Grant: Collaborative Health Research Projects

While bone loss in osteoporosis is well treated today, therapy is usually initiated only after considerable bone loss has occurred. Therefore, there is an important medical need for agents that are effective at restoring lost bone to normal levels. Bisphosphonate compounds, for example, alendronate, are regarded as standards of care for treating osteoporosis and related bone diseases; these agents target and bind to bone, and halt and partially reverse osteoporotic bone loss by inhibiting osteoclasts, specialized cells that remove bone tissue.Unfortunately, bone loss reversal is small and unsustained, even after prolonged treatment. The natural hormone PGE2 stimulates bone growth via agonism at the EP4 receptor subtype in animals and in humans, but is associated with unacceptable side effects (generally gastrointestinal disturbance). To avoid these side effects and to derive an additive or synergistic effect for stopping bone loss in osteoporosis and restoring bone mass to normal levels, we have designed and synthesized several novel dual-action bone-targeting pro-drugs wherein alendronic acid is conjugated through an enzymatically-cleavable linker to one of two potent and selective EP4 receptor agonists. We have shown that when these conjugates are dosed intravenously, they are well tolerated acutely, and they are taken up by bone, where they bind to the bone tissue and liberate the two active drugs over an extended period of time. This project seeks to further optimize and characterize the best conjugates, to select the optimal compound, to define its minimum effective dose and optimal route of administration and then to develop an extensive preclinical data package, in collaboration with CDRD Ventures Inc. (CVI), that is suitable to support full clinical development of the drug. This approach offers the promise of a once-a-week or once-a-month treatment that will dramatically impact the health of millions of people in Canada and around the world.