Chimerix Remains Positive As it Assesses Steps Forward
This article was originally published in Scrip
After a late-stage failure, Chimerix is closing down two other late-stage trials and reassessing the path forward for its lead compound. Yet, management struck a positive tone on a conference call with analysts, indicating other formulations and better physician education could remedy the issues.
Chimerix stock tanked in late December when the company announced that its lead compound brincidofovir failed to meet its primary endpoint in the Phase III SUPPRESS study. The company is now trying to clarify those results and find some way to salvage the program.
Unfortunately, further analysis of the results have shown the company that the drug is unlikely to be effective in other patient populations – in particular, kidney transplant patients – leading to the decision to end trials SURPASS and SUSTAIN. Both Phase III trials were in this patient population and enrollment was stopped in December when the negative results of SUPPRESS came to light. The company will now conduct another Phase II study in kidney transplant patients to assess activity of the drug.
Chimerix executives explained this weekend at the BMT Tandem meetings, the combined annual meetings of the Center for International Blood and Marrow Transplant Research and the American Society of Blood and Marrow Transplantation, that the negative study results were largely due to a misdiagnosis and overtreatment of graft-versus-host disease (GVHD) in patients in the treatment arm of the study.
The SUPPRESS study included 452 high-risk patients who had just undergone an allogeneic stem cell transplant and were highly susceptible to cytomegalovirus (CMV) infection. Patients were randomized to either the brincidofovir arm or a placebo and the main goal of the study was to prevent CMV infection reactivation. Patients were given the drug or placebo for the first 14 weeks after transplant and then followed for another 10 weeks.
Issues With The Results
Like previous mid-stage study results have shown, during the 14 treatment weeks, patients on brincidofovir had statistically significant fewer CMV infections than those patients on placebo. CMV reactivation was only 24% in the brincidofovir patients compared with 38% on placebo.
At Week 24, a numerical but non-statistically significant increase in mortality was observed in subjects randomized to brincidofovir, with 15.5% mortality on the brincidofovir arm and 10.1% mortality on the placebo arm. CMV infections were higher in the drug arm of the study during the follow-up period, with 22% of brincidofovir patients experiencing infection compared with 11% of placebo patients.
"The use of high-dose corticosteroids importantly results in an increased immune suppression and is known to increase the rate of late CMV infection. And the reason for the difference in mortality was also fully accounted for by diagnosis of graft versus host disease and the use of this corticosteroids to treat that condition," said Chief Medical Officer Garrett Nichols.
Nichols explained that GVHD is a common problem in stem cell transplant patients and is commonly diagnosed when a patient experiences an increase in diarrhea as well as a skin rash. It is treated with corticosteroids that suppress the immune system.
The drug is known to cause an increase in diarrhea and Chimerix put a safety monitoring and management plan (SMMP) in place to mitigate issues with diarrhea. Under the SMMP, physicians were supposed to temporarily stop giving the patients the drug to see is the diarrhea went away and then resume the drug once the problem was resolved. According to the company, only about two-thirds of patients who experienced diarrhea were temporarily taken off drug.
"It's important to note that there is no definitive test for graft versus host disease. There is a strong desire by clinicians to treat early Grade 1 to Grade 2 graft versus host disease due to the high mortality in patients who progress to Grade 3 or Grade 4 graft versus host disease," said Nichols.
"It's important to note that the median cumulative exposure to corticosteroids and patients that were treated on the brincidofovir arm was eight-fold higher when compared to those on placebo. Amongst the patients who develop diarrhea on the brincidofovir arm, we've demonstrated that the interruption of study drug led to improved CMV prevention and lower mortality."
Ultimately, the company hopes that using an IV formulation of the drug, which is slated to enter clinical testing in mid-2016, will not have the same gastrointestinal issues as the oral compound and could help overcome the misdiagnosis of GVHD in this patient population.
"And it's obvious to us that enhanced education on adherence to the safety monitoring and management plan will be critical moving forward," added the exec.
For now, Chimerix will discuss results with regulatory authorities in both the US and elsewhere in hopes of determining the best path forward.