-- First-Line Use of Brincidofovir for CMV May Preserve Subsequent Therapeutic Options --
-- Data Presented at 2014
"Drug resistance can be a significant issue in the treatment of viral diseases, particularly in immunocompromised patients," said
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.
About Brincidofovir (CMX001)
Adenovirus causes upper respiratory infections, including the common cold, in individuals with intact immune systems; however, it is often rapidly fatal in patients with compromised immune responses. Adenovirus is most common during the post-transplant period when the immune system is weak. No therapies are approved for the treatment of adenovirus.
About Cytomegalovirus (CMV)
CMV is a member of the herpes virus family and remains the most common cause of fatal infections in hematopoietic cell transplant (HCT) recipients. Two-thirds of adults have been exposed to CMV, generally in childhood, with lifelong viral latency established following the initial infection. In immunocompromised individuals, such as transplant recipients, CMV often reactivates during the post-transplant period when the immune system is weak. CMV itself is immunosuppressive and reactivation of the virus can predispose a person to other opportunistic infections. No therapies are approved for the prevention of CMV in HCT recipients.
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