PharmaMar Presents the First Results of its Pharmacogenomics Anticancer Drug Development Programme at the EORTC-NCI-AACR Conference

Geneva, Switzerland (ots/PRNewswire) - PharmaMar presented data from six studies, four of which were from pharmacogenomics research projects at the EORTC-NCI-AACR[1] International Conference on Molecular Targets and Cancer Therapeutics, held in Geneva, Switzerland, from 28 September to 1 October 2004. Pharmacogenomics is the science that examines the inherited variations in genes which dictate drug response and explores the way these variations can be used to predict how a patient will respond to a given drug. PharmaMar launched its pharmacogenomics research programme two years ago on the basis of data generated from its clinical trials of Yondelis, Aplidin and Kahalalide F. Whereas all three of these drugs have been shown in clinical trials to be active in pre-treated cancer patients, as with all drugs, not all patients benefit from such treatment. This research programme examines polymorphisms(i), gene expression levels and gene mutations to predict the impact of a given treatment on different groups of cancer patients and provides a tool to develop customised chemotherapy models for individual patients. The pharmacogenomics results presented at the EORTC-NCI-AACR Conference reported on two studies of Yondelis, one of Aplidin and one of Kahalalide F. YondelisTM An in vitro study completed in collaboration with the Spanish National Cancer Centre (CNIO) identified a set of genes whose expression is correlated with sensitivity and resistance to Yondelis. The data provides a rationale to explore at the clinical level whether this correlation can contribute to the identification of those patients who might benefit from Yondelis therapy. A second, multi-centre retrospective pharmacogenomics study (UZ Gasthuisberg (Belgium), Memorial Sloan-Kettering Cancer Centre (US) and Hospital Universitari Germans Trias i Pujol (Spain)), aimed to correlate some DNA polymorphisms and mRNA expression levels of some DNA repair related genes, in paraffin embedded tumor samples, with the clinical outcome of 53 sarcoma patients included in the study after Yondelis therapy. The goal of such studies was the characterisation of patients prone to respond to Yondelis, which is a step towards the development of customised therapeutic approaches. The results conclude that low expression of BRCA1 mRNA is associated with better Progression Free Survival (PFS) and statistically significant longer survival of sarcoma patients after treatment with Yondelis and that high mRNA expression levels of XPD or ERCC1 genes do not have a negative impact on the clinical outcome of those patients. Also, polymorphisms Lys751Lys and Asp312Asp genotypes in XPD gene are associated with better clinical outcomes. These results warrant additional prospective studies for patient selection based on molecular markers. A preclinical study (in collaboration with the Università Cattolica Sacro Cuore of Rome and the Istituto di Ricerche Farmacologiche Mario Negri of Milan) on the effect of YondelisTM in combination with Irinotecan - the topoisomerase I inhibitor - in vitro and in vivo in xenograft models, showed that the combination of the two drugs produced a greater anti-tumoural effect than that achieved when each drug is given as a single agent. This result suggests that this combination should be further studied in clinical trials for the treatment of patients with rhabdomyosarcoma. A fourth poster reporting on the results of a clinical trial of Yondelis performed in San Antonio, Texas, compared the tolerability of Yondelis when administered as a 1-hour weekly infusion with the results of a prior study of a 3-hour infusion. The study demonstrated that the 1-hour weekly infusion was similarly tolerated to the 3-hour schedule and concluded that the 1-hour weekly infusion of Yondelis is convenient, active and well tolerated. Clinical activity has been seen in selected soft tissue sarcoma subtypes. Aplidin(r) A study on the gene expression profiling of leukaemic blasts and the correlation with their sensitivity to Aplidin showed that genes in Acute Myeloblastic Leukaemia(ii) samples resistant to Aplidin are involved mainly in NF-kB activation. In contrast, Acute Lymphoblastic Leukaemia(iii) samples sensitive to Aplidin presented higher expression of DNA damage response genes. The data presented supports the idea of a differential profile applicable to leukaemic cells sensitive to Aplidin and offers a framework for validation studies in phase II trials. This study was completed in collaboration with CNIO of Spain and the VU University Medical Centre of The Netherlands. Kahalalide F (KF) The study (conducted in collaboration with VU University Medical Centre, Amsterdam) concluded that ErbB3 and Akt are major determinants of the cytotoxic activity of KF in vitro. These results should be considered in upcoming phase II clinical trials of KF. Dr José Jimeno, VP of Scientific Development and Pharmacogenomics Programmes at PharmaMar, said: "Our commitment to fuse classical clinical development with a programme of rational and ethical pharmacogenomics studies is key to the growth strategy of Pharmamar. We believe this can only lead to better use of our marine anticancer drugs and therefore much higher patient benefit." i) Polymorphism - the occurrence of more than one form of individual in a single species with an interbreeding population. ii) Acute Myeloblastic Leukaemia - a form of leukaemia, which is characterised by the proliferation of immature white blood cells (granulocytes) in the bloodstream. Occurs primarily in adults and in infants under 1 year of age. Complications include abnormal bleeding and susceptibility to infections. iii) Acute Lymphoblastic Leukaemia - the most common form of childhood cancer. It affects lymphocytes, a type of white blood cells. Leukaemic cells accumulate in the bone marrow, replace normal blood cells and spread to other organs including liver, spleen, lymph nodes, central nervous system, kidneys and gonads. PharmaMar PharmaMar is a biopharmaceutical company, advancing cancer care through the discovery and development of innovative marine-derived medicines. PharmaMar's clinical portfolio currently includes YondelisTM in phase II clinical trials (co-developed with Johnson & Johnson Pharmaceutical Research & Development), designated Orphan Drug for STS by the EMEA in 2001 and Orphan Drug for ovarian cancer in 2003; Aplidin(R), in phase II, designated Orphan Drug for acute lymphoblastic leukaemia by the EMEA in 2003 and by the FDA in 2004; Kahalalide F in phase II and ES-285 in phase I clinical trials. PharmaMar, based in Madrid, Spain, is a subsidiary of the Zeltia Group (Spanish stock exchange: ZEL.MC; Bloomberg: ZEL SM; Reuters: ZEL.MC). PharmaMar can be found on the Web at [1] EORTC-NCI-AACR: European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research ots Originaltext: PharmaMar Im Internet recherchierbar: Contact: For more information, please contact: Lola Casals, PharmaMar, Tel: +34-91-846-6000 David Yates & James Strong, Financial Dynamics, Tel: +44-(0)20-7831-3113

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