EXECUTIVE SUMMARY Project Synopsis The overall goal of this effort is to develop and evaluate a new therapy for treating acute myeloid leukemia (AML), a common and aggressive form of blood cancer. The applicant has developed a technology platform for producing small particles called nanomicelles, which can be imbued with drugs and decorated with biological molecules for delivering targeted doses of chemotherapy to diseased tissues. In this project, nanomicelles will be coated with peptide ligands recognizing a specific molecule on the surface of leukemic stem cells (LSC), the entities responsible for AML initiation and progression. Upon target recognition, the particles will release their payload, thereby enabling a concentrated dose of chemotherapy to be delivered directly to the LSC. In addition, drug released from nanomicelles directly into a patient’s circulation will enable leukemic cells and LSC-derivatives to be targeted throughout the body. Project goals include completion of manufacturing other preclinical activities to enable filing of an investigational new drug (IND) application. In addition, a Phase I clinical trial will be initiated to obtain safety and dosing information. Significance and Impact - The target product profile (TPP) is reasonable and addresses a significant unmet need for less toxic, more effective treatments for AML. However, some reviewers felt that the Phase I trial plan was not described in sufficient detail to determine its potential to inform the TPP. - The clinical impact of this approach may be limited. A number of other liposomal chemotherapies have been developed in industry and have provided only modest improvements in patient outcome. In addition, dose escalation studies suggested that only modest increases could be achieved when administering these drugs. Reviewers were uncertain whether the unique features of the proposed methodology would translate into meaningful advantages. - If successfully developed, this platform could prove broadly useful for delivering other types of cancer drugs to a desired target. - The proposal describes a single candidate and proposes activities that are fully in scope with the RFA. One or more project objectives are very likely to be achieved within the allotted time frame. Project Rationale and Feasibility - The rationale for specifically targeting LSC and leukemic cells to eradicate AML is strong, and the use of the proposed nanomicelle platform represents a clever extension of the applicant’s ongoing research. - Reviewers expressed mixed opinions about the validity of the LSC-targeting ligand. While one reviewer deemed it promising, others were skeptical, asserting that specificity of the target ligand to AML and LSCs is uncertain and no convincing data was provided to support the ligand as a robust target for LSCs in AML. - Much of the preclinical data provided to support this approach were obtained using different drugs and models than the ones to be developed and are therefore of questionable relevance for determining developmental readiness. - Reviewers considered the project plan to be overly aggressive for a four-year time frame. They recommended scaling goals back to IND-enabling preclinical studies and manufacture, as both sets of activities are likely to prove more involved and laborious than anticipated by the applicant. - Reviewers made the following suggestions to strengthen future submissions: Include greater discussion of potential mechanisms of drug resistance in AML with respect to the actual drug to be used; determine the release kinetics of the drug from nanomicelles, particularly for storage sterility and stability of clinical trial material for IND and eventual product; clarify efficacy of the actual product (specific ligand-nanomicelle- drug formulation) to be developed; provide more details on the clinical trial, including whether patients would receive standard of care in addition to the experimental treatment; discuss or consider duration of leukopenia as a potential safety issue. Principal Investigator (PI) and Planning Leader - The PI is a pioneer in combinatorial chemistry and nanotechnology with an extensive track record of publications and patents. He/she is an experienced basic and translational investigator and is well qualified to lead this effort. -The Planning Leader (PL) is scientifically qualified and has experience in conducting clinical trials and submitting INDs. However, he/she has a limited record of project management experience or leading a large group and keeping them on track. A reviewer recommended appointing a qualified industry-experienced project manager to assist the PL.