Primary sclerosing cholangitis (PSC) is a disease of the bile ducts, which carry the digestive liquid bile from the liver to the small intestine. In PSC, inflammation causes scars within the bile ducts, hardening and narrowing the ducts and gradually causing liver damage. A majority of people with PSC also have an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.
PSC may eventually lead to liver failure, repeated infections, and tumors of the bile duct or liver. Care for PSC focuses on monitoring liver function, managing symptoms and, when possible, procedures that temporarily open blocked bile ducts. A liver transplant is the only known cure for advanced PSC, but the disease may recur in the transplanted liver.
PSC is considered a rare disease, occurring in about one per ten thousand people in the United States.
In 2014 Dr. Paul Bollyky (BOY-kee), selected as a Harrington Scholar-Innovator in 2016, discovered that an accumulation of hyaluronan — an extracellular and cell-surface-associated polysaccharide that participates in lubricating joints and holding together gel-like connective tissues — is able to override the body’s normal protection against autoimmune attacks. Unfortunately, this is a build-up that is essential for the development of type 1 diabetes.
To address the accumulation of hyaluronan, Dr. Bollyky and his team chose to experiment with the idea of repurposing hymecromone, a drug used for over five decades in Europe and Asia to prevent gallstones. They had found that hymecromone inhibits hyaluronan production, thereby preventing the autoimmune attack on the pancreas that occurs in type 1 diabetes. “We knew that hymecromone got into the biliary system at quite good concentrations,” Dr. Bollyky says.
“However, we encountered certain concerns that arose regarding the pharmacokinetics and pharmacodynamics of our working hymecromone compound. So, we leaned into our personalized pharma development team within Harrington’s Therapeutic Development Center, to find a better path to drug development.”
“In considering other ways to exploit this new insight into the role hyaluronan plays in immune regulation, our Harrington advisory team was instrumental in helping us pivot from thinking about a hymecromone drug for type 1 diabetes, to one for PSC. They helped us do a survey of the market — the economics of developing a drug for PSC — and they generated a lot of data that was helpful for making the financial argument that this would be a wise path to pursue.”
Yet Dr. Bollyky's Harrington team was to play yet another key role in the hymecromone drug development. The literature that was available on hymecromone indicated that it was very quickly metabolized, rendering the drug only about 3% bioavailable — the measure of how much of a drug will have an active effect. Regarding bioavailability, the higher the percent the better, because then more drug is getting distributed and can have the action it needs to on the body.
So the Bollyky Lab assumed that they needed to formulate a prodrug — a chemical that is transformed, either inside or outside of cells, before it has pharmacological effects. For instance, codeine, an opioid used to treat pain, is a prodrug — after entering the body, a particular enzyme transforms codeine into morphine.
It appeared that the Bollyky Lab had a long road ahead, testing various hymecromone formulations in order to find one that wasn't metabolized so quickly.
However, one of the Harrington Therapeutic Development Center advisors, Dr. Perry Molinoff, a neuropharmacologist with more than 30 years of experience in both the academic and industrial sectors, had a sense that even after metabolism, hymecromone was still largely active — and that the metabolite was actually responsible for most of the bile activity.
“Perry's insight was tremendous because it allowed us to pivot from making prodrugs to thinking about simply alternate formulations of hymecromone itself,” Dr. Bollyky says.
The Bollyky team has completed a Phase 1 clinical trial of their drug in healthy human subjects in order to study the pharmacokinetics and pharmacodynamics, and to demonstrate to the FDA that it is safe. The trial showed that their compound indeed inhibits concentrations of hyaluronan and that it's safe at the dosages that they were using. A paper on this was published in 2022 in the Journal of Clinical Investigation.
Building on that success, at this writing they have begun enrolling in a Phase I/II clinical trial, which will test the safety, side effects, and best dose of the treatment, and how well PSC responds to the treatment – making this scientific discovery one step closer to a medicine helping patients.
Dr. Bollyky is an immunologist and infectious disease specialist, and is Associate Professor of Medicine (infectious diseases) and of Microbiology and Immunology at Stanford Medical Center. He received his medical degree from Harvard Medical School, and he is a Fellow of the Infectious Disease Society of America.
The Bollyky lab studies the innate immune response to infection and injury. Its goals are to gain insights into the pathogenesis of inflammatory diseases and to generate novel therapies to improve human health.
Endocrine, Immunology, Metabolic, Rare/Orphan