Mining Old Drugs for New COVID Tricks

Early in the pandemic, researchers began exploring various avenues to repurposing drugs for COVID-19.

There are many paths to repurposing, including high-throughput drug screening, which uses automated methods to screen thousands or even millions of molecules for targeted biological activity in a disease of interest. Other approaches include focusing on a certain biological mechanism of action (like testing other antivirals in COVID); combing through clinical trial data and public records; or, in the case of sildenafil citrate (Viagra), incidental clinical observation. (See MedPage Today‘s full story on how drug repurposing is gaining momentum as demand for a COVID “pill” grows.)

Researchers at the NIH’s National Center for Advancing Translational Sciences (NCATS) began doing high-throughput screening of all approved drugs from the U.S., Europe, Japan, and other regions of the world — there are more than 10,000 of them — for activity in COVID-19. They’ve continued their work throughout this past year and made their datasets available to the scientific community on the NCATS open data portal.

The NIH has also launched the ACTIV-6 trial to investigate the effectiveness of up to seven drugs approved for other conditions in mild-to-moderate COVID-19. Those medications haven’t yet been named.

Researchers at the California Institute for Biomedical Research (Calibr) — a nonprofit that bridges the academic, public, nonprofit, and for-profit sectors and is affiliated with Scripps Research in La Jolla — also started screening their ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library. With about 12,000 compounds, ReFRAME is home of the largest library of drug repurposing assay data in the world. Since the start of the COVID-19 pandemic, Calibr has published 40 full data sets on their portal and sent their collection to over 70 groups.

Other repurposing efforts have looked at drugs that are already being used, mostly off-label, to treat patients with COVID-19. The COVID19 Registry of Off-label & New Agents (CORONA) project is a good example of this approach.

David Fajgenbaum, MD, MBA, of the University of Pennsylvania, started CORONA in March 2020 with the goal of tracking every drug that has ever been used in humans for COVID-19.

Fajgenbaum got into drug repurposing in medical school, when he was diagnosed with Castleman disease, a rare disorder that causes abnormal growth of lymph node cells. Fajgenbaum nearly died several times. While he was doing lab research, he discovered that a generic drug called sirolimus, originally developed for kidney transplants, had activity against his disease. He tried it and has been in remission for seven years.

Fajgenbaum now runs the Castleman Disease Collaborative Network (CDCN), which is focused on drug repurposing for immune conditions.

“CORONA really was motivated based on the reason I’m alive,” Fajgenbaum said. “I felt it was critical that we had in one central place the ability to track all of the treatments being tried in COVID-19 and pull out the most promising candidates.”

CORONA relies mostly on volunteers. About 100 medical students and lab workers have spent nights and weekends scouring 29,000 scientific papers and pulling data from over 300,000 patients with COVID-19. CORONA now contains about 500 drugs, the “vast majority” of which are generic, according to Fajgenbaum. It’s now the world’s largest database of COVID-19 treatments used in humans.

Meanwhile, Armand Balboni, MD, PhD, has been organizing the PRESECO trial to evaluate the oral generic favipiravir in COVID-19, based on its mechanism of action as a broad-spectrum antiviral.

Balboni is CEO of Appili Therapeutics, which has a total staff of 18 and is focused on treatments for unmet needs in infectious diseases. He spent 18 years on active duty in the U.S. Army, working on pandemic preparedness and serving as deputy director of clinical and regulatory affairs at the U.S. Army Research Institute for Infectious Diseases. During the 2014 Ebola outbreak, he was on loan to the FDA where he was doing clinical review in the office of the commissioner. He left the army to join the private sector in 2015, because he “really wanted to do things more quickly.”

“We took a direction of using broad spectrum antivirals to deal with Ebola. As part of my review, I saw three drugs that look important for COVID-19, remdesivir, favipiravir, and molnupiravir,” he said.

PRESECO is a phase III double-blind randomized controlled trial that is taking place at 27 outpatient sites in the U.S., with plans to expand to Mexico and Brazil.

Appili Therapeutics has partnered with Fujifilm (which holds the manufacturing patents for favipiravir and has chosen not to enforce them during a pandemic), Dr. Reddy’s Laboratories (a large generics manufacturer in India), and Global Response Aid (a large logistics company in Dubai). If favipiravir obtains FDA authorization, Appili will receive a share of the profits on U.S. and Canadian sales, and royalties on sales in Europe and Latin America, for a certain period of time.

The PRESECO trial has relied completely on private funding, with costs estimated at $12 to $14 million.






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