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Gallium-containing compounds are potent inhibitors of bone resorption. These agents target bone tissue and are actively incorporated into bone mineral at sites where bone is metabolically active.
Bone is a living tissue that is constantly being remodeled in response to the stresses of daily life. However, certain regions (i.e. the ends of long bones and in the middle interior regions of all bones) are more active than other sites (the outer cortex). The bone remodeling process is dynamic and generally in equilibrium, whereby bone resorption (breakdown) is generally balanced by new bone formation.
Many diseases are associated with accelerated bone loss, including osteoporosis, cancer, Paget’s disease, and others. In some diseases, the alteration in the bone remodeling equilibrium is subtle and slow, while in others it is very rapid and acute. For example, in osteoporosis, the most prevalent bone-losing condition, the process of bone loss extends over a period of years (even decades) before the disease manifests itself. Conversely, in cancer-related hypercalcemia, bone is being lost at such a rapid rate that it overwhelms the kidney’s ability to excrete calcium from the system. In this condition, the calcium level in the blood can rise to levels that can quickly become fatal.
Gallium reduces bone loss by inhibiting calcium resorption from bone. Preclinical evidence suggests that the mechanism of gallium action is multifactorial and different from other current therapies used to treat bone loss, such as estrogen or selective estrogen receptor modulators (SERMs), calcitonin, or bisphosphonates (e.g., Zometa® or Fosamax®). Gallium preferentially accumulates in metabolically active regions of bone, inhibits osteoclast-mediated bone resorption, and favorably alters bone mineral composition and properties.
Genta believes an important market opportunity exists for an orally bioavailable gallium-containing compound. An oral may potentially be used to both treat acutely life-threatening diseases, such as cancer-related hypercalcemia, as well as for diseases with less extreme bone loss, including bone metastases, Paget’s disease, or osteoporosis. G4544 could potentially be used for extended periods (i.e. over a period of years) at low doses in order to maintain bone integrity and to prevent complications associated with accelerated loss of bone mass, such as fractures and pain.
Genta’s immediate interest is to secure rapid regulatory approval for marketing in the U.S. by establishing bioequivalence of G4544 to our marketed product, Ganite®. Genta currently intends to develop plans for future clinical development in oncology, and the Company will seek a partner for development in osteoporosis and Paget’s disease.
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