By Mary Welch
A group of scientists on both sides of the Atlantic formed IgX Oxford Hepatitis Corp. to develop new imino sugar protein-folding inhibitors to treat viral hepatitis.
The spin-off, based in Summit, N.J., originated from a collaborative research effort between scientists at Jefferson Medical College in Philadelphia and the University of Oxford in Oxford, U.K, with support from St. Louis-based Monsanto Co. and its subsidiary, G.D. Searle & Co., of Skokie, Ill., as well as IgX Corp., of Summit, N.J.
"It's a bit complicated, but it's an incredible group of people," said Donald Picker, president of both IgX Corp. and IgX Oxford Hepatitis Corp.
"We have a lead compound that already has all its preclinical efficacy data completed, as well as some toxicity reports, but we have to do more," said Picker. "Hopefully, we'll file an IND [investigational new drug application] this year."
The compound, N-nonyl-DNJ, interferes with a specific step in the life cycle of the hepatitis virus, preventing it from reproducing, thus shutting down its ability to infect a cell. Studies have been carried out on the woodchuck, the best known animal model for hepatitis B virus (HBV) infection in humans.
Researchers will meet with the FDA in the next several weeks to go over criteria for filing an IND, Picker said.
A few years ago, Timothy Block, a professor of biochemistry and molecular pharmacology and medicine at the Jefferson Medical Center of Thomas Jefferson University, in Philadelphia, went to the University of Oxford to work with Raymond Dwek, director of the Glycobiology Institute (funded by Monsanto) at the university, and Baruch Blumberg, Nobel Prize winner and the discoverer of HBV. Blumberg is a professor at Oxford, as well as a researcher at the Fox Chase Cancer Center in Philadelphia. Block is also the director of the Jefferson Center for Biomedical Research and Agricultural Medicine in Philadelphia.
"I went to England to do a sabbatical with them, to look for antiviral agents for [HBV], and we were looking at imino sugars and their effects on [HBV]," said Block. "We eventually came across N-nonyl-DNJ. As we made inroads into the basic science and things started to look better, we saw the possibility of hepatitis C [HCV] also being part of this. The general aim was inhibiting the virus."
By blocking the creation of a virus "envelope," the drug locks the virus's DNA within the infected cell, causing levels of the virus in the animals' bloodstreams to plummet.
"This points to a new way to inhibit [HBV]," Block said. "We've discovered that a very specific step in the life cycle of the virus can be selectively inhibited by N-nonyl-DNJ. The other ways to inhibit the virus work against an enzyme, viral polymerase. This comes at a different step in the virus life cycle. The virus still makes DNA, but gets stuck in the cell."
Specifically, N-nonyl-DNJ inhibits the first step in the glycosylation processing pathway (glucose removal), which is the step involved in the folding and trafficking of some glycoproteins. This inhibition doesn't affect the host cell itself, since host cellular glycoproteins appear to be far less dependent upon this step than are HBV, BVDV (a tissue culture surrogate for HCV), and possibly HCV glycoproteins. Rather, the drug selectively inhibits the virus's replication cycle, since viral-envelope proteins are essential to the virus's life cycle.
Researchers found the drug worked in two cancer targets, as well.
Monsanto maintains an interest in the hepatitis company, by holding a position on IgX Oxford's drug development steering committee, plus the right of first refusal to N-nonyl-DNJ at the filing of the IND, as well as at the end of Phase II. n