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NIH/NCI 471 - Drug-Loaded Carrier Particles for Improved Oral Delivery for Colon Cancer Prevention

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 2-4

Budget (total costs, per award):

Phase I: up to $400,000 for up to 12 months

Phase II: up to $2,250,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Patients with inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease, are at an increased risk of colorectal cancer (CRC). Existing IBD treatments do not achieve long-term remission in the majority of the estimated 3.1 million IBD patients. The risk of CRC in these individuals therefore progressively increases throughout their lifetime. The cumulative risk of UC-associated CRC was 2%, 8%, and 18% after 10, 20, and 30 years, respectively. Thus, cancer prevention is the key to achieving better health outcomes for these high-risk individuals. 

CRC prevention in IBD patients requires not only the development of safe and efficacious agents, but also a safe and effective drug delivery system targeting the cancer-predisposed colon. Emerging evidence indicates that carrier particles (e.g., microspheres, nanoparticles) can address limitations of conventional oral drug delivery platforms by allowing agents to pass through biological barriers without degradation and providing sustained release of agents in the colon with improved bioavailability and reduced systemic toxicity. Some examples of agents being developed as carrier particle formulations targeting colon include mesalazine, 5-fluorouracil, progesterone, curcumin, and hydrocortisone. However, there remain challenges including confirmation of efficacy of the agent-loaded carrier particles in relevant animal IBD models and optimization of formulations to improve encapsulation efficiency, sustained release, controlled release, reproducibility, and mass production of dosage forms. The successful development and commercialization of carrier particles for drug delivery to the colon could be transformative for IBD patients and lead to better survival rates, improved quality of life, and increased treatment adherence.


Project Goals

The goal of this topic is to further the development of oral carrier particle formulations with CRC preventive agents by confirming efficacy and optimizing prevention regimens in suitable IBD animal models. Carrier particle formulations supported under this topic are expected to better protect agents from the harsh gastrointestinal environment, reduce the first pass metabolism, enhance the half-life and bioavailability of the agent, ideally reduce dosing requirements, and provide prolonged and constant colon concentrations with a wider therapeutic index for lower drug toxicities.

Projects supported under this contract topic should extend the formulation development and testing of carrier particles in suitable in vivo animal models for oral delivery of cancer prevention agents to the colon. The carrier particles may include but are not limited to microspheres, nanoparticles, liposomes, and hydrogels. Projects aiming to enhance the efficacy of cancer preventive agents or reduce the toxicities or the severity and duration of adverse effects of the agents using carrier particles will be supported. Agents may include but are not limited to small molecules (e.g., mesalazine, sulfasalazine, JAK inhibitors, SIP receptor modulators, and STAT3 inhibitors) and biologics (e.g., infliximab, adalimumab, risankizumab, and Myc-targeting biologic agent), which have shown preclinical or clinical activity in IBD treatment and/or colon cancer prevention. Responsive proposals under this topic should have: an identified IBD cohort (UC or Crohn’s); relevant IBD animal models that recapitulate the IBD disease pathophysiology, IBD-associated CRC onset and progression, and disease outcome (e.g., AOM/DSS colitis model); a validated CRC preventive target and agent; an optimized carrier particle formulation; and preliminary data using appropriate in vitro models (cell lines and/or intestinal organoids) that demonstrate agent-loaded carrier particles are bioavailable and safe and that the agent is released in the colon. For the future development of agent-loaded carrier particle formulation, offerors can seek support from alternative NCI programs (e.g., NCI PREVENT Program and under CP-CTNet).

Activities not responsive to this announcement:

Proposals for cancer treatment will be considered non-responsive. Activities involving clinical trials will be considered nonresponsive.

Phase I Activities and Deliverables:

  • Demonstrate that the carrier particle formulation is orally administrable in vivo.
  • Demonstrate that the agent-loaded carrier particles show preliminary efficacy in preventing colon cancer in a suitable IBD animal model.
  • Demonstrate that the agent is only released in the predisposed target tissues such as the colon in ulcerative colitis and colon/terminal ileum in Crohn’s disease.
  • Demonstrate that the carrier-formulated agent significantly accumulates in the colon rather than in the blood and other organs compared to unencapsulated agent.
  • Demonstrate the specificity of the carrier particle formulation through on-target effects of the agent in the colon compared to other tissues.
  • Determine the preliminary safety profile of the carrier particle formulation and assess toxicity, if any.
  • Determine lead carrier particle formulation(s) that meet the predetermined criteria and top-ranked selected formulation(s) to move forward to Phase II.

Phase II Activities and Deliverables:

  • Perform pharmacokinetic studies of the agent, including, but not limited to, ADME, PK, and bioavailability.
  • Perform pharmacodynamic testing to demonstrate that the agent remains active in the carrier particle formulation in the colon.
  • Determine optimal dosing and prevention regimen that yields the best in vivo efficacy.
  • Evaluate long-term toxicity in vivo by comparing with orally administered unformulated agent.
  • Conduct long-term efficacy studies in suitable colon cancer prevention animal models that are known to recapitulate colon carcinogenesis of the high-risk cohort (from Phase I) and compare therapeutic indices with orally administered unformulated agent.
  • Evaluate stability and scale-up feasibility of the carrier particle formulation.
  • Optional: Develop an appropriate regulatory strategy.
  • Optional: Engage with FDA to obtain preliminary feedback via an INTERACT and/or pre-IND meeting.

 

Receipt date: Friday, October 18, 2024, 5:00 p.m. ET

Apply for this topic on the Contract Proposal Submission (eCPS) website.

View the full PHS2025-1 Contract Solicitation.

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