Chimerix, Inc., a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, announced the final study design for the phase III SUPPRESS trial of CMX001 in the prevention of cytomegalovirus (CMV) infection following an allogeneic hematopoietic stem cell transplant (HSCT). CMX001 is an investigational oral nucleotide analog lipid-conjugate that has shown broad-spectrum antiviral activity against double-stranded DNA (dsDNA) viruses including all of the herpesviruses, adenoviruses and polyomaviruses.

Since the end of phase II meeting with the US Food and Drug Administration (FDA) in May 2012, Chimerix has been working closely with the FDA on the study design of the phase III SUPPRESS trial, and has now finalized the population, specifics and timing of the primary and multiple secondary endpoints, as well as the dose and duration of CMX001 therapy. Initial study designs considered that two active doses of CMX001, 100 mg twice weekly and 75 mg twice weekly, be carried forward into the phase III trial in order to mitigate the risk of gastrointestinal side effects. However, results from a phase I trial of CMX001 administered with food and a Safety Monitoring and Management Plan implemented in ongoing clinical trials supported a decision to explore a single dose of CMX001 in SUPPRESS, 100 mg administered twice weekly.

Following successful screening, SUPPRESS subjects will be randomized to receive 100 mg doses of CMX001 twice weekly or placebo. Chimerix anticipates that SUPPRESS will enroll approximately 450 patients who have evidence of prior CMV infection, with approximately 300 of the 450 enrolled subjects receiving CMX001 (2-to-1 ratio). The final study design dictates that dosing of CMX001 or placebo will begin shortly after subjects receive their stem cell transplants, and does not require evidence of stem cell "engraftment" (evidence of production of blood cells by the new transplant), a safety precaution in the phase II trial of CMX001 and other recent trials of investigational agents for CMV prevention. A review of safety data for CMX001 from earlier trials and from the CMX001 Compassionate Use Programme found no evidence of toxicity that would restrict early dosing in the phase III trial, and the ability to begin a potential prevention during the early post-transplant period may decrease CMV infection in patients at risk of early CMV reactivation.

SUPPRESS subjects will receive CMX001 or placebo from the early post-transplant period through Week 14, and will continue to be monitored through Week 24 for evidence of CMV disease or for CMV in the blood at levels high enough to require alternative antiviral therapy. The recently approved Roche TAQMAN real-time polymerase chain reaction assay will be used to monitor levels of CMV in the blood, with a single measurement of CMV in the blood greater than or equal to 1,000 copies/mL considered failure of CMV prevention in any enrolled subject. In addition, subjects who are at risk of rapid progression to CMV disease (e.g., recipients of umbilical cord blood stem cells) will have a lower threshold for initiation of an alternative antiviral, reaching the primary endpoint with any CMV level in the blood greater than or equal to 150 copies/mL (the lower limit of quantification of the assay).

SUPPRESS is designed to demonstrate the superiority of CMX001 over placebo in prevention of CMV infection, as no therapy is currently approved for prevention of CMV in HSCT recipients. Failure to prevent CMV reactivation through Week 24 will be the primary endpoint for the trial. The trial is powered to detect a 50 per cent decrease in CMV reactivation in the subjects receiving CMX001 versus those on placebo.

SUPPRESS is anticipated to be conducted at approximately 40 sites, and is expected to begin dosing in mid-2013. Data from SUPPRESS are anticipated in 2015 and, if positive, may support accelerated approval of CMX001 for the prevention of CMV infection.

"Although great strides have been made in HSCT, we still face approximately 20 per cent non-relapse mortality in the first year after transplant, often related to infection. We are hopeful that through preventing reactivation of CMV, and the toxicity associated with preemptive therapy, we can begin to have a positive impact on the medical risks faced by HSCT recipients," said M Michelle Berrey, MD, MPH, chief medical officer of Chimerix. "We are enthusiastic about the opportunity to take CMX001 forward into a phase III study in these patients who have such a high unmet medical need."

In a post hoc analysis of the data from the phase II trial of CMX001 for CMV prevention, CMX001 was associated with a stable measure of kidney function in patients with evidence of BK virus (BKV) infection, known to be associated with kidney dysfunction in HSCT and solid organ transplant patients. These data were presented at the BMT Tandem meetings in February 2013, and represent the first evidence of a potential positive clinical effect of CMX001 in the setting of BKV. Secondary endpoints in the phase III SUPPRESS trial will include measures of CMX001 activity against BKV and other dsDNA viruses that have significant impact on the morbidity and mortality of patients undergoing HSCT.

Chimerix recently completed dosing CMX001 in a phase II trial in paediatric and adult stem cell transplant recipients with adenovirus (AdV) infection, a potentially fatal viral infection with no available therapies. Data from this trial will be available in the second half of 2013.

Chimerix's lead product candidate, CMX001, is a broad-spectrum oral nucleotide analogue that blocks replication of all five families of dsDNA viruses that infect humans, including CMV, AdV, BKV and herpes simplex viruses. In a phase II trial, CMX001 demonstrated potential clinical utility in prevention of CMV infection in high-risk patients who had received a HSCT. Chimerix anticipates initiating SUPPRESS, its phase III trial of CMX001 for the prevention of CMV infection in adults undergoing HSCT, in mid-2013. In December 2012, Chimerix completed enrollment of a phase II trial in pediatric and adult HSCT recipients evaluating CMX001 as a preemptive therapy for AdV disease, an often-fatal infection with no approved therapies. Since 2009, Chimerix has made CMX001 available through a Compassionate Use Program to over 80 medical centers worldwide for the treatment of over 430 patients with life-threatening dsDNA viral infections and no alternative treatment.

Chimerix is committed to the discovery, development and commercialization of novel, oral antiviral therapeutics designed to transform patient care in areas of high unmet medical need.