Paving the Way to Phase 2 Trials of CMS121 for Alzheimer's Disease

Nearly all of the many therapeutic drug candidates for the treatment of Alzheimer's Disease (AD) have failed in clinical trials. Although the two recently approved drugs for AD reduce Aβ plaque load, their long-term effects on the key clinical aspects of the disease, such as impaired memory and loss of executive function, are not yet clear. Thus, there is a continued need for additional AD drug candidates, especially ones that address these debilitating features of AD that play a major role in its impact on quality of life. A truly disease-modifying drug with long-term therapeutic benefits would be a tremendous benefit to the millions affected by AD. CMS121 was derived using a novel approach to AD drug development and interacts with targets distinct from those of other AD drugs and drug candidates, thereby providing an altogether new approach to disease treatment. CMS121 was developed in conjunction with Salk Institute scientists. The parent compound, identified from a broad screen of compounds for neuroprotective activity, was modified to obtain a series of derivatives with vastly superior neuroprotective and pharmacological characteristics. The derivative, CMS121, prevents and even reverses multiple behavioral changes, including loss of short- and long-memory and executive function, that are associated with AD and age-related cognitive impairment in both genetic and sporadic mouse models of the disease. CMS121 is an orally-delivered, small molecule that offers a novel therapeutic approach for the treatment of AD and has now been shown to be safe in healthy human subjects dosed daily for 7 consecutive days in a recently completed First-In-Human Phase 1 clinical trial. With the conclusion of the successful Phase 1 trial, in which no serious adverse effects were observed, our goal now is to advance CMS121 toward a Phase 2 clinical trial. In this application we request funding to accomplish two critical components needed to support a longer-term clinical trial. 1) A 13-week toxicology study in rats and dogs is proposed which will allow a similar 13 weeks or possibly longer daily dosing of human MCI and AD subjects with mild to moderate disease. The 13-week toxicology study is a critical step toward long term treatment of human patients. 2) The second component of this proposal is the development of a tablet formulation of CMS121 to replace the use of capsules. For the Phase 1 trial, CMS121 was loaded manually into capsules for dosing. Tablets will provide multiple important advantages over capsules for the upcoming clinical trials of CMS121.