Drug may still be viable as CMV prophylaxis
Photo by Chad McNeeley
HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).
As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.
However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.
The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.
The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.
Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).
Key results
The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.
However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).
The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).
Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).
In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).
There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.
The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.
Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.
Additional endpoints
Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.
And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).
