Tasidotin Hydrochloride

Tasidotin HCl (tasidotin) is a novel, third generation, synthetic, water-soluble, dolastatin pentapeptide analog of dolastatin 15.  Tasidotin is metabolically stable and orally bioavailable.

Tasidotin has a unique mechanism of action that appears to differ from other microtubule stabilizers such as taxanes and epothilones and tubulin inhibitors such as Vinca alkaloids.  Mechanistically, tasidotin is believed to inhibit cell proliferation by suppressing spindle microtubule dynamics through a reduction of the shortening rate, reduction of the switching frequency from growth to shortening and reduction of the time microtubules grow. 

Three Phase I dose-escalation studies have been conducted to evaluate tasidotin in adult patients with metastatic or inoperable solid tumors for which no standard therapy existed or that had progressed or recurred following standard therapy.

Phase II studies have been conducted in the following populations to further evaluate the efficacy of tasidotin administered intravenously (IV): melanoma, non-small cell lung cancer, and hormone-refractory prostate cancer. 

Overall, tasidotin (IV) was well tolerated, but did not show sufficient efficacy to warrant further single agent development using this route of administration. 

Tasidotin will be investigated as an orally administered antineoplastic agent (as the hydrochloride salt) for patients with advanced, refractory neoplasms based on new preclinical data.

GC1008

GC1008 is a pan-neutralizing IgG4 human antibody directed against all three isoforms of Transforming Growth Factor β (TGFβ).

TGFβ is implicated in the progression of late-stage tumors via a number of different mechanisms, of which the most notable is downregulation of the ability of the patient to mount an immune response to the tumor.  In preclinical research studies TGFβ has been shown to upregulate the production of regulatory T cells and downregulate the responsiveness of cytotoxic T lymphocytes, leading to compromised immune capability.  Metastatic melanoma and renal cell carcinoma (RCC) are being investigated as possible targets for anti-TGFβ therapy as both are known to be immunogenic cancers.

GC1008 is currently being studied in a Phase I/II dose-escalation study in patients with advanced metastatic melanoma or renal cell carcinoma (RCC).

GC1008 is also being investigated for focal segmental glomerulosclerosis (FSGS) and idiopathic pulmonary fibrosis (IPF).

Topoisomerase I Inhibitor

Genzyme Oncology is in preclinical development with a novel inhibitor of Topoisomerase I.

Topoisomerases are enzymes that play a pivotal role in facilitating DNA replication. Topisomerase I inhibitors based on camptothecin are an established class of agents playing important roles in the management of several types of cancer. 

Genzyme’s Topoisomerase I inhibitor is a novel non-camptothecin small molecule. The structure of the compound is designed to eliminate the lactone ring that is part of the camptothecin compounds. This significantly alters the metabolism of the drug and may provide the basis of the observed unique patterns of in vitro and in vivo preclinical activity.

Clinical investigation of the drug will include study of the effect of the compound on multi-drug resistant tumors and will also explore the development of biomarkers that might predict response to the drug.

Discovery Research

Genzyme Oncology is conducting an active internal discovery program to identify new agents for unmet needs in cancer. Approaches include target discovery using genomics technologies, identification of novel antibody and small molecule agents and validation using in vitro and in vivo testing. In addition Genzyme works closely with collaborators in academic institutions and is actively seeking in-licensing opportunities.

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