Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Mental Health (NIMH)

Purpose

Background

Clinical experience for HIV treatment and prevention has demonstrated that adherence to a drug regimen schedule is a significant factor in the success of the HIV treatment regime and/or prevention strategies. Effective treatment of HIV-infected individuals requires strict adherence to a multi-component regimen of antiretroviral agents taken at least daily for the remainder of a patient’s life. Non-adherence can lead to emergence of drug-resistance and loss of therapeutic effectiveness. Among people living with HIV, morbidity and mortality is increasingly driven by co-infections, such as tuberculosis (TB) and hepatitis B, where the compliance and completion of prolonged multidrug regimens are significant factors in treatment success.

Effective prevention requires that the inhibitor be present at the right time, place, and concentration to stop HIV transmission and acquisition.Although many factors (social, behavioral, and individual preference) can influence adherence, the use of drug delivery systems to provide for a longer therapeutic exposure or window of protection and/or less frequent administration may improve their consistent use, reduce dosing intervals, and potentially improve adherence to the drug regimens.

Development of safe, effective, and well-tolerated sustained release (SR)/long acting (LA) products and strategies that maintain consistent and effective drug levels in plasma and target tissues for longer periods of time is critical for successful treatment and prevention of HIV and HIV-associated co-infections.

Research Objectives

The purpose of this Notice is to encourage new applications to support further development of a diverse and comprehensive portfolio of SR/LA products for prevention and treatment of HIV. SR/LA antiretroviral products will have a minimum window of protection of three (3) months from either a single dosing (injection, oral administration) or continuous dosing regimen (implant, transdermal patch, etc.) to reflect current state of SR/LA drug market for HIV treatment or prevention.

This Notice also encourages applications to develop once-a-month SR/LA strategies for treatment of latent TB and hepatitis B. It is highly likely that in populations with a high burden of TB and/or hepatitis B, HIV patients receiving LA antiretrovirals often require treatments for these infections. Thus, the development of SR/LA drug products for latent TB and hepatitis B that are compatible with SR/LA antiretrovirals are sorely needed. Preferably, these new SR/LA treatments for latent TB and hepatitis B will have suitable pharmacological and safety profiles to enable co-administration with SR/LA antiretrovirals with similar dosing requirements.

Well-conceived milestone driven applications that consider optimal and minimally acceptable properties and targets for proposed technically feasible SR/LA products are encouraged. End-user assessments of the product attributes (route, dosing frequency, volume, location of application sites, etc.) and factors that might influence product implementation and dissemination, such as availability of drug substance, cost of goods, cold chain requirements, intellectual property (IP), and regulatory needs should be considered.

The SR/LA platforms and drug products to enable intermittent dosing may include:

• Small and large chemically defined active pharmaceutical ingredients (small molecules, proteins, peptides, antibodies, and gene-silencing techniques) with proven activity against HIV, hepatitis B virus (HBV) or M. tuberculosis, with characteristics compatible to SR/LA formulations.
• Single drugs or drug combinations.
• Drug delivery strategies may consist of oral, implant, injection (in situ-forming depots and small volume injectables), and transdermal products. For HIV prevention, direct mucosal delivery platforms may be considered, but must meet the requirement for a minimum window of protection of three (3) months.

For all forms of SR delivery, development of SR/LA strategies that provide the minimal windows of therapy or protection (as identified above) or longer are strongly encouraged. Applicants may propose a shorter duration, but only as their initial target. Collaborative research partnerships are encouraged, but not required.

Specific Areas of Research Interest

Applications may include but are not limited to the following:

NIAID

• Lead optimization studies to enable once every three (3) months dosing for HIV treatment or prevention and once-a-month for treatment of latent TB or hepatitis B.
• Development of marketed antiviral and anti-TB drugs as novel SR/LA products for treatment and prevention of HIV and HIV-associated co-infections
• Development of existing classes of active pharmaceutical ingredients (APIs) with known activity against HIV, HBV, or Mycobacterium tuberculosis, safety, and resistance patterns as SR/LA agents to enable intermittent dosing.
• In vitro and/or in vivo pharmacokinetic/pharmacodynamic evaluations to support the proposed duration. Pharmacology studies in laboratory animals to confirm that the proposed delivery systems are providing effective drug levels in plasma and target tissues (e.g., CNS/CSF, semen, genital and/or gastrointestinal tract mucosa, lymph nodes, GALT) are highly desired.
• In-vitro and in-vivo studies to evaluate the potential toxicity and resistance profiles of drug products.
• Use of appropriate animal disease models for efficacy evaluations.
• Use of pharmacokinetic (PK) modeling tools in drug product design.
• Drug-drug interaction studies.
• Pre-formulation studies that include chemical and physical characterization of the selected API and drug products. This might include performance of U.S. Pharmacopeia Convention (USP) compliant stability and drug release testing.
• Projects that incorporate end-user assessments of the attributes of the proposed formulations during formulation development

NIMH

• Research designed to inform the development of SR products by investigating relevant healthcare system delivery factors and patient and provider preferences regarding dosing schedules and administration routes.
• Research to identify product attributes that may differentially affect consumer uptake, adherence to, and persistence with sustained release products.
• Studies to determine which SR products and delivery systems are preferred, and factors that moderate product preferences.
• Studies to understand how partner and situational or contextual factors influence product preferences.
• Studies examining whether SR formulations improve product adherence and persistence.
• Development of behavioral, healthcare provider, and systems interventions that will facilitate patient adherence and healthcare delivery of sustained release formulations.
• Studies that model the cost-effectiveness of SR products for HIV treatment or prevention.

NOTE: Areas of research that are not of special interest:

• Sustained release strategies for HIV or sexually transmitted infections (STI) vaccines.
• Further preclinical development of long-acting nanosuspension formulations of TMC278 (rilpivirine) or S/GSK1265744 (cabotegravir) as sustained release injectable strategies for adults.
• Development of multipurpose prevention technologies (MPT) and/or approaches designed to inhibit STIs.
• Research focused on use of bacterial delivery of antivirals to mucosal compartments.
• Sustained release approaches using intravaginal rings (IVR).
• Screening of chemical or natural product libraries to discover candidate molecules, including development of an uncharacterized natural product consisting of a complex mixture of potentially active and inactive ingredients.
• Clinical trials.

Application and Submission Information

This notice applies to due dates on or after September 7, 2022 and subsequent receipt dates through May 7, 2025.

Submit applications for this initiative using the following funding opportunity announcement (FOAs) or any reissues of this announcement through the expiration date of this notice.

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

For funding consideration, applicants must include “NOT-AI-22-042” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
 

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Marina Protopopova, Ph.D.
Treatment
National Institute of Allergy and infectious Diseases (NIAID)
Telephone: 301-761-7653
Email: [email protected]

James E. Cummins, Jr., Ph.D.
Prevention
National Institute of Allergy and infectious Diseases (NIAID)
Telephone: 240-292-4800
Email: [email protected]

Teri Senn, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-761-7852
Email: [email protected]