Council Clearance for IND-enabling Small Business NOFO

Title: Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use Disorder and Alcohol-Associated Organ Damage (AAOD)

Authors: Jenica Patterson, Ph.D; Megan Ryan, M.B.A.; Raye Litten, Ph.D.; Kathy Jung, Ph.D.

Purpose:

DTR intends to re-issue PAR 18-578 “Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use Disorder and Alcohol-Related Organ Damage (U44)”. NIAAA may also consider an option to issue a NOSI, RFA, PAR (grant applications/cooperative agreements) and/or RFP (contracts) based on this concept should a need arise within the next five years.

The purpose of this Notice of Funding Opportunity (NOFO) is to provide support to small business concerns (SBC) for the optimization, development, and translation of pharmaceutical research discoveries into new treatments for disorders that fall under the mission of NIAAA. The goal is to advance small molecules, natural products or biologics for alcohol use disorder (AUD) or alcohol-related health effects and diseases through the drug development pipeline towards commercialization and ultimately, FDA approval.  Due to the urgency of this public health need, projects supporting a lead compound with a robust body of background data in the basic science and early discovery phases to be poised for transition to the preclinical and clinical phases of medications development will be prioritized. Background data may include rigorous preclinical testing, sufficient bioactivity, stability, manufacturability, bioavailability, and in vivo efficacy and/or target engagement. Applications focusing solely on basic science research are not within scope. Examples of out-of-scope applications include: novel target identification/validation, generation of new animal models, development/testing of new human laboratory models, assay development, new biomarkers, or mechanistic studies of the neurobiology of AUD. By the end of the funding period, projects are expected to achieve milestones that significantly move the compound towards the next phase of drug development (e.g., pre-IND meeting, IND application).  While the Phase I supports the preparatory activities needed before launching IND-enabling studies (such as manufacturing for IND-enabling toxicology and verification of such manufactured material for its activities), the Phase II phase supports the IND-enabling studies (e.g., GLP toxicology, biodistribution, immunogenicity evaluations) and early stage clinical studies (e.g., Phase I, Phase IIa).

Background:

In the United States, approximately 14.5 million people, ages 12 and up have alcohol use disorder. Alcohol is the third-leading preventable cause of death in the United States alone. The Centers for Disease Control and Prevention estimates that alcohol misuse costs the United States $249 billion per year due to health care expenses, lost workplace productivity, crime, property damage, and other adverse outcomes. Currently, there are only three medications (four formulations) approved by the Food and Drug Administration (FDA) for the treatment of AUD. The need for additional medications to treat those affected by AUD is urgently needed. In addition, alcohol misuse affects virtually all tissues and is linked with dysfunction and failure of many organs and systems including the liver, heart, pancreas, lung, bone, and skeletal muscle, as well as digestive, vascular, endocrine, and immune systems. There are currently no FDA-approved therapies for alcohol-related organ damage so effective therapies to prevent and treat alcohol-associated organ damage (AAOD) are urgently needed.

Scope/Objectives/Statement of Work:

This NOFO seeks applications from small businesses that propose to advance the following classes of therapeutics beyond pre-clinical development by preparing to seek regulatory approval for future trials: small molecules, natural products, and biologics, which broadly include peptides, proteins, oligonucleotides, gene therapies, and cell therapies. 

Phase I Scope – generally 6 months to 1 year 

Examples of studies that can be proposed during this Phase include, but are not limited to:

• Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology tests
• Pharmacokinetic evaluations in species relevant for toxicology or human dose-prediction
• Final characterization and definitive verification of in vitro and in vivo activities such as preclinical target engagement and/or efficacy studies, using the final manufactured material (using final cGMP process depending on regulatory requirement) intended for IND-enabling toxicology studies (If needed for certain therapeutic modalities).
• Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
• Optimizing and/or validation of appropriate assays for pharmacokinetics, bioactivity (potency), target engagement markers or other assays to monitor safety to be used in human trials

Phase II Scope – generally 1-3 years

The Phase II will support IND-enabling development activities. For more advanced projects, a small early phase clinical trial can also be supported when feasible during the Phase II, but is not required.  Applications seeking to support only early-stage clinical trials are not appropriate. Applicants with preliminary POC efficacy and safety data supported outside the SBIR/STTR program, may apply for a Direct to Phase II.

Preclinical development activities appropriate for Phase II include, but are not limited to:

• IND-enabling toxicology, with toxicokinetics, if applicable
• Drug interaction studies between the medication and alcohol
• Tumorigenicity evaluations particularly for gene therapies and cell therapies, if applicable
• Immunogenicity evaluations, if applicable
• Biodistribution studies, if applicable
• Large animal study to assess biocompatibility of means of clinical delivery of the candidate, if applicable
• Validation of appropriate assays such as for target engagement markers to enable human use
• IND and other regulatory submissions

Small, early-phase clinical trials that are appropriate include:

• Population: patients with indicated disease, or healthy volunteers
• Design is single dose or single ascending dose treatment, and may be placebo-controlled or open-label studies; multiple ascending dose may be requested only if agent has a short half-life
• Outcomes are safety, pharmacokinetics and pharmacodynamics/target engagement/target modulation. Note that clinical efficacy outcome data may be collected to prepare for Phase 2 clinical studies, but efficacy cannot be the primary objective of the study
• The duration of the clinical trial, from initiation at first informed consent signature to the completion of data analysis, should rarely exceed 3years.

Activities that are appropriate for clinical trial preparatory activities (only if clinical trials are proposed), which may be performed concurrently with IND-enabling preclinical studies during Phase II include, but are not limited to:

• Manufacturing of cGMP (current Good Manufacturing Practices) material for the small, early-phase clinical trial if not done already in Phase I
• Development and validation of biochemical assays required for clinical trials if not already complete (e.g., pharmacokinetic, pharmacodynamic, and/or immunogenicity assays)
• Preparation of clinical trial protocol, Investigator's brochure
• Preparation of documents required to support a clinical trial (e.g., case report forms, pharmacy manual, study coordinator manual, monitoring plan)

Clinical trial activities that are appropriate during Phase II include, but are not limited to:

• Patient/subject recruitment and enrollment
• Site monitoring
• Data collection and quality assurance
• Statistical analysis
• Safety reviews

Justifications/Outcomes.

In the United States, approximately 14.5 million people, ages 12 and up have alcohol use disorder. Alcohol is the third-leading preventable cause of death in the United States alone. The Centers for Disease Control and Prevention estimates that alcohol misuse costs the United States $249 billion per year due to health care expenses, lost workplace productivity, crime, property damage, and other adverse outcomes. Considering the serious adverse consequences associated with alcohol misuse, treating AUD and ameliorating the negative health effects associated with it are crucial.

Medications Development to treat AUD and AAOD is a program priority at NIAAA as referenced in the 2017-2021 NIAAA Strategic Plan. There are currently three medications approved by the FDA for treating AUD: disulfiram, naltrexone, and acamprosate and none to treat AAOD. Additional AUD pharmacotherapies are needed, including for people with co-occurring health conditions, such as post-traumatic stress disorder (PTSD), HIV, and alcoholic liver disease (ALD), as well as other substance use disorders. 

Due to the complexity of drug development for AUD and AAOD, especially IND-enabling activities, support is needed to help bridge the gap and overcome the valley of death that disrupts the drug development pipeline. Through this PAR, NIAAA will provide support to de-risk drug development and stimulate interest in the development of compounds to treat AUD and AAOD.