Help NIAID accelerate the development of safe and effective long-acting drug delivery systems to improve treatment of HIV-1 in children through the notice of funding opportunity (NOFO) Long-Acting Drug Delivery Systems for ART Optimization in Children Living with HIV-1 II (LADDS II) (R61/R33, Clinical Trial Not Allowed).
Despite recent advances in antiretroviral therapy (ART) coverage for children with HIV-1, significant gaps remain and limitations of current ART regimens for pediatric participants can result in suboptimal viral suppression. This NOFO supports the development of Long-Acting Drug Delivery Systems (LADDS) which can overcome limitations of daily oral ART in children living with HIV-1.
Research Objectives and Scope
This initiative will stimulate the optimization and evaluation of LADDS formulations in suitable preclinical animal models at an earlier age of adult drug development. This work should accelerate clinical translation in pediatric populations and improve HIV-1 treatment outcomes.
A successful application should include:
- A long-acting drug delivery platform that must include the following attributes:
- Platform is already in development, ideally for ART use in adult populations. Innovative platforms in development for non-pediatric or non-ART use are also acceptable.
- A single platform that can deliver a complete ART regimen [consisting of two or more antiretrovirals (ARVs)] for HIV treatment. Inclusion of a single ARV is allowable, if needed, to meet the minimum required dosing interval, even if separate administrations of the ARVs are required, provided that a complete ART regimen is proposed as part of the application.
- LADDS are able to support a minimum dosing interval of 8 weeks of delivering ARV exposures that are expected to match adult exposure associated with efficacy or that remain above four times the protein adjusted IC90 (palC90) for each ARV at the end of the dosing interval.
- ARVs and ART regimen chosen should be clinically relevant and ideally supported by existing treatment guidelines or if in pre-approval stages, recognized as high-priority ARVs with early data supporting their high-potential for future development.
- Platform development that targets pediatric populations less than 12 years of age and preferably children less than 6 years of age and is well suited to accommodate unique growth and development characteristics of the target pediatric population.
- Innovative PB-PK modeling and other in silico approaches to inform optimization of LADDS formulations for pediatric use and ARV dose selection to be applied in future pediatric clinical studies.
- Appropriate use of preclinical animal models including:
- Preclinical in vitro studies to characterize potential platforms and select ARV candidates during the initial (R61) phase of the award.
- An animal antiviral efficacy study of the LADDS candidate in age/maturation-matched nonhuman primates (NHPs) during the second (R33) phase of the award.
- Socio-behavioral studies initiated during the R61 phase to assess end-user preferences and inform final production design. Where possible, preferences from all stakeholders (e.g., caregivers, children, providers) should be considered. The methods should be appropriate to the stage of product development, and could involve qualitative methods, discrete choice surveys, or other novel product acceptability methods.
- A behavioral scientist with expertise in the proposed behavioral methods.
- An industry/drug development partner which could be an established company, startup biotech company, or non-profit organization with knowledge and resources to support early product development and regulatory interactions to enable a possible future path to market.
- Planning for a pre-investigational new drug (pre-IND) meeting with the FDA before the end of the R33 phase.
In addition, we recommend including a pediatric-focused Quality Target Product Profile (pQTPP) at the R61 stage to summarize long-acting drug product critical properties and targets for development, with attention to those properties of key relevance to pediatric populations living with HIV in low- and middle-income settings. The pQTPP might describe the essential product attributes (product release profile and duration of action, target age, optimal dosing regimen, dose flexibility, acceptable duration of PK lag periods and tails, maximum and minimum PK targets, PD targets, stability and storage requirements, desirable acceptability/desirability-derived attributes, and cold chain/storage equipment, regulatory pathway) by identifying optimal and minimally acceptable attributes for the drug and its platform.
Refer to Section I of the NOFO linked above for a list of nonresponsive research studies and approaches that NIAID will not review for funding.
Phased Innovation Awards
Due to the high-risk, high-impact nature of the research, this funding opportunity will use the R61/R33 phased innovation grant award mechanism. NIAID will provide support for up to 2 years (R61 phase) for preclinical research to optimize the long-acting platform and ARV payload, characterizing duration of action, setting up and initiating the end user preferences studies, and other related activities.
Up to 3 years of support may follow (R33 phase) for additional activities as appropriate, such as completion of end user studies, evaluation of optimized delivery system in suitable NHP models, preparation of the pre-IND package, and pre-IND meeting with the FDA.
NIH program staff will review and negotiate applicants’ proposed transition milestones prior to award. Before the end of the R61 phase, recipients will submit an R33 transition package, to include a detailed progress report describing advancement toward the initial milestones and a description of how the completed work justifies continuation with the originally proposed R33 studies. NIH program staff will evaluate these materials and grants eligible for continued funding may transition to an R33 award.
Budget, Deadline, and Project Period Information
NIAID plans to fund three or four awards in fiscal year 2025. Application budgets are limited to $850,000 in annual direct costs for the R61 phase and $1,250,000 in annual direct costs during the R33 phase. Requested budgets should reflect the actual needs of the proposed project and the maximum project period cannot exceed 5 years total.
Applications are due on March 13, 2024, by 5 p.m. local time of the applicant organization.
Contact Information
Direct your questions to Dr. Tania Lombo, our scientific/research contact at tania.lombo@mail.nih.gov or 301-761-7612. Direct peer-review related questions to Dr. Poonam Pegu, our peer review contact, at poonam.pegu@nih.gov or 240-292-0719.