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MMPD (new HCV Drug), Pegasys, & Ribavirin Study
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Vertex Press Release: Vertex Announces Ph IIb METRO Study & Supply Agreement w/Roche
Vertex Pharmaceuticals Announces Plans for the METRO Study: Triple Combination of Merimepodib (MMPD), Pegasys(R) and Copegus(R) in Hepatitis C Patients
-- Roche Agrees to Provide Pegasys and Copegus for Phase IIb Clinical Trial --
In this report below you will find explanation of the planned study, description of MMPD, and report on Phase II study results from recent EASL Conference in Berlin in April 2004.
CAMBRIDGE, Mass., May 25 /PRNewswire-FirstCall/ -- Vertex
Pharmaceuticals Incorporated (Nasdaq: VRTX) announced today the design of a Phase IIb clinical that it plans to conduct with merimepodib (MMPD), an investigational oral therapy for the treatment of hepatitis C virus (HCV) infection, in patients who are non-responders to prior treatment with pegylated interferon (peg-IFN) and ribavirin. The clinical trial will be conducted at centers in the United States and is expected to enroll approximately 315 patients who will receive merimepodib or placebo in combination with Pegasys(R) (peginterferon alfa-2a) and Copegus(R) (ribavirin). Roche will provide Pegasys and Copegus to Vertex for use in this study, providing support for the clinical development of merimepodib as an investigational agent that may enhance the antiviral activity of Pegasys and Copegus, which is the most frequently prescribed treatment combination for HCV infection in the United States. As part of the supply agreement with Roche, Vertex will share data and data analysis with
Roche at predetermined intervals during the course of the study. Vertex owns worldwide development and commercialization rights to merimepodib."HCV-infected patients who do not respond to initial combination therapy with pegylated interferon plus ribavirin face limited treatment options and the prospect of worsening liver disease," stated John J. Alam, M.D., Senior Vice President of Drug Evaluation and Approval at Vertex. "Preclinical and clinical data reported to date for merimepodib, Vertex's lead oral therapy for HCV infection, have highlighted the potential for this drug candidate to enhance the standard of care in hepatitis C. In this Phase IIb clinical trial, we will seek to evaluate the ability of a triple combination of merimepodib plus peginterferon alfa-2a and ribavirin to increase viral clearance in patients who are refractory to prior combination treatment."
Report on Phase II Study of MMPD (or VX-497) plus Peginterferon and Ribavirin
Reported by Jules Levin
At the 39th EASL Conference in Berlin, Germany April 2004, P Marcellin reported on 31 patients who were randomized to receive PegIntron dosed at 1/5 mg/kg/wk plus ribavirin (800, 1000, or 1200 mg/day, based n body weight); and patients were randomized to receive placebo, 25 mg MMPD twice daily or 50 mg MMPD twice daily. Here is the report from EASL by Marcellin. MMPD demonstrated potent antiviral activity in the HCV replicon system. The authors concluded 25 & 50 mg doses of MMPD were well tolerated. At week 24, the addition of 50 mg MMPD twice daily showed an enhanced antiviral effect compared with PegIFN/RBV alone, as measured by the proportion of subjects undetectable at week 24 in the 50 mg MMPD group. Attrition (breakthrough/relapsers) will need to be accounted for in subsequent studies in non-responders.
Patients were genotype 1 and non-responders to standard interferon treatment with IFN-a/RBV combination therapy. Patients were randomized for 24 weeks (CORE Study) and those with undetectable HCV RNA received another 24 weeks (Extension Phase) of therapy. All patients were followed for sustained viral response. Average age was 48-51. 18 men. 30 caucasians. Mean weight 64 kg in 25 mg arm, 72 kg in 50 mg arm, 75 kg in placebo arm. Log HCV RNA at baseline about 8.50. ALT at baseline 71-85 IU/L. They used an ITT analysis (any subject who received one dose of study treatment). And they also used a Completers (COMP) analysis (any subjects who completed the 24-week Core Study).
Preliminary week 24 viral responses were reported. Using the ITT analysis, "responders anytime": 8/11, 73% in the 50 mg MMPD arm; in the 25 mg MMPD arm, 2/10, (20%), in placebo, 3/10 (30%). Using COMP analysis, "responders at week 24": 3/9 (33%) in placebo; 2/6 in 25 mg arm; 6/7 (86%) in 50 mg MMPD arm.
11 subjects who were HCV RNA undetectable at week 24 were offered an additional 24 weeks of study treatment in the Extension Phase. The rate of breakthrough/relapse seen was consistent with other studies of re-treatment in nonresponders: 1 of 3 control subjects and 3/7 MMPD-treated subjects who were responders at week 24 and completed the Extension Phase achieved an SVR at week 72. Safety profile reported for continued treatment is consistent with CORE Study. On MMPD, no adverse events of abdominal pain were reported: 1 subject reported diarrhea and 1 subject reported fatigue. One subject discontinued in the Extension Phase for hyperthyroidism.
In the CORE Study (first 24 weeks): 4/11 withdrew from 50mg MMPD arm; 4/11 withdrew from 25mg MMPD arm; 1/11 from placebo. Completed= 9 in placebo, 6 in 25 mg, and 7 in 50mg. Withdrawn prior to extension: 6 (treatment failure) in placebo, 4 (3-treatment failure) in 25 mg MMPD, 1 in 50 mg MMPD (1 treatment failure).
SAFETY RESULTS
Adverse events profile was similar to that seen with interferon-based therapies. Hemoglobin (g/L) declined at week 4, -31, -20, and --22 in the placebo, 25 mg MMPD, and 50 mg MMPD arms, respectively. At week 24 declines were --31, -26, and --24 in the 3 arms respectively. At week 48, declines were --37, -31, and --24, respectively. Decline in platelets (GI/L): week 4, -20, -22, and --4.5, in PLB, 25 mg, & 50 mg arms, respectively. At week 24: -33, -42, and --53, respectively. At week 48: -31, -44, and --23, respectively. Neutrophils (GI/L): at week 4, -1.4, -3.0, and --1.5, respectively. At week 48: -1.4, -2.8, and --1.2, respectively.
ALT
Median ALT at baseline was 71 in placebo, 71 in 25 mg MMPD, and 67 in 50 mg MMPD. At week 48, median ALT was 40 (n=3), 40 N=2), and 18.5 (n=6), in the 3 arms, respectively.
Adverse events reported more frequently in the placebo than MMPD groups (difference >15%): fatigue (33% vs 10%); diarrhea (24% vs 0%); injection site erythema (50% vs 10%); tachycardia and gastroesophageal reflux disorder (20% vs 0%). 4 subjects discontinued for adverse events: 2 subjects for low hemoglobin (both in 50 mg MMPD), one for xerosis (25 mg MMPD) and one for vagal atrial fibrillation (placebo). Two serious adverse events considered at least possibly related to study treatment both resolved without stopping medications: asthenia with depressive syndrome; vomiting.
Merimepodib Triple Combination Study (The METRO Study)
The MErimepodib TRiple cOmbination study (the METRO study) has been designed as a double-blind, placebo-controlled, randomized Phase IIb study, with a goal of evaluating the antiviral activity of two doses of merimepodib (MMPD) in combination with Pegasys and Copegus. Vertex anticipates that the trial will enroll approximately 315 patients who were previously non-responders to combination therapy, defined as at least 12 weeks of prior pegylated interferon-alfa and ribavirin treatment without having achieved undetectable HCV-RNA (< 50 I.U.) at any timepoint. The trial is designed so that patients will be treated with 50 mg MMPD, 100 mg MMPD, or placebo twice daily in combination with standard doses of Pegasys and Copegus for an initial period of 24 weeks. At the end of 24 weeks, patients with undetectable HCV-RNA will receive combination therapy with Pegasys and Copegus, only, for an additional 24 weeks. Patients completing the 48-week treatment period will be followed for an additional 24-week treatment-free period.
The study is expected to involve more than 40 clinical centers and will be conducted in the United States. Study site selection is underway, and the first centers are expected to begin enrolling patients in the third quarter of 2004.
The goal of the METRO study will be to evaluate the safety, pharmacokinetics and efficacy of MMPD in combination with pegylated interferon. The primary endpoint of the study is to evaluate the antiviral activity of MMPD and perform an assessment of the proportion of MMPD-treated patients who achieved a sustained virologic response (SVR) compared to placebo at week 72 (end of follow-up). Secondary endpoints include evaluation of the antiviral activity of MMPD-treated patients at 12, 24, and 48 weeks. The doses and duration of MMPD treatment in this study have been selected based on comprehensive analysis of the relationship between plasma exposure and antiviral effect in previous clinical studies of merimepodib, as well observations from previous clinical studies that suggest that merimepodib enhances the antiviral activity of combination therapy primarily in the first 24 weeks of treatment.
About Merimepodib and HCV
Merimepodib is a small molecule, orally administered inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH). IMPDH inhibition leads to a reduction in intracellular guanosine triphosphate (GTP), a molecule required for DNA and RNA synthesis. Six-month results from a Phase II study presented at the Annual Meeting for the European Association for the Study of the Liver (EASL) demonstrated that relative to placebo treatment, merimepodib treatment produced a statistically significant, dose-dependent increase in the percentage of treatment-refractory patients with HCV genotype 1 who achieved undetectable levels of HCV-RNA at six months.
Recent reports in the medical literature suggest that IMPDH inhibitors such as merimepodib may enhance the antiviral activity of ribavirin in vitro by depleting GTP and increasing the rate of incorporation of ribavirin into viral RNA, rendering the virus nonfunctional. The antiviral activity observed clinically when merimepodib is added to ribavirin-containing HCV therapies is consistent with these preclinical findings.
In combination with the standard of care, MMPD may help to increase the sustained viral response rate in HCV patients, the principal goal of treatment. Chronic hepatitis C virus (HCV) infection is a serious public health concern affecting approximately 2.7 million people in the United States. HCV causes inflammation of the liver, which may lead to fibrosis and cirrhosis, liver cancer, and ultimately, liver failure. Cirrhosis of the liver resulting from chronic HCV infection is the leading indication for liver transplantation in the U.S. Due to the asymptomatic nature of HCV infection, it often goes undetected for up to 20 years following initial infection. Worldwide, the disease strikes as many as 185 million people. Each year, 8,000 to 10,000 people in the U.S. die from complications of HCV.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical partners. Vertex's product pipeline is principally focused on viral diseases, inflammation, autoimmune diseases and cancer.
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading innovation-driven healthcare groups. Its core businesses are pharmaceuticals and diagnostics. Roche is number one in the global diagnostics market, the leading supplier of pharmaceuticals for cancer and a leader in virology and transplantation. As a supplier of products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche employs roughly 62,000 people in 150 countries. The Group has alliances and research and development agreements with numerous partners, including majority ownership interests in Genentech and Chugai.
This press release may contain forward-looking statements, including statements that (i) merimepodib holds promise as part of combination therapy for HCV patients who have limited treatment options and represents an attractive commercial opportunity for Vertex; and (ii) a Phase IIb clinical study of merimepodib will be initiated in the second half of 2004. While management makes its best efforts to be accurate in making forward-looking statements, such statements are subject to risks and uncertainties that could cause Vertex's actual results to vary materially. These risks and uncertainties include, among other things, the risks that clinical trials for merimepodib may not be initiated or, if initiated, may not proceed as planned due to technical, scientific, or patient enrollment issues, that results from planned clinical trials with merimepodib will not reflect the positive results from earlier trials, that positive nonclinical study results for merimepodib will not be duplicated in future nonclinical or clinical studies and other risks listed under Risk Factors in Vertex's form 10-K filed with the Securities and Exchange Commission on March 15, 2004. Lexiva(TM) is a registered trademark of the GlaxoSmithKline group of companies. Vertex's press releases are available at www.vrtx.com.
SOURCE- Vertex Pharmaceuticals Incorporated Corporate Communications(T) 617-444-6668
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