EXTON, Pa., Dec. 11 /PRNewswire-FirstCall/ -- ViroPharma Incorporated today announced additional supportive results from the company's Phase 2 evaluation of maribavir, an oral antiviral drug candidate in Phase 3 development to prevent cytomegalovirus (CMV) disease in transplant patients, at the 48th Annual Meeting of the American Society of Hematology (ASH), held in Orlando, Florida. Data from the Phase 2 study of maribavir presented at the meeting elaborates previously presented data on the antiviral activity and tolerability of the compound, and new data including the results of analyses of the rates of graft versus host disease (GvHD) in patients receiving maribavir compared to placebo. Additional data from a pharmacokinetic study in subjects with renal impairment were also presented.
"These data show that maribavir appears to be well-tolerated and had impressive anti-CMV activity in stem cell transplant patients," stated study lead author Drew Winston M.D., UCLA Medical Center. "This marks an exciting advancement for preventing this serious infection."
"This is the first presentation of a more extensive Phase 2 data set at a scientific meeting. These data clearly demonstrate, among other outcomes, that prophylaxis with maribavir significantly reduces the incidence of CMV infection in this population," remarked Stephen Villano, M.D., ViroPharma's vice president of clinical research and development. "In addition to the favorable overall safety profile, there was no evidence of myelosuppression or renal toxicity at any of the doses tested; these are essential elements of any future anti-CMV therapeutic. These results provide strong support for our ongoing phase 3 program studying CMV prevention in the stem cell transplant population."
Phase 2 Results in Stem Cell Transplant Recipients
The maribavir Phase 2 clinical trial was a randomized, double blind, placebo-controlled, dose-ranging study at 13 transplant centers across the U.S. involving CMV-seropositive subjects who have undergone allogeneic stem cell transplantation. A total of 111 subjects were randomized 3:1 to receive maribavir or placebo in each of three ascending dose groups (100 mg BID, 400 mg QD, 400 mg BID). All subjects were monitored frequently for CMV infection by CMV pp65 antigenemia and plasma CMV DNA PCR. If CMV was detected, study drug (maribavir or placebo) was discontinued and the subject was managed according to current standards of care at each transplant center, including starting preemptive anti-CMV treatment at the discretion of the investigator.
The objectives of this study included an evaluation of the safety and tolerability of maribavir administered orally for up to 12 weeks, and an evaluation of the prophylactic activity of maribavir in preventing CMV reactivation in CMV-seropositive recipients of allogeneic stem cell transplants. The term "prophylaxis" in this setting refers to therapy given to subjects starting before there is any evidence of CMV replication, to prevent CMV infection and in turn prevent CMV disease.
These Phase 2 data were presented at ASH in a presentation entitled "Prevention of CMV Disease in Allogeneic Stem Cell Transplant Recipients" by Drew Winston, M.D., UCLA Medical Center:
-- Incidence of CMV infection: Within the first 100 days post-transplant, separate analyses of the incidence of CMV infection as measured by different CMV assays such as CMV pp65 antigenemia or plasma CMV DNA PCR showed fewer CMV infections in each of the maribavir groups compared to placebo. -- In most cases, the reduction in rates of infection between patients in the maribavir groups and placebo were statistically significant (p= less than or equal to 0.05, Cochran-Mantel- Haenszel test). -- Analysis of patients receiving 100 mg BID of maribavir (the lowest dose and the dose taken into Phase 3 evaluation in SCT) showed statistically significant results compared to patients on placebo in the incidence of CMV infection, irrespective of the method used to detect CMV infection. -- Initiation of anti-CMV therapy: Analyses of initiation of anti-CMV therapy were consistent with the results for CMV infection, showing that fewer subjects in each of the maribavir groups required preemptive anti-CMV therapy compared to the placebo group. Results were statistically significant for the 100 mg BID and 400 mg BID dose groups (for each, 15 percent of subjects initiated anti-CMV therapy vs. 57 percent for placebo, p= less than or equal to 0.002). -- Incidence of CMV Disease: There were no cases of CMV disease in any of the maribavir groups during the study, which included follow-up to a maximum of approximately 150 days post-transplant for those completing 12 weeks of study drug therapy. In the placebo group, CMV disease occurred in 3 subjects (11 percent). -- Graft versus Host Disease: Moderate or severe GvHD is a potentially serious complication following allogeneic stem cell transplantation. GvHD occurred in only 14 percent to 29 percent of patients receiving maribavir, compared to 46 percent of patients receiving placebo. -- Mortality: In the maribavir treatment arms, only 11 percent to 14 percent of patients died during the entire study period, compared to 21 percent of those on placebo. The most common causes of death were relapse of underlying malignancy and GvHD. -- Safety and Tolerability: Maribavir administered for up to 12 weeks had a favorable tolerability profile: -- The most notable adverse events that appeared to be associated with maribavir were taste disturbance, nausea, and diarrhea. These effects may be dose-dependent. -- In the 100 mg BID dose group, the most commonly reported adverse event considered related to maribavir was taste disturbance (21 percent). -- A similar number of patients on placebo and the 100 mg BID dose of maribavir withdrew from the study due to what was considered to be a drug-related adverse event (11 percent vs. 14 percent, respectively). -- Laboratory data showed that maribavir did not cause myelosuppression or renal toxicity at any of the doses tested. Pharmacokinetic Data in Patients with Renal Impairment
In this open-label study, 31 subjects with varying renal function (12 with normal renal function; 10 with mild/moderate renal impairment; 9 with severe renal impairment) were enrolled. Following administration of a single 400 mg oral dose of maribavir, blood samples were collected through 36 hours post dose. Pharmacokinetic (PK) parameters for maribavir and VP 44469, maribavir's N-dealkylated metabolite, were assessed.
These data were presented at ASH by Dr. Villano in a poster entitled "Pharmacokinetics of Oral Maribavir, a Novel Anti-Cytomegalovirus agent, in Subjects with Renal Impairment".
Numerous pharmacokinetic parameters of maribavir, including Cmax (the highest concentration of drug in the blood), Tmax (the time it takes to reach the maximum concentration of drug in the blood), AUC (the overall amount of drug in the bloodstream) and t1/2 (the amount of time it takes for the drug concentration in the blood to decline by half) were assessed in this study. All parameters were found to be similar across all renal function groups, suggesting that renal impairment, a significant issue affecting transplant patients, does not affect the PK of maribavir.
These data also showed that a single oral dose of maribavir 400 mg was well-tolerated by subjects in all 3 renal function groups. No serious adverse events occurred during this study, and no subject withdrew from the study due to an adverse event. Taste disturbance was the only adverse event reported by more than one subject, occurring in six (50 percent) subjects with normal function, five (50 percent) with mild/moderate impairment, and two (22 percent) with severe impairment. No subject experienced any adverse event related to abnormal laboratory findings, vital signs, or ECG results.
Recent News
In September 2006, ViroPharma announced that it had initiated a randomized, double blind, placebo-controlled, multicenter pivotal Phase 3 study intended to enroll approximately 500 patients who have undergone allogeneic stem cell transplantation. Per the final protocol, following transplantation and transplant engraftment, eligible patients will be randomized to receive maribavir or matching placebo in a 2:1 randomization ratio. Patients will receive maribavir 100 mg BID or placebo for a maximum duration of 12 weeks.
The primary efficacy endpoint will be the incidence of CMV disease within 180 days post-transplant. Following extensive dialogue with the FDA, a number of key secondary endpoints associated with CMV reactivation have been identified and assessment of these endpoints will play an important part in assessing the clinical benefit of maribavir. These key secondary endpoints include incidence of initiation of preemptive anti-CMV therapy, incidence of graft-versus-host disease, mortality and CMV disease-free survival.
ViroPharma expects to initiate an additional Phase 3 trial in solid organ transplant patients in the first quarter of 2007. The company plans to submit the maribavir New Drug Application (NDA) with the U.S. Food and Drug Administration in 2009.
About Maribavir
Maribavir is a potent and selective, orally bioavailable, antiviral drug with a unique mechanism of action against cytomegalovirus and a favorable clinical safety profile through Phase 2 studies. It is a potent member of a distinct class of drugs called benzimidazole ribosides. Unlike currently available anti-CMV agents that inhibit CMV DNA polymerase, maribavir inhibits viral DNA assembly and inhibits egress of viral capsids from the nucleus of infected cells. Maribavir is active in vitro against strains of CMV that are resistant to commonly used anti-CMV drugs.
About Cytomegalovirus
CMV is a member of the herpes virus group, which includes the viruses that cause chicken pox, mononucleosis, herpes labialis (cold sores), and herpes genitalis (genital herpes). Like other herpesviruses, CMV has the ability to remain dormant in the body for long periods of time. Human CMV infection rates average between 50 percent and 85 percent of adults in the U.S. by 40 years of age, but in healthy adults causes little to no apparent illness. However, in immunocompromised individuals including cancer patients, HIV patients, and transplant patients, and in children born with primary CMV infection, CMV can lead to serious disease or death. Patients who are immunosuppressed following hematopoietic stem cell (bone marrow) or solid organ transplantation are at high risk of CMV infection. In these patients, CMV can lead to severe conditions such as pneumonitis or hepatitis, or to complications such as acute or chronic rejection of a transplanted organ. While currently available systemic anti-CMV agents are effective against the virus, their use is limited by toxicities, most notably bone marrow suppression and renal impairment.
About ViroPharma Incorporated
ViroPharma Incorporated is a biopharmaceutical company dedicated to the development and commercialization of products that address serious diseases treated by physician specialists and in hospital settings. ViroPharma commercializes Vancocin(R), approved for oral administration for treatment of antibiotic-associated pseudomembranous colitis caused by Clostridium difficile and enterocolitis caused by Staphylococcus aureus, including methicillin- resistant strains (for prescribing information, please download the package insert at http://www.viropharma.com/docs/pulvules_pi.pdf). ViroPharma currently focuses its drug development activities in viral diseases including cytomegalovirus (CMV) and hepatitis C (HCV). For more information on ViroPharma, visit the company's website at http://www.viropharma.com/.
Certain statements in this press release may contain forward-looking statements that involve a number of risks and uncertainties, including those relating to our expected timeframe to initiate an additional Phase 3 study in solid organ transplant, and the plan to file the maribavir New Drug Application (NDA) with the U.S. Food and Drug Administration in 2009. Our actual results could differ materially from those results expressed in, or implied by, these forward-looking statements. The development and commercialization of pharmaceutical products is subject to risks and uncertainties. Further testing such as the Phase 3 clinical trials, may not support any or all of the statements in this press release. There can be no assurance that the solid organ transplant Phase 3 study will be initiated within the timelines described in this press release or at all, that our Phase 3 program will yield positive results, that our NDA will be filed in 2009, or that maribavir will ever be approved by the FDA. These factors, and other factors, including, but not limited to those described in ViroPharma's quarterly report on Form 10-Q for the quarters ended March 31, 2006, June 30, 2006 and September 30, 2006 filed with the Securities and Exchange Commission, could cause future results to differ materially from the expectations expressed in this press release. The forward-looking statements contained in this press release may become outdated over time. ViroPharma does not assume any responsibility for updating any forward-looking statements.
