The commonly found adenovirus poses little problem for healthy people, whose immune systems can fight the respiratory and gastrointestinal infections the virus can cause. But in bone marrow and organ transplant patients, adenovirus often becomes deadly. Their weakened immune systems can’t fight off the virus, which studies show can be fatal in up to 80 percent of such cases.
There are no FDA-approved drugs to treat adenovirus, leaving some doctors to turn to a different drug that is associated with a high risk of kidney damage. But an experimental antiviral developed by Durham, NC, pharmaceutical company Chimerix (NASDAQ: CMRX) is showing potential as a safer alternative. A late-stage clinical trial is still underway and Chimerix is taking an unusual approach to the study, but early results show that the Chimerix drug brincidofovir cut adenovirus mortality rates by more than half.
If the Chimerix drug sounds familiar, it might be in the context of Ebola. Brincidofovir was in the spotlight last fall as one of several experimental antiviral drugs pressed into emergency use treating Ebola patients. But a year ago, Chimerix found itself in the spotlight for a different reason. Then 7-year-old Josh Hardy, whose body was weakened by cancer treatment and a bone marrow transplant, was dying from adenovirus infection. A “#SaveJosh” social media campaign and nationwide news coverage built pressure on the tiny company to release the still unapproved drug under so-called compassionate use. The Virginia boy was eventually administered brincidofovir—not under compassionate use but as the first patient in a late-stage trial of the drug.
The gold standard of drug testing in diseases where no treatments are yet available is a double-blind study that compares patients who receive the experimental drug against a second group receiving only a placebo. But Garrett Nichols, Chimerix’s chief medical officer, says treatment centers and their patients are reluctant to participate in studies where some participants receive only a sham treatment because adenovirus is so deadly for these patients.
The idea gave Chimerix pause as well. “It’s difficult to imagine doing a placebo-controlled trial for an infection with 60 to 80 percent mortality,” Nichols says.
At this time last year Chimerix, which had already taken brincidofovir as far as mid-stage clinical trials in adenovirus, was discussing with the FDA what a late-stage study would look like. Hardy’s case gave the company and regulators “that extra push,” he says, toward agreement on a clinical trial design.
Chimerix is now studying its drug in transplant patients, like Hardy, who have adenovirus infection. But instead of comparing the treatment group against a placebo group, Chimerix is using “historic control.” The group of patients treated with the Chimerix drug will be compared against historic data of adenovirus cases.
Historic controls are typically reserved for drug studies in fatal diseases, such as some rare cancers, Nichols explains. In an effort to make the data as comparable as possible, the adenovirus patients will be compared against those who received the same types of transplants and were treated at the same sites where the current trials are taking place.
In the absence of an FDA-approved treatment for adenovirus, many physicians turn to the intravenously administered drug cidofovir (Vistide), says Michael Grimley, a pediatric hematologist/oncologist at Cincinnati Children’s Hospital Medical Center. The drug is approved to treat cytomegalovirus eye infections in AIDS patients. But Grimley, who is also the principal investigator of the Chimerix adenovirus trial at Cincinnati Children’s, adds that without any alternatives, some physicians consider cidofovir the standard of care for treating adenovirus. The drug, however, brings the risk of kidney damage.
“Everybody I’ve treated with IV cidofovir has significant renal impairment from the treatment and that is troubling,” he says. “It’s a double-edged sword. What you do to get your immune system better has other troubling complications.”
Cidofovir, which is marketed by Gilead Sciences (NASDAQ: GILD), interferes with the way that viruses make copies of themselves. But that drug is also picked up by a protein that takes it right to the kidney, leading to kidney damage, Grimley explains. Brincidofovir never latches on to that protein so the kidney never sees the cidofovir.
To produce brincidofovir, Chimerix binds cidofovir with a lipid molecule that makes it absorbable in the gut. This means Chimerix can make its drug into a pill—something that is not possible with regular cidofovir, Nichols says. The lipid also shepherds the drug directly into the target cells, where it then releases the cidofovir molecule, which means that those cells receive much higher levels of the drug compared with intravenous cidofovir.
The Chimerix drug was developed in the laboratory of Karl Hostetler at the University of California San Diego. Hostetler developed the lipid technology under a government contract for use in a smallpox antiviral. That program, funded by the Biomedical Advanced Research and Development Authority, continues at Chimerix today. Chimerix’s work in transplant patients came from the company’s search for other applications of its drug.
So far, Chimerix has data from 85 patients who received brincidofovir in its Phase 3 adenovirus study. In the study, the mortality rate in bone marrow transplant patients with disseminated adenovirus infection was 37 percent after 75 days. Brincidofovir has gastrointestinal side effects, including diarrhea. Grimley says those side effects were known but they occurred less frequently compared with their occurrence in an earlier study. Three patients dropped out of the Phase 3 trial due to those side effects, but Grimley says it’s possible that they were instead suffering the effects of adenovirus in their intestinal tract. Most important, he says, there was no evidence of damage to the kidneys or bone barrow. The study, which is enrolling both children and adults, is expected to include 200 total patients.
Chimerix hopes that brincidofovir finds applications in other viruses. The company is also in a separate late-stage clinical trial studying the drug’s ability to prevent cytomegalovirus infection in bone marrow transplant patients. This placebo-controlled study will be important in filing for FDA approval of the drug, Nichols explains, since Chimerix plans to file drug applications in adenovirus and cytomegalovirus at the same time. Nichols says efficacy and safety data from the cytomegalovirus trial will help support the company’s submission of the drug in adenovirus. The company expects to have data from the cytomegalovirus study in about a year.
Meanwhile, the adenovirus study results so far help support Chimerix’s case for applying brincidofovir in multiple viruses. Grimley says half of the patients enrolled in the adenovirus study suffered from additional viral infections.
“Brincidofovir worked on those as well,” he says.