SUPPRESS is designed to demonstrate the efficacy and safety of brincidofovir for the prevention of CMV infection versus a placebo control, as no therapy is currently approved for the prevention of CMV in HCT recipients. The primary endpoint for SUPPRESS is the rate of clinically significant CMV infection through the first 24 weeks post-transplant. The trial is powered to detect a relative 50% decrease in clinically significant CMV infection in subjects receiving brincidofovir versus those receiving placebo. Secondary endpoints in the SUPPRESS trial include clinical and virologic evidence of dsDNA viral infections, including AdV, BKV and other herpesviruses such as HHV-6 and varicella zoster virus that contribute to morbidity and mortality in the first year following HCT.
SUPPRESS is anticipated to enroll approximately 450 HCT recipients who are at increased risk of CMV infection, with approximately 300 subjects receiving 100 mg twice weekly brincidofovir and 150 receiving placebo (2-to-1 ratio). Approximately 40 transplant centers will participate in SUPPRESS. Dosing of study drug will begin shortly after subjects receive their transplant, and will not require evidence of stem cell "engraftment" (evidence of production of blood cells by the new transplant), a safety precaution incorporated in the Phase 2 trial of brincidofovir and other recent trials of investigational antivirals for CMV prevention. Enrolled subjects will continue on brincidofovir or placebo through Week 14 post-transplant, the period of highest risk for viral reactivation. Subjects will continue to be monitored for evidence of CMV and other dsDNA viral infections through Week 24 post-transplant.
Data from SUPPRESS are anticipated in mid-2015 and, if positive, may support Accelerated Approval of brincidofovir for the prevention of CMV infection.
Chimerix Presents Brincidofovir (CMX001) Adenovirus Phase 2 Results
DURHAM, NC, September 11, 2013 – Chimerix, Inc. (NASDAQ: CMRX), a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, today announced the results from its exploratory Phase 2 Study 202 evaluating brincidofovir (CMX001) in hematopoietic cell transplant (HCT) recipients with early adenovirus (AdV) infection. Study 202 was the first trial of an antiviral agent in AdV infection. Brincidofovir (CMX001) is an investigational oral nucleotide analog lipid-conjugate that has demonstrated activity against all pathogenic families of double-stranded DNA (dsDNA) viruses, including herpesviruses, adenoviruses, and polyomaviruses.
Michael Grimley, MD, Associate Professor of Clinical Pediatrics in the Division of Bone Marrow Transplant and Immune Deficiency at Cincinnati Children’s Hospital Medical Center, and the lead investigator in Chimerix’s Phase 2 AdV study, presented the trial results during the “Viral Infections in Immunosuppressed Hosts” session at the 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting on September 10, 2013 in Denver, CO.
“These data strongly support the continued development of CMX001 as a global prevention for dsDNA viruses, a leading cause of non-relapse mortality in the months following a transplant,” said Dr. Grimley.
Although AdV in HCT recipients has been recognized as a severe and often-fatal infection in pediatric and adult patients who have undergone recent HCT, there are no approved antiviral treatments. Potential risk factors associated with an increased risk of rapid progression to AdV infection have been identified in the scientific literature, but the frequency of AdV in the blood or AdV disease was unknown prior to this trial. Early data from patients who had received CMX001 for AdV infection through Emergency Investigational New Drug (EIND) regulations had provided anecdotal evidence of improved outcomes compared with historic data. This exploratory Phase 2 trial was designed to initiate CMX001 or placebo during early AdV infection, prior to symptomatic disease, and to evaluate the potential to decrease AdV viral load or prevent progression to AdV disease.
Results: Safety and tolerability data from this 48-subject trial confirmed the lack of hematologic and renal toxicity for once-weekly (QW) or twice-weekly (BIW) CMX001 dosed for 6-12 weeks, and showed the successful implementation of the Safety Monitoring and Management Plan (SMMP) to address gastrointestinal side effects reported in earlier trials. Temporary dose interruptions for grade 3 diarrhea were successfully utilized in the trial, with one permanent discontinuation for diarrhea in the CMX001 QW cohort. Three additional discontinuations in the trial were reported for abdominal pain (CMX001 BIW cohort), lower GI hemorrhage (CMX001 BIW cohort), and severe rash (placebo cohort). No new serious safety issues were identified in this trial, and no changes were necessary in the safety monitoring in the recently initiated Phase 3 SUPPRESS trial for prevention of CMV.
Efficacy outcomes for Study 202 were progression to possible or probable AdV disease or significant changes in AdV viremia. Although statistical significance was not achieved, numerical benefit was demonstrated for CMX001 100 mg BIW for multiple endpoints:
Adenovirus in the blood was chosen as a potential early indicator of AdV disease based on the accepted clinical utility of viremia as an early trigger for initiation of antiviral therapy for CMV in these patients. Results from this study bring into question whether AdV viremia is an indicator of early AdV disease. For low-level AdV viremia (< 3.0 log10 copies/mL), a significant proportion of subjects spontaneously cleared viremia prior to initiation of therapy or during placebo therapy. These data indicate that low level AdV viremia may be a transient phenomenon in some subjects. In contrast, high level AdV viremia (> 3.0 log10 copies/mL) at screening was often associated with rapid development of symptoms and end-organ disease even before therapy could be started. Further research is needed to identify clinical indicators of early AdV disease which could be used for early intervention, but prevention of AdV continues to be the preferred strategy through which diseases caused by dsDNA viruses can be avoided.
“The acceptable safety and tolerability of CMX001, and successful incorporation of the Safety Monitoring and Management Plan in this study, were important milestones for the brincidofovir program as we initiate dosing in the Phase 3 SUPPRESS trial for CMV prevention in HCT recipients,” said M. Michelle Berrey, MD, MPH, Chief Medical Officer of Chimerix. “Additionally, consistent trends toward decreased progression of AdV disease and a decrease in overall mortality for subjects randomized to CMX001 BIW reaffirm our belief that earlier intervention in viral disease is the preferred strategy to decrease morbidity and mortality from AdV and other dsDNA viral diseases. Ultimately, we believe that broad use of CMX001 as a prevention for CMV, AdV, and other viral diseases that impact immunocompromised patients will prove to be the best approach.”
Summary of CMX001 Study 202 Results Presented at ICAAC
CMX001 BIW initiated at the time of detection of AdV viremia showed potential clinical benefit in reducing progression to AdV disease and all-cause mortality. Subset analyses of disease progression and all-cause mortality were consistent in trends favoring the CMX001 BIW regimen over placebo or CMX001 QW. A greater proportion of subjects randomized to CMX001 BIW achieved undetectable levels of AdV viremia during randomized therapy and a lower proportion of subjects on the BIW regimen progressed to symptomatic disease compared to placebo or CMX001 QW.
CMX001 Study 202 Design
Study 202 was a randomized, blinded, placebo-controlled proof-of-concept trial assessing the use of CMX001 as a preemptive therapy for AdV infection. HCT recipients were randomized into the study upon appearance of detectable AdV viremia but before the appearance of symptoms of AdV disease. Subjects were randomized to one of three dosing regimens: CMX001 BIW, CMX001 QW or placebo. Forty-eight pediatric and adult subjects were randomized into the trial beginning in June 2011.
The design of the study was based on the limited information available on the natural history of AdV infection in immunocompromised subjects, preliminary and uncontrolled data available on the activity of CMX001 against AdV, ethical considerations due to the placebo-controlled design and high mortality associated with AdV disease in HCT recipients and epidemiologic data indicating a low incidence of AdV viremia in subjects post-HCT.