CMV Drug Developed in the Labs of Professors Townsend and Drach Enters Phase 2 Clinical Trials.

The compound maribarvir, developed by long-time research collaborators Albert B. Prescott Emeritus Professor of Medicinal Chemistry Leroy B. Townsend and Medicinal Chemistry and School of Dentistry Professor John C. Drach, has entered phase two clinical trials for the treatment of cytomegalovirus infection in stem cell transplant patients.

During this phase, maribarvir, which is licensed by ViroPharma Inc., will be tested at up to 15 transplant centers across the U.S. The trial will focus on CMV-seropositive patients who have undergone allogeneic stem cell transplantation.

CMV is part of the herpes virus family, which also includes the viruses that cause chicken pox, mononucleosis, and herpes simplexes 1 and 2. Like other herpes viruses, CMV can remain dormant in the body for long periods of time.

In most people with intact immune systems, CMV causes little to no apparent illness. However, in people with weakened immune systems, CMV can lead to serious complications or death.

Patients who are immunosuppressed following transplant of hematopoietic stem cells, such as a bone marrow transplant or solid organ transplantation, are at high risk of CMV infection, as are AIDS patients, fetuses, and newborns. In these patients, CMV can lead to conditions such as pneumonitis or hepatitis, or to complications such as acute or chronic rejection of a transplanted organ. When contracted in utero or at birth, CMV can cause babies to be born with birth defects or impairment such as hearing loss.

Drach, a biochemist and virologist, and Townsend, a world-renowned synthetic-organic chemist, began researching cytomegalovirus in the 1980s, prompted by a National Institutes of Health call for proposals to find drugs to treat CMV infections.

The U-M researchers collaborated with scientists at what is now GlaxoSmithKline, leading to prompt clinical evaluation of maribavir. But advances in treatment of HIV and AIDS patients temporarily slowed interest in the compound and development work ceased. CMV was a common cause of blindness and ultimately death in HIV patients and as the medical community invented drugs to treat the HIV infection directly, there was less urgency by large pharmaceutical firms to develop a CMV drug.

“We had mixed feelings,” Drach explains. “Naturally, we were pleased to see the remarkable progress in treating HIV and the dramatic decrease in death from AIDS-related complications, but we also wanted to see our compound get to market for other people with CMV.”

More than 30 years ago, Drach teamed with fellow dentistry Professor Charles Shipman to study herpes simplex and to discover drugs to treat resulting diseases that manifest orally as cold sores. When Townsend came to Michigan in 1979, his focus had been primarily the design and synthesis of new anticancer drugs.

Townsend agreed to peruse his library of anticancer compounds so Drach could test them for potential effectiveness against CMV. Drach explained that chemotherapy drugs work by killing cells, and they hoped that if Townsend’s compounds had not been effective in killing cancerous cells, maybe they would instead work to block replication of virus cells without killing healthy cells. In fact, that was the case for the class of benzimidazole compounds to which maribavir belongs.

Maribavir works differently than other CMV treatments. It inhibits the function of three previously undiscovered CMV genes

The collaboration of faculty from Dentistry and Pharmacy to study cancer drugs for their effectiveness in treating a herpes virus is a classic example of what researchers say is a major strength of U-M: the ease of teaming with others outside their discipline to find new approaches to questions bigger than any one way of answering them.

E-mail: jcdrach@umich.edu, ltownsen@umich.edu.