[Updated 2/22/16, 11:43 am. See below. ] Chimerix is shutting down two late-stage trials for a drug meant to prevent infections in kidney transplant patients, a decision that follows the drug’s recent Phase 3 failure in people who have received stem cell transplants.
Durham, NC-based Chimerix (NASDAQ: CMRX) announced over the weekend that it would close the trials after reporting detailed results of the failed Phase 3 trial during the tandem meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation. The company now plans to reassess the drug in new Phase 2 studies of its pill, known as brincidofovir, and meet with the FDA to determine the next steps.
When Chimerix initially announced in December that the brincidofovir had failed, the company said that in the 24 weeks following a stem cell transplant, the drug reduced infections from cytomegalovirus (CMV), a virus that can take advantage of patients with compromised immune systems. But those infections returned. Once off of the Chimerix drug, patients showed a higher rate of CMV infection in the weeks afterward compared to the group that received a placebo, the company reported.
Chimerix said over the weekend that the drug’s failure appears to be associated with higher use of corticosteroids and other immune system-suppressing therapies to treat graft versus host disease, a sometimes fatal complication that can develop when newly transplanted donor cells attack the body of a transplant recipient. Chimerix said that use of immune-suppressing drugs to prevent graft versus host disease is known to increase the risk of infections, including CMV infections, after a patient stops taking antiviral drugs.
One sign of graft versus host disease is diarrhea, which is also a known side effect of the Chimerix drug. In an earlier study, Chimerix developed a safety plan to monitor and manage diarrhea by temporarily stopping treatment with the drug when it occurred. The problem continued to occur in Chimerix’s Phase 3 trial, as patients on its drug had more frequent diarrhea than those on placebo.
[The following four paragraphs were added to include details from the conference call.] On a Monday morning conference call to explain the clinical trial results, CEO Michelle Berrey said that at some of the clinical trial sites, the diarrhea was presumed to be graft versus host disease and was treated with corticosteroids, rather than temporarily stopping administration of the Chimerix drug according to the safety plan the company had developed in Phase 2. Interrupting dosing of the drug should improve the diarrhea, if it is caused by the drug, according to the safety plan. If the diarrhea does not improve, the plan instructs physicians to look for other causes, such as graft versus host disease.
In clinical trial sites that followed the safety plan and interrupted dosing of the Chimerix drug, patients had better outcomes, Chief Medical Officer Garret Nichols said. He added that even though Chimerix staff briefed investigators on the safety plan at each clinical trial site, there were still differences in how closely the sites followed the plan. In one third of sites, patients were treated with corticosteroids without stopping the Chimerix drug. Nichols said the results of the trial underscored the need to emphasize to physicians the importance of interrupting dosing of the Chimerix drug early and allowing the gut to heal before resuming treatment.
Chimerix said there were no statistically significant differences in patient deaths when comparing brincidofovir to a placebo. Though 15 more people died on its drug than on placebo, Chimerix attributed the deaths to higher use of immunosuppressive therapies. The Chimerix drug also failed a secondary goal of the clinical trial—preventing infections with a virus known as BK, which like CMV can also cause trouble for patients with weakened immune systems.
Despite closing the trials in kidney transplant patients, Berrey said the on the call that Chimerix remains committed to addressing infections in these patients. While kidney transplant patients are not at risk for graft versus host disease, they can experience diarrhea. Berrey said that the company needs to have a more complete understanding of the failed trial before it invests in additional late-stage studies. “We are not walking away from the kidney transplant population,” Berrey said on the call. “We continue to believe this unmet need can be met with brincidofovir.”
Nor is Chimerix isn’t giving up on brincidofovir as a preventative therapy for CMV in stem cell transplant patients, who currently have no FDA-approved drugs to help them fight the virus. Rather, it’s taking them back to Phase 2 testing, where Chimerix hopes to confirm the drug’s activity against BK virus. The company says these studies will also explore ways to manage adverse events associated with its drug.
The Chimerix drug is also in a separate late-stage clinical trial for adenovirus infections in patients with weakened immune systems that is expected to produce data in mid-2016. Chimerix is also studying its drug as a smallpox countermeasure, research that is funded by the Biomedical Advanced Research and Development Authority. Chimerix plans to discuss the full results of the failed trial with the FDA, including the data it has so far for adenovirus and smallpox.
Chimerix still wants to proceed with an intravenous form of brincidofovir in preclinical testing that the company says might avoid the diarrhea caused by the pill form of the drug. If those results hold up in human testing, Chimerix says it could explore dosing patients with the IV form of the drug in the weeks after a transplant, with the pill form of the drug made available when they go home.