April 19, 2018

VUMC drug repurposing initiative gaining momentum

Drug repurposing involves establishing an additional approved indication for a drug already at market.


Drug repurposing involves establishing an additional approved indication for a drug already at market.

Compared to the usual lengthy drug discovery and development route, repurposing can be a far quicker and more economical way to bring needed therapies to bear on patient problems. Repurposing a drug may also involve developing a new formulation for the new indication.

In 2016 the Vanderbilt Institute for Clinical and Translational Research (VICTR) launched a drug repurposing initiative focused on drugs with known molecular mechanisms, with a view to leveraging Vanderbilt University Medical Center’s scientific expertise, as well as data from BioVU, the VUMC biobank linking human DNA samples and genotype data to de-identified electronic health records.

This year, to test the efficacy of an initial set of repurposing candidates, researchers at VUMC will launch four phase II clinical trials, and the team at VICTR is seeking funding to test an additional five drugs.

“That’s a lot. The size of the drug company you would have to have for that size pipeline would come to hundreds of people, but this team has gotten there on a shoestring,” said Jill Pulley, MBA, operations director for VICTR.

BioVU is one of the largest repositories of its kind, and according to Pulley, it’s a resource that nearly any drug company would envy.

“In BioVU we have a clue to drug repurposing that very few drug companies have. What we do is basically look in BioVU for people walking around with genetic variants that look like the effect of a drug, and we make a match. So if you have a variant that reduces a particular protein and there’s a drug that works by inhibiting that protein, that’s a match,” she said.

With a given variant matched to a drug effect, researchers can look in BioVU for drug repurposing signals, that is, they can scan health records for other beneficial effects that might be linked to the variant, and thus might be induced by the drug.

Running in tandem with this approach, an inverse approach begins by identifying variants that might be positively associated with a disease or condition treated by a drug, and scans then look for other diseases or conditions positively associated with these variants, with a view to whether these other diseases might respond to the drug.

The two-way analysis always starts with a drug, and is limited to variants within the gene that makes whatever molecular entity the drug is targeting. And for now, the initiative is focused primarily on generic drugs without serious side effects.

As repurposing signals appear in BioVU, literature reviews and pre-clinical studies can help identify the most promising candidates. A faculty member is identified to carry the research forward, a clinical trial is designed to test efficacy for the new indication, and research grant writing begins, with VICTR staff providing support all along the way. Funding for clinical trials may come from public sources, private foundations or institutional investment.

While the evaluations begin with signals from BioVU, the phase II clinical trials beginning this year are motivated by a range of evidence, often including results from pre-clinical studies:

  • David Aronoff, MD, professor of Medicine and director of Infectious Diseases, will lead a trial of misoprostol for Clostridium difficile infection recurrence. The drug was originally used to prevent gastrointestinal ulcers. C. diff infection causes colitis, and in genes for the cell receptor targeted by misoprostol, data from BioVU show variants associated with colitis.
  • Ingrid Mayer, MD, MSCI, professor of Medicine, will lead a trial of ifetroban for prevention of cancer metastasis. The drug was originally developed for cardiovascular indications. In the gene for the receptor targeted by ifetroban, data from BioVU show a variant associated with metastasis.
  • Leslie Crofford, MD, professor of Medicine and director of Rheumatology and Immunology, and Laura Dugan, MD, professor of Medicine, will lead a trial of memantine for aphasia and cognitive fog associated with neuropsychiatric systemic lupus erythematosus. The drug is used to treat Alzheimer’s disease. In the gene for the receptor targeted by memantine, data from BioVU show a variant associated with neuropsychiatric syndromes posed by lupus.
  • David Edwards, MD, PhD, assistant professor of Anesthesiology and chief of Pain Medicine, will lead a trial of guanfacine for trigeminal nerve pain. The drug is used to treat hypertension and attention deficit hyperactivity disorder. In the gene for the receptor targeted by guanfacine, data from BioVU show a variant associated with trigeminal nerve pain.

“As more repurposing candidates emerge, we look forward to working with additional investigators from across the enterprise to test drugs for new indications,” said Gordon Bernard, MD, Executive Vice President for Research and VICTR program director.

When someone repurposes and reformulates a generic drug, they receive exclusive marketing rights for the new formulation for up to seven years. As new formulations are developed, Vanderbilt Health will seek to license the rights to drug companies.

“If we’re able to show a new indication for a generic drug but find there are no companies interested in picking up the marketing rights, that’s OK too. We’ll just make the new use known through publication, and doctors can use the drug based on the results of our studies,” Bernard said.

Ken Holroyd, MD, MBA, Assistant Vice Chancellor for Research, is medical director and science officer for the initiative.