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MethylGene Discloses Preliminary MGCD0103 'an Oral HDAC Inhibitor' Phase I Clinical Data at ASCO-Interim Results Reported for Ongoing Clinical Trials.

MONTREAL -- MethylGene Inc. (TSX:MYG), a biopharmaceutical company focused on cancer and infectious disease, today announced preliminary Phase I clinical data for its oncology product candidate, MGCD0103, an oral, non-hydroxamate, isotypic selective histone deacetylase (HDAC) inhibitor.The preliminary results demonstrated the safety, tolerability, pharmacokinetic and pharmacodynamic properties of MGCD0103 in patients with advanced solid tumours and non-Hodgkin's lymphoma. The updated preliminary results were released in conjunction with two abstracts published in the Proceedings of the 2005 American Society of Clinical Oncology's (ASCO) annual meeting in Orlando, Florida being held from May 13-17, 2005.

An abstract entitled "Phase I trials of the oral histone deacetylase (HDAC) inhibitor MGCD0103 given either daily or 3x weekly for 14 days every 3 weeks in patients with advanced solid tumours," highlighted preliminary and interim results of two Phase I trials in patients with advanced solid tumours and non-Hodgkin's lymphoma. The primary purpose of these open label, dose escalation, multi-center clinical trials, conducted in the United States and Canada, was to determine the safety, maximum tolerated dose (MTD), dose-limiting toxities (DLT), pharmacokinetics, and pharmacodynamic properties of MGCD0103 in patients with relapsed or refractory advanced tumours. Disease response is also being evaluated. Available peripheral blood samples from patients in these trials are also being evaluated for histone H3 and H4 acetylation and inhibition of total cellular HDAC activity. Thirty-three eligible patients were given oral doses ranging from 12.5-36mg/m2 either daily for 14 days every 3 weeks or 3x per week for 2 weeks every 3 weeks. In the daily dosing schedule trial, 12 patients were enrolled. The DLT on this schedule was fatigue and the MTD was12.5mg/m2. In the 3x weekly trial, 21 patients have been evaluated and received a total of 46 cycles. These patients were enrolled into four cohorts (12.5, 20, 27, or 36mg/m2). These results demonstrated that MGCD0103 was administered safely and repetitively in patients with advanced solid malignancies at doses up to, and including 36mg/m2, 3x/week in 3 week cycles. Pharmacokinetic evaluation and pharmacodynamic assessments of enzyme activity in buffy coat white cells were performed in all patients. Initial results indicated that the majority of patients in both trials showed increases in histone acetylation and/or decreased total cellular HDAC activity using MethylGene's proprietary Whole Cell assay. MGCD0103 is orally available and preliminary pharmacokinetics indicated that the Cmax and AUC were generally dose-proportional. The mean terminal plasma half-life of 9.1 hours was seen across the dose cohorts. Moreover, initial pharmacodynamic data suggested that, in some patients, the inhibition of HDAC activity in whole cells extended beyond the plasma half-life of the drug, lasting as long as 48 hours post-drug administration. Preliminary efficacy results showed 1 patient with previously treated thymic carcinoma experienced stable disease and received 7 cycles on the daily dosing schedule. A second patient who was previously treated, with renal cell carcinoma experienced stable disease and received 6 cycles on the 3x per week schedule. The most common adverse events observed in this study included fatigue, nausea and anorexia, the majority of which were all less than or equal to Grade 2. No significant myelosuppression was observed in patients on either trial. All patients were also monitored by ECG both prior and post the initial administration of MGCD0103. Preliminary evaluation indicated that no clinically significant ECG abnormalities have been reported to date. MethylGene expects enrolment for the 3x weekly trial to be completed and additional results available by year end 2005.

"The preliminary data suggest that the absence of hematological side effects and ECG abnormalities, coupled with a favourable half-life positively differentiates MethylGene's compound from some of the other HDAC inhibitors in clinical trials," commented Dr. Jeffrey M. Besterman, Senior Vice President, Research & Development for MethylGene.

A second abstract entitled "Pharmacodynamic effect of MGCD0103 on histone deacetylase (HDAC) enzyme inhibition and histone acetylating induction in Phase I clinical trials in patients with advanced solid tumours or non-Hodgkin's lymphoma" disclosed novel methods used to monitor the pharmacodynamic effect of MGCD0103 in clinical samples and outlined the positive correlation between HDAC enzyme inhibition, determined using MethylGene's proprietary Whole Cell assay, and histone acetylation in peripheral white cells from patients treated with MGCD0103. MethylGene used two novel methods for assaying histone acetylation in patients: ELISA and fluorescence-based (FACS) cytometry. Both methods measured histone acetylation with improved sensitivity compared to immunoblotting-based methods. HDAC enzyme inhibition and induction of histone acetylation in patients treated with MGCD0103 are well correlated. In patients with greater than 20% total enzyme inhibition, 50% exhibited induction of histone acetylation, while in patients with greater than 50% enzyme inhibition, 67% exhibited induction of histone acetylation.

"The ability to detect HDAC inhibition by MGCD0103 in patients means that we can now assess a pharmacodynamic response and better understand the relationship between pharmacokinetics, pharmacodynamics and clinical benefit for MGCD0103.We are encouraged by the preliminary results emerging from these Phase I studies.These trials have helped set the stage for further Phase I/II combination trials and/or Phase II monotherapy trials, the first to start in the third quarter of 2005," said Mr. Donald F. Corcoran, President & CEO of MethylGene.

MGCD0103 has also begun Phase I evaluation in hematological malignancies.The Company continues to enroll patients in an open label, dose escalating multi-center 3x weekly schedule in refractory hematological tumours such as AML, CML and advanced MDS.A second dose escalating, open label, multi-center hematological trial using a twice weekly dosing is expected to be initiated in the second quarter of 2005.

About MethylGene

MethylGene is a publicly traded biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics in cancer and infectious disease.Two cancer product candidates, MG98, partnered with MGI PHARMA, Inc. for North America and MGCD0103, partnered with Taiho Pharmaceutical Co., Ltd. for certain Asian countries, are currently in clinical trials.

MG98 has entered a randomized two-step Phase II combination trial with interferon alpha in metastatic renal cell cancer.MGCD0103 is currently in Phase I dose-escalation monotherapy trials against solid tumours and hematological malignancies.In collaboration with Merck, MethylGene is developing small molecule beta-lactamase inhibitors to overcome antibiotic resistance.MethylGene has a portfolio of preclinical programs for its multi-targeted kinase and histone deacetylase (HDAC) inhibitors for both oncology and non-oncology indications, and is exploiting its core HDAC expertise for the treatment of neurodegenerative diseases with EnVivo Pharmaceuticals, Inc.Please visit MethylGene's website at

Except for historical information, this news release may contain forward-looking statements, which reflect the Company's current expectation regarding future events.These forward-looking statements involve risk and uncertainties(which can be found in the Company's Annual Information Formfor the year ended December 31, 2004, and can be found on which may cause but are not limited to, changing market conditions, the successful and timely completion of clinical studies, the establishment of corporate alliances, the impact of competitive products and pricing, new product development, uncertainties related to the regulatory approval process and other risks detailed from time to time in the Company's ongoing quarterly and annual reporting.
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Publication:Business Wire
Geographic Code:1CANA
Date:May 16, 2005
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