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Cytomegalovirus—a ‘stealth’ pathogen—gains attention in the drug development realm

OCytomegalovirus is sometimes called ‘the stealth virus’ because many people, including more than 50% of adults in the US, harbor the infection. But few individuals ever feel the effects of CMV unless something else squelches their immune system first—such as the immunosuppressing drugs given before a bone marrow transplant. Wherever the virus gains a foothold, it can create serious problems such as pneumonia, unrelenting diarrhea or inflammation in the eye. It’s also the most common viral infection in newborns and 1 out of every 750 infants born with CMV in the US will suffer permanent harm—hearing loss, brain damage, or even death—from this virus.

At present, more than three-quarters of people being treated for CMV infection who receive the antiviral drugs ganciclovir or valganciclovir respond to therapy. Both medications stop the virus from replicating, but they only work as long as the treatment is given. So the virus can make a comeback later on. Also, these drugs lower white blood cell counts, making it harder for the immune system to fight CMV on its own. If the virus develops resistance to these first-line drugs, then there are effective back-up treatments with foscarnet and cidofovir, but these compounds can cause kidney damage.

One new option, described in a paper published today in the New England Journal of Medicine, is an investigational drug called CMX001 that shows about the same efficacy as the current drugs. CMX001, also called brincidofovir, is a less-toxic, lipid-coated version of the current second-line drug, cidofovir. But this drug escapes the toxic kidney problems seen with cidofovir and doesn’t cause a drop in white blood cell counts. Additionally, CMX001 can be given in a pill form, an advantage over some of the other drugs used against CMV that must be injected intravenously.

“There’s a perception in the scientific community that we need to do better in our treatments for cytomegalovirus. This drug is better than what we’ve had,” says first author on the paper Francisco Marty, an oncologist at the Dana-Farber Cancer Institute in Boston.

The phase 2 clinical trial for CMX001, led by Marty and sponsored by Chimerix, the North Carolina-based company that developed the drug, involved 230 individuals undergoing bone marrow transplantation. CMX001 showed 90% effectiveness in keeping the virus from flaring up in patients, compared with about 70% virus suppression among those who received a placebo.

The next phase

Chimerix is currently recruiting for phase 3 clinical trials that will test the drug at similar doses but give the drug immediately after the transplant occurs, instead of waiting 10-14 days to make sure the new donor cells have taken hold in the patient’s bone marrow. The US Food and Drug Administration approved the new timing of this protocol because brincidofovir shows no side effect that lowers the white blood cell counts, a major concern when patients already have weak immune systems.

Two more small molecule drugs against CMV are also in clinical trials. Merck, headquartered in New Jersey, will soon be moving into phase 3 trials with their oral CMV antiviral, called letermovir, which was licensed last year from the German drugmaker AiCuris. There are phase 2 clinical trials** in the US and Europe for ViroPharma’s maribavir, that also comes in pill form. Unlike CMX001, which was originally developed as a bioterrorism counterweapon against smallpox, these two new drugs are specific in their action against CMV. This could be a drawback for immune-compromised patients who often also suffer complications from other viruses, such as human herpes virus 6, a source of severe inflammation in the brain.

Prevention of CMV infection is also in the works. A handful of vaccines are now in clinical trials, including TransVax, developed by Astellas Pharma of Northbrook, Illinois, in partnership with the San Diego pharmaceutical company Vical.  Phase 3 clinical trials of TransVax are underway in the US and Europe. But TransVax might face competition from CMV vaccines in development from the UK’s GlaxoSmithKline and Sanofi Pasteur of France.

With all these options in the pipeline, it seems surprising that there aren’t already more drugs on the market. “It’s public awareness that’s lacking,” says Stuart Adler, a pediatric infection specialist at the Virginia Commonwealth University in Richmond. “If CMV caused a rash [in everyone with an infection], we’d already have a drug to prevent it. But no one knows about it.”

Image via the Centers for Disease Control and Prevention Public Health Image Library

**Correction (26 September): An earlier version of this story incorrectly stated that ViroPharma’s maribavir is in multi-site phase 2 and 3 clinical trials in the US and Europe when in fact Maribavir is in a phase 2 clinical trial. Nature Medicine regrets the error.

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