Genta Incorporated has announced the release of final results from the Company's Phase 1 clinical trial of G4544, a proprietary small molecule that is intended as a treatment for diseases associated with accelerated bone loss. Results showed that the drug was very well-tolerated, and that blood levels were achieved in a range that is known to be clinically bioactive. The data were featured in a poster session at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago on Saturday, May 31, 2008.
G4544 is a new tablet formulation using delivery technology developed by Emisphere Technologies, Inc. that enables oral absorption of the active ingredient contained in Ganite(R) (gallium nitrate injection). Ganite(R) is marketed by Genta and is approved in the U.S. for treatment of cancer-related hypercalcemia that is resistant to hydration. Low doses of the active ingredient in Ganite administered by intravenous (IV) or subcutaneous injections have shown clinical activity in a range of skeletal diseases, including hypercalcemia, bone metastasis (myeloma and breast cancer), Paget's disease, and osteoporosis.
The Phase 1 clinical study tested escalating single doses of G4544 in 30 normal volunteers. The endpoints of the study were to determine safety and to assess pharmacokinetics and oral bioavailability. The drug was tested over a range of doses from 30 to 150 mg. No adverse effects attributable to G4544 were observed. The mean peak plasma concentration at the highest dose was approximately 0.4 micrograms/ml with a mean area under the plasma x concentration curve of approximately 20 micrograms/ml x hr.
"G4544 offers both ease of administration and patient convenience that could considerably expand the usefulness of this highly active compound," said Dr. Raymond P. Warrell, Jr., Chairman and Chief Executive Officer of Genta. "We concluded our initial conference with FDA's Endocrinology and Metabolism Division to clarify next steps. Completion of abbreviated toxicology work should enable multi-dose studies to proceed that are needed to secure regulatory approval. The published clinical activity using low doses should be highly informative in guiding further clinical development."
Experimental work by Genta personnel and others first established that low doses of the active ingredient in Ganite(R) directly inhibited calcium release from bone, principally by decreasing bone resorption and possibly by also stimulating bone formation.
Many diseases are associated with accelerated bone loss, including osteoporosis, bone metastases in cancer, Paget's disease, and hypercalcemia - a disease in which the rate of bone loss may become acutely life-threatening. In patients with cancer-related hypercalcemia who were resistant to hydration, randomized double-blind trials have been conducted with Ganite compared with calcitonin and with two bisphosphonates (etidronate [Didronel(R); Proctor and Gamble] and pamidronate [Aredia(R); Novartis, Inc.]).
G4544 was developed to enable extended administration of the active ingredient in Ganite, which may greatly improve patient convenience and avoid the current need for extended IV infusion or hospitalization. The initial focus of clinical studies with G4544 will be to evaluate bioequivalence with the IV product, potentially enabling rapid regulatory approval. Genta holds or has exclusively licensed the intellectual property related to G4544.