HEAL Initiative: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain - (U44 Clinical Trial Not Allowed)

Purpose:

 

The purpose of this funding opportunity announcement (FOA) is to support preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising small molecule and biologic hits/leads towards clinical trials. Applicants must have a promising hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, and assembly of Investigational New Drug (IND) application. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress.

 

Background:

 

This study is part of the NIH's Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis.  The NIH HEAL Initiative will bolster research across the NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management.  More information about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative?.

 

More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments. This program announcement is intended to create a foundation to initiate the optimization and development of pain therapeutics and catalyze the development of partnerships between the academic and industrial sectors so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

 

Scope:

 

This program announcement is specifically focused on the preclinical translational development necessary to advance small molecules and biologics to the point of clinical testing of therapeutic candidates for pain. The program supports preclinical optimization and development of small molecules and biologics leading to assembly of IND applications for the FDA. The scope of this program excludes clinical research, basic research, and studies of disease mechanism or mechanistic/mechanism of action studies of the intended therapeutic. Further, development of animal models, diagnostics, biomarkers, rehabilitation strategies, or therapeutic devices is out of scope.

 

General Entry Criteria:

 

All projects must enter the U44 Phase I of the program. For entry, projects must have a promising small molecule or biologic starting point for optimization, a rigorous biological rationale for the intended approach, and scientifically sound assays to test the agent.

 

For the U44 Phase I, this FOA encourages projects proposing the following optimization activities:

• Optimization using potency and efficacy screens
• Preliminary efficacy testing in appropriate pain animal models
• Characterization and testing for ADME (absorption, distribution, metabolism, and excretion)

 

It is expected that by the end of the U44 Phase I, awardees will have characterized and selected a lead candidate that is ready for in vivo efficacy testing, though additional optimization may be necessary.

 

For advancement to the U44 Phase II, the following development activities are in scope:

• Any further optimization activities as listed above, if needed
• Non-GLP toxicology studies (e.g. dose range finding toxicology)
• Pharmacokinetics (PK)
• Formulation and stability studies
• Cell bank development and testing
• Gene expression level
• Biodistribution, tumorigenicity, and immunogenicity
• Process development
• Manufacturing of candidate therapeutics for IND
• IND-enabling safety pharmacology, genotoxicity, hERG and toxicology studies

 

Additional Resources:

 

To support these projects, additional existing NIH resources may be made available to the applicant outside of this grant budget. Applicants are strongly encouraged to contact NIH staff to discuss these options. These resources include, but are not limited to the following:

 

NINDS

 

NINDS has established contract support for pharmacokinetic studies, toxicology (GLP and non-GLP) and safety testing and can provide access to experts in therapeutics development through a consulting service. Additionally, as part of the HEAL Initiative, NINDS anticipates establishing support for a preclinical screening platform for pain and make available variety of in vivo animal models to test promising lead compounds. Applicants must contact NINDS staff (contacts provided below) in order to utilize these resources and determine how to best leverage these as part of the application.

 

NCATS

 

Applicants are also strongly encouraged to utilize the state-of-the-art capabilities at the NIH National Center for Advancing Translational Sciences (NIH/NCATS). Depending on the nature of the proposed collaboration, NCATS will make available its comprehensive capabilities in support of HEAL initiatives. The capabilities include, but are not limited to, screening and scalable production of relevant stem cells; biofabrication of 3D functional tissues for drug testing; using quantitative high-throughput screening to identify promising compounds to be optimized by medicinal chemists; and implementing IND-enabling studies. A more detailed description of the capabilities can be found at: https://ncats.nih.gov/heal/intramural-capabilities*

 

Milestones:

 

Because therapeutics optimization and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Go/No-Go milestones will be established by a team consisting of the PD/PI and NIH program staff at the start of each project and updated as needed. These will be tailored to the therapeutic agent to make sure that investigators have the appropriate resources to advance the proposed projects and will differ between therapeutic candidates. Program staff may consult as necessary with independent consultants with relevant expertise.

 

NIH program staff and leadership will conduct an annual administrative review. At the end of the U44 Phase I, NIH program staff and leadership will determine if the project will advance to the U44 Phase II. If needed, additional meetings to administratively review progress may take place. If justified, future year milestones may be revised based on data and information obtained during the previous project period. The reviews will be based on:

 

• Successful achievement of milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• Competitive landscape for the disease indication and drug target
• Program priorities
• Availability of funds

Intellectual Property:
 

Since the ultimate goal of this program is to bring new pain therapeutics to the market, the creation and protection of appropriate intellectual property are significant considerations in designing research strategies and prioritizing projects for funding. Each applicant is expected to address intellectual property issues related to the proposed therapeutics, with input from the institution's technology transfer officials, if applicable. Peer reviewers will be instructed to comment on the intellectual property landscape for each application. The project milestone plan may include commercialization milestones to protect and leverage intellectual property. Recipients of awards are encouraged to identify potential licensing and commercialization partners early in the therapy development process. The PD(s)/PI(s) is encouraged to work closely with technology transfer officials at his or her institution, if applicable, to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. (See Section IV.2. Other Project Information for details.) 

 

Implementation:

 

The program provides funding through the U44 Fast Track cooperative agreement mechanism. As a cooperative agreement, implementation will involve participation of NIH program staff in the planning and execution of the therapy-directed projects. This program is envisioned as a 5-year program in two stages U44 Phase I and Phase II. The U44 Phase I portion of the award is designed to support optimization research for two years. Our goal is to fund 6-8 projects with a limited budget for the first 2 years. Based on the progress to milestones, only a limited number of projects will proceed to the U44 Phase II phase (3 years) for the remainder of the award period which will include final optimization and development leading to IND-enabling studies, either through the grant budget or through additional contract resources outlined above.

 

IC-Specific Areas of Interest

 

NCCIH

 

The National Center for Complementary and Integrative Health (NCCIH) will support research on optimization of non-addictive therapies for acute or chronic pain conditions, including chronic low back pain, that are treated with complementary and integrative health approaches.  Examples of complementary and integrative health approaches relevant to this FOA include, but are not restricted to, herbal products, dietary supplements, special diets, probiotics, or a combination of any of these therapies with each other or with conventional pharmacological therapies.

 

NICHD

 

The Eunice Kennedy Shriver ?N?a?t?i?o?n?a?l? ?I?n?s?t?i?t?u?t?e? ?o?f? ?C?h?i?l?d? ?H?e?a?l?t?h? ?a?n?d? ?H?u?m?a?n? ?D?e?v?e?l?o?p?m?e?n?t? ?(?N?I?C?H?D?) is interested in supporting research aimed at developing novel, non-addictive pharmacotherapies for (1) more effective and safer treatment of pain in pediatric or obstetric populations; (2) the treatment of chronic gynecologic pain syndromes, including vulvodynia/vestibulodynia, chronic pelvic pain, and dysmenorrhea, and post-operative gynecologic pain; (3) the management of persistent pain associated with multiple chronic conditions in individuals with physical impairments. Investigators are strongly encouraged to discuss their research plans with NICHD Scientific/Research contact prior to submitting their application.

 

NIDCR

The National Institute of Dental and Craniofacial Research (NIDCR) is interested in preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

 

NIDDK

The NIDDK encourages applications that identify non-addictive therapies in children, adolescents, and adults with diabetic neuropathy; pancreatitis, irritable bowel syndrome, and other gastrointestinal diseases; and kidney and lower urinary tract symptoms.

See Section VIII. Other Information for award authorities and regulations.