Targeted Therapy for Cancer- and Cancer Therapy-Related Cachexia

382. Targeted Therapy for Cancer- and Cancer Therapy-Related Cachexia

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Cachexia is characterized by a dramatic loss of skeletal muscle and adipose tissue mass, which cannot be reversed by nutritional intervention. More than half of all cancer patients experience cachexia, and it is estimated that nearly one-third of cancer deaths can be attributed to cachexia. Patients suffering from cachexia are often so frail and weak that walking can be extremely difficult. Cachexia occurs in many cancers, usually at the advanced stages of disease. Cancer cachexia is most prevalent in gastric, pancreatic, and esophageal cancer (80%), followed by head and neck cancer (70%), and lung, colorectal, and prostate cancer (60%). Despite cachexia's impact on mortality and data strongly suggesting that it hinders treatment responses and patients' abilities to tolerate treatment, no effective therapies have been developed to prevent or hamper its progression. Even for patients able to eat—appetite suppression or anorexia is a common cachexia symptom—improved nutrition often offers no respite. Overall, cachexia is characterized into three prominent stages, namely pre-cachexia, cachexia, and refractory cachexia. Pre-cachexia is characterized by some metabolic and endocrine changes, but weight loss is minimal. In cachexia, the patient undergoes more prominent weight loss, anorexia, muscle mass depletion, and reduced muscle strength. At this point, weight loss can be somewhat countered by health supplements and corticosteroids, but improved muscle function has not been achieved. In refractory cachexia, there is severe body weight, muscle, and fat loss; the reversal of weight loss is negligible even with the dietary supplements.

Over the last few years, researchers have begun to better understand the underlying biology of cancer- and cancer therapy-related cachexia. Findings from several studies point to potential therapeutic approaches, and a number of clinical trials of investigational drugs and drugs approved for other uses have been conducted or are under way. For recent research on the biological pathways involved in cachexia, please refer to Abstracts from the 3^rd Cancer Cachexia Conference published J Cachexia Sarcopenia Muscle. 2017 Feb; 8(1): 145–160. Published online 2017 Feb 27. doi:  10.1002/jcsm.12186.

Project Goals

The goal of this SBIR contract solicitation is to provide support for the development of targeted agents, including small molecules and biologics, to prevent or treat cachexia related to cancer and/or cancer therapy, including chemotherapy and/or radiotherapy. Proposals submitted in response to this topic must focus on cancer indications with the highest prevalence of cancer- and cancer therapy-related cachexia. Any route of administration is acceptable, but it must be kept in mind that once cachexia has developed, absorption in patients may be impaired.

To apply for this Topic, offerors should:

• Identify a therapeutic target and explain in detail the mechanism by which their drug will exhibit efficacy in preventing or treating cancer- or cancer therapy-related cachexia.
• Provide preliminary data or cite literature to support the role of the target in the development of cancer- or cancer treatment-related cachexia.
• Demonstrate ownership of, or license for, at least one lead agent (e.g., compound or antibody) with preliminary data showing that the agent hits the identified target.
• Possess experience with well-validated in vitro assays and in vivo models. Preliminary animal studies establishing proof-of-concept efficacy must be completed in Phase I. Common animal models used in cachexia research include: Lewis Lung Carcinoma (LLC), C-26 colon adenocarcinoma and Apc^Min/+ mice. More recently, orthotopic patient-derived pancreatic xenograft models have been employed to more closely recapitulate the muscle wasting seen in human disease.
• The scope of work proposed may include structure activity relationships (SAR); medicinal chemistry for small molecules, antibody, and protein engineering for biologics; formulation; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies; as well as production of GMP bulk drug and clinical product. These data will establish the rationale for continued development of the experimental agent to the point of filing an investigational new drug application (IND).
• Offerors must also have the appropriate team members including expertise in: cachexia, drug development, and regulatory strategy.

Activities not supported by this Topic: 

Proposals involving supplements and food products will not be considered.

Projects proposing to develop anti-tumor agents will not be considered.

Phase I Activities and Deliverables

• Demonstrate in vitro efficacy for the agent(s) in appropriate models.
• Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate).
• Perform animal toxicology and pharmacology studies as appropriate for the agent(s) selected for development.
• Perform animal efficacy studies in an appropriate model of cancer- or cancer treatment-related cachexia (see examples above). Include controls to preclude drug-drug interactions (e.g., the drug for cachexia should not decrease efficacy or increase toxicity for standard-of-care cancer drug).
• Develop a detailed experimental plan necessary for filing an IND or an exploratory IND (for potential SBIR phase II award).
   

Phase II Activities and Deliverables

• Complete IND-enabling experiments and assessments according to the plan developed in Phase I (e.g., demonstration of desired function and favorable biochemical and biophysical properties, PK/PD studies, safety assessment, additional preclinical efficacy as warranted, GMP manufacturing, and commercial assessment). The plan will be re-evaluated and refined as appropriate.
• Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agent.
• Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.