic pipeline

Though first-generation vaccines against COVID-19 have proven remarkably effective, and have spurred optimism that the rate of severe illness and death will be drastically reduced, there is growing consensus that the virus will continue to mutate and circulate in for some time.

Consequently, therapeutics that treat patients infected with the virus will be in demand. Two discoveries by researchers associated with the Lady Davis Institute (LDI) hold promise in this regard.

Dr. Donna Senger

Dr. Stephen Robbins, the new Director of the LDI, and Dr. Donna Senger, of the LDI’s Cancer Axis, have developed a drug candidate called Metablok that has entered Phase II clinical trials to determine its efficacy in preventing acute respiratory distress syndrome (ARDS), acute kidney injury, and other organ injuries caused by inflammation in hospitalized patients with severe cases of COVID-19.

This effort has been awarded up to $6.7 million from the Canadian government’s Strategic Innovation Fund as part of its ongoing Plan to Mobilize Science to Fight COVID-19.

“Our research began long before COVID-19 even existed, so this is really serendipitous,” says Dr. Robbins.“The applications for Metablok extend well beyond this pandemic, as acute lung injury is a leading cause of death in critical care in Canada.”

Metablok has received approval from the U.S. Food and Drug Administration and Turkey’s Ministry of Health for Phase II clinical trials, and dosing of patients in those countries has begun. Having received approvalfrom Health Canada as well, dosing at centres in this country will begin shortly.

Dr. Brent Richards

Dr. Brent Richards, a geneticist with the Centre for Clinical Epidemiology, and his team have discovered that increased levels of the protein OAS1 are associated with reduced mortality and less severe disease requiring ventilation among patients with COVID-19. Using drugs that boost OAS1 levels could be explored to try to improve these outcomes.

“Our analysis shows evidence that OAS1 has a protective effect against COVID-19 susceptibility and severity,” explains Dr. Richards. “This is a very exciting development in the race to identify potential therapies because there are already OAS1 boosters in pre-clinical development that could be explored for their effect against SARS-CoV-2 infection.”

Researchers in Dr. Richards’ lab explored proteins detectable in peripheral blood as a potential target. The challenge lay in determining which proteins play a causal role in disease progression, since their levels may also be influenced by COVID-19 itself, or other confounding factors.

Recent advances in proteomic technology – that is, the capacity to isolate and measure hundreds of circulating proteins at once – combined with genetic analyses through Mendelian randomization (MR) made possible the delicate work of untangling which proteins affected COVID-19 adverse outcomes, rather than vice versa.

Based upon an analysis of up to 14,134 COVID-19 cases and 1.2 million controls, the researchers observed a 50% decrease in the odds of very severe COVID-19 – that is hospitalization, ventilation, or death – when OAS1 levels were elevated.

Over the short- and near-term, therapeutics will be needed in tandem with vaccines. Research will play an indispensable role in getting the pandemic under control, saving lives, and easing the burden on the healthcare system.