Clasped within several flat, light blue binders, the papers form a column on the desk of pathology Professor Richard Tidwell. Tidwell estimates the stack to be a foot high. Grabbing a ruler, he measures the column. "It's exactly ten inches," he says. "It looked higher.
"You spend an awful lot of time writing the IND," Tidwell says, referring to the Investigational New Drug brochure. On the corner of his desk, the IND towers over the numerous papers covering his desk. Tidwell lists the people who helped write the IND, including the scientists at RiboGene, the California pharmaceutical company which has sub-licensed the patent UNC-CH holds on the investigational new drug, RG-201. (The RG is for RiboGene.) This past summer, the Food and Drug Administration approved the IND, granting permission for RG-201, created in Tidwell's lab at UNC-CH, to be tested in humans. The approval is both a triumph and a beginning.
"The volume of this room could be literally filled with the paperwork it's going to take to get this drug through the clinical trials," Tidwell says. "That's no joke. That's not imaginary." Despite the work involved, Tidwell is enthusiastic about the drug, the collaborations that brought it into being, and the need it could meet.
RG-201 is active against a one-celled organism called Pneumocystis carinii, which resides in everyone's lungs. In healthy people, the organisms are harmless. In people whose immune systems are compromised, the organisms multiply and fill the hollow spaces in the lungs. "If you look at lungs infected with Pneumocystis, you'll see why people die or why their pulmonary efficiency is way down," Tidwell says. "It's because they really have no space for air." Pneumonia caused by Pneumocystis carinii is a leading cause of death in people with AIDS.
Pneumocystis carinii is often fatal even though a drug called trimethoprim/sulfameth-oxazole (TMP-SMZ) is effective both in treating the pneumonia and in warding it off in AIDS patients with low immune cell counts. "TMP-SMZ is an outstanding drug against the organism," Tidwell says. "The only problem is a number of people develop allergies to the drug." Because sulfa compounds are found in many foods and drugs, a sulfa allergy is considered serious. If a patient on TMP-SMZ shows signs of developing an allergy to the drug, its use is discontinued. Estimates vary, but somewhere between 20 and 60 percent of patients using TMP-SMZ must discontinue it.
It is hoped that RG-201 will at least serve as a backup drug for people who cannot take TMP-SMZ. "If RG-201 turns out to be very effec-tive, with very low toxicity, there might be a lot of physicians who would prefer never to put AIDS patients on sulfa drugs," Tidwell says.
Since 1991, Tidwell and a network of researchers at four universities have worked together to create and test compounds against opportunistic infections, which flourish in people with weakened immune systems. Initially, the research was funded only by a National Cooperative Drug Development Groups grant. More recently, funding has also been provided by Pharm-Eco, the company which has licensed the U.S. and foreign patents for RG-201 as well as other of the group's compounds.
Tidwell describes the process of getting a drug into clinical trials, beginning with the synthesis of new compounds. "The joy of it is you're making something that's never been before, an actual molecule," says Tidwell.
Once the compounds are made, the research team tests them to see how they act against the organism. One way the compounds seem to work is by binding to a specific stretch of DNA in the one-celled organism, and there-by preventing topoisomerase, an enzyme in the cell, from binding to that stretch of DNA. Because it is essential for topoisomerase to bind to DNA before replication of the DNA can occur, the compound prevents the cell from reproducing. When the cells cannot reproduce, they eventually die out. The topoisomerase work was done by Christine Dykstra, formerly at UNC-CH, now at Auburn University.
"We determine how strongly the compounds bind to DNA and where they bind," Tidwell says. Using this information, the group can then make hypotheses about how the compounds affect the organism and what changes to the molecule might make it more effective against the organism. The researchers go back to synthesize more new compounds.
Eventually, the researchers find compounds that seem promising and send them to collaborator James Edwin Hall, associate professor of epidemiology at UNC-CH. Hall tests the compounds against the organisms to determine which compounds are most effective, and if particular compounds are more effective against one organism than another.
If a particular compound still seems promising, the researchers ask Pharm-Eco whether the company is interested in licensing and developing the compound. In the case of RG-201, Pharm-Eco not only licensed the drug, but began developing it. Pharm-Eco made large batches of the drug, and RiboGene contracted with laboratories to do toxicity studies in several species of animals, as well as advanced pharmacokinetic testing. "Pharmacokinetics," explains Tidwell, "is studying how the drug is distributed through the body and how it's excreted." The researchers examined the data from these pre-clinical studies. "We asked, based on the activity, based on the toxicity, based on the pharmacokinetics, can we put together an IND that looks like it could be approved by the FDA?" says Tidwell. The researchers submitted an IND, and RG-201 was approved.
"The sheer fact that we have a compound that's going into humans is a tremendous accomplishment for us," Tidwell says.
The research discussed in this article has been funded in part by a National Cooperative Drug Development Groups grant of $2,528,589 from the National Institutes of Health.
©1995 by the University of North Carolina at Chapel Hill in the United States. All rights reserved. No part of this publication may be reproduced without the consent of the University of North Carolina at Chapel Hill.
Last modified: 4/2/96