Twice-Weekly Brincidofovir (CMX001) Shows Promising Antiviral Activity in Immunocompromised Transplant Recipients with Asymptomatic Adenovirus Viremia

Background: Adenovirus (AdV) infection causes morbidity and mortality in immunocompromised patients, particularly in pediatric patients. There is no approved therapy for the prevention, preemption or treatment of AdV infection. Brincidofovir (BCV, CMX001), an orally bioavailable broad-spectrum nucleotide analog, has demonstrated in vitropotency against all AdV species tested, including those most often associated with severe disease. Two recent clinical trials initiated brincidofovir twice weekly (BIW) in transplant recipients who presented with AdV viremia and no evidence of end-organ AdV disease.

Methods:Study 202 was a randomized, placebo-controlled trial that evaluated BCV as preemptive treatment of asymptomatic adenoviremia in hematopoietic cell transplant (HCT) recipients. Study 350 was an open-label, expanded access trial in immunocompromised patients with no alternative therapeutic intervention. Adult subjects were treated with BCV 100 mg BIW; pediatric subjects were treated with BCV 2 mg/kg BIW. AdV viremia was monitored weekly. Antiviral responses and mortality results are reported.

Results: A total of 26 subjects in Study 202 (n=14) and Study 350 (n=12) received BCV BIW based on AdV viremia at screening. Subjects ranged from 7 months to 68 years of age and all but one were HCT recipients. AdV was detected at the central laboratory in 21 subjects at the time of first dose. Baseline viremia (BL) ranged from 100 (the lower limit of detection for the assay, LLOD) to 2.2 x 10⁷ copies/mL (median 3700). AdV viremia decreased to ≤LLOD for 67% (14 of 21) subjects within the first week of therapy; an additional 4 subjects (18 of 21, 86%) reached ≤LLOD at some time during treatment. High levels of AdV viremia (>1000 c/mL) detected in 14 subjects decreased to ≤LLOD in 79% (11 of 14) within a median of 9 days of BCV, and with a mean decrease of 1.8 log₁₀c/mL. Observed all-cause mortality during a median 8 weeks (range 3 to 47) of follow-up was 15% (4 of 26). Two of the 4 subjects who died had undetectable AdV viremia at the time of death.

Conclusions: High risk transplant patients receiving twice-weekly brincidofovir had rapid decline in their AdV viremia, with limited progression to all-cause mortality. BCV is a promising therapy for AdV and further study is warranted.