DISCOVERY AND DEVELOPMENT OF CANCER THERAPEUTICS FOR NEXT PROGRAM

The mission of NExT is to develop agents that eventually become approved anticancer therapeutics. Numerous interconnected activities need to be successfully completed before an IND can be filed with the FDA to move into clinical trials. As is the case with scientific research projects, drug discovery is often fraught with unforeseen technical difficulties, biological dead ends, and the need to retrace one’s steps along the way.

Successfully navigating the drug discovery process requires the ability to quickly take advantage of new knowledge, the flexibility to change technical approach mid-stream, and an understanding that project timelines and budgets can and will deviate at many times along the way. Therefore, although the drug discovery process is often depicted as a linear series of stage gates, in reality projects seldom follow a predictable linear path, but rather entail the performance of numerous, not always sequential, and often iterative, activities, the exact timing of which can rarely be predicted a priori.

This has been one of the main, and in fact the hardest, lesson learned from more than a decade of drug discovery in DCTD.

DCTD’s mission to advance new therapies into patients requires that promising compounds navigate numerous technical activities in order to qualify for IND directed studies. This process includes the development of a high throughput screening assay, running the high throughput screen (often with >200,000 compounds), validation of hit compounds, development and use of secondary assays assessing the specificity and selectivity of the hit compounds against the target, medicinal and synthetic chemistry, in vitro and in vivo (e.g. animal) dose and schedule, efficacy, PK and PD studies in order to consider a compound sufficiently validated to have the intended biological outcome.

The experience of DCTD’s drug discovery efforts, over the past decade has demonstrated that 6 - 10-years is required to go from conducting a high-throughput screen to having a clinical candidate and conducting IND-enabling studies, and that many projects fail at different stages along the way to reaching that goal.

Under a previous NS TO (#34), the contractor successfully demonstrated the ability to deliver to NCI at least 1 Clinical Candidate (p97 AAA ATPase inhibitor), were close to nominating a Clinical Candidate for a second project (Mcl-1 inhibitor) when it was terminated by the applicant so they could pursue commercialization with a Pharmaceutical company, and were close to nominating a Clinical Candidate for a third

project (WDR5-MLL1 inhibitor) within a 5-year POP. At the conclusion of TO-34 we therefore initiated another NS-TO (20-019) with the same goal in mind to deliver at least 1 Clinical Candidate. Due to the nature of the deliverable, only projects which were further along in the pipeline were considered under the NS TO.

For this reason, NCI is submitting this new NS TO to allow for projects at earlier stages in the pipeline that, if successful, would feed into TO20-019. Additionally, this new Task Order would also allow for activities required subsequent to the identification of a Clinical Candidate, such as scale-up and manufacturing to support IND-enabling studies and Phase 1 Clinical Trials, particularly in the case of Biologics.