Chimerix Announces Brincidofovir Suggests Favorable Resistance Profile in Adenovirus, CMV

Chimerix, Inc. CMRX, a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, announced new data today that suggests a potentially favorable resistance profile for brincidofovir for the treatment of life-threatening adenovirus and the prevention and treatment of cytomegalovirus (CMV). Results of the in vitro (cell culture) and Phase 2 studies were presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, D.C. "Drug resistance can be a significant issue in the treatment of viral diseases, particularly in immunocompromised patients," said M. Michelle Berrey, M.D., M.P.H., President and Chief Executive Officer of Chimerix. "We are encouraged by the high barrier to resistance seen in early studies for brincidofovir in adenovirus and we look forward to gathering more data through our Phase 3 AdVise study, which is currently enrolling patients. Additionally, the data for CMV suggest that first-line use of brincidofovir preserves the option for subsequent therapies, clearly a desirable feature in any first-line CMV prevention." Resistance Profile of Adenovirus Exposed to Brincidofovir In Vitro and In Vivo (Abstract V-1302) In an in vitro study of human adenovirus, brincidofovir and cidofovir were evaluated in increasing concentrations for antiviral activity. The development of brincidofovir-resistant adenovirus required two mutations to decrease brincidofovir's activity by four-to-eight-fold. These mutations required more than five months of exposure to brincidofovir in cell culture before they emerged. In an exploratory Phase 2 study, 48 allogeneic hematopoietic cell transplant recipients with asymptomatic adenovirus levels ≥ 100 c/mL were randomized to placebo, brincidofovir once weekly, or brincidofovir twice weekly for 12 weeks. At 12 weeks, only one subject was identified with adenovirus containing one of the mutations detected in vitro. The mutation observed may have been present prior to brincidofovir therapy since previous use of antivirals, including cidofovir, was not excluded. These data provide preliminary evidence that brincidofovir resistance to adenovirus may be slow to emerge in humans. Combination Activity and Emerging Resistance Profile of Brincidofovir in CMV Prevention and Treatment (Abstract V-677) The combination activity and resistance profile of brincidofovir for CMV were evaluated in vitro and in two Phase 2 clinical trials. Study 201 enrolled 171 antiviral-naïve patients with CMV and Study 350 enrolled 210 heavily pre-treated patients with life-threatening DNA viral infections, including 107 patients with CMV as the primary viral infection. In vitro, brincidofovir selected a unique mutation in the CMV DNA polymerase that led to slower virus replication and resistance to brincidofovir or cidofovir, but not cross-resistance to ganciclovir or foscarnet. In Study 201, no resistance-associated mutations were detected, suggesting first-line use of brincidofovir may not cause cross-resistance. In Study 350, 59 patients were evaluable and had baseline sequence data available. Two evaluable patients had baseline CMV DNA polymerase mutations associated with resistance to ganciclovir, cidofovir, or brincidofovir. These two patients did not achieve viral levels below measurable quantity (less than 200 virus copies per mL in plasma) at the last time on therapy. However, of the remaining evaluable patients with baseline sequence available, including many who were resistant to ganciclovir with common mutations, 25 (44%) achieved viral levels below 200 copies per mL and 36 (63%) had at least a 0.5 log10 decrease in viral load. The results suggest that while the prior use of CMV antivirals leading to resistance-associated mutations can reduce brincidofovir activity, first-line use of brincidofovir for CMV prevention may preserve subsequent therapeutic options.