Purpose and Scope

The objective of this FOA is to support the development of new and innovative sustained/extended release HIV prevention products with rheological and biophysical properties that provide product user perceptions (look and feel) compatible with sustained/extended use of the drug delivery system (DDS) for people at-risk of HIV/AIDS infection. These products are needed to enable users to more easily adhere to HIV prevention dosing regimens by reducing dosing frequency while simultaneously increasing effectiveness through enabling longer durations of effective drug coverage. The ultimate sustained/extended release product should provide months to years of HIV prevention coverage, be reversible through removal of the DDS, while offering set it and forget it protection from HIV infection. For the purposes of this FOA, the target populations are males and females, including transgender and gender non-conforming populations (ages 14 years and older) desiring sustained/extended release products to prevent HIV acquisition /transmission. Populations of specific interest include men and women in serodiscordant partnerships, men who have sex with men (MSM), gay men, blacks, Hispanics, intravenous drug users (IDUs) and alcohol users and abusers.

Due to the high-risk, high-impact nature of the research, this FOA will use milestone-driven, phased research activities with investigator-provided milestones. Support will be provided for up to three (3) years for the R61 phase, and up to two (2) years of support may follow for the R33 phase. Prior to the end of the R61 phase, awardees will submit the R33 transition package, which will be evaluated by NIH Program staff for completion of milestones. R33 transition decisions will be based on successful completion of negotiated milestones, Program priorities, and availability of funds. It is expected that approximately half of the projects supported during the R61 Phase will continue into the R33 Phase. A plan to submit a pre-IND or communication with the FDA by the end of the fourth year is required in the application, and documentation of submission of the pre-IND is required to be eligible for year 5 funding.

Background

The results of numerous non-vaccine biomedical prevention (nBP) clinical phase III trials have demonstrated conclusively that both adolescents and adult men and women face adherence barriers when required to use prevention products around coitus (pre- or post). This includes taking a daily pill, using a daily or sex-act associated vaginal gel or a 30-day intravaginal ring (IVR) for HIV prevention. Multiple user perception factors (individual, cultural, stigma-derived, DDS-related, etc.) have been identified that can contribute to low adherence for prevention products. In addition to user perceptions, biological and pharmacological barriers may also play a role in the effectiveness of prevention strategies where individual use decisions control adherence to the prevention regimen. In vitro modeling and direct observed therapy pharmacokinetic (PK) studies of daily oral emtricitabine/ tenofovir disoproxil fumarate (TDF/FTC pre-exposure prophylaxis (PrEP) have shown that approximately 28% adherence by men, and 85% adherence by women are required for a weekly pill-taking regimen to achieve sustained protective levels of Tenofovir-diphosphate (TFV-dp) and emtricitabine triphosphate (FTC-tp) in the blood and mucosal tissues. To increase adherence and potentially reduce its impact on prevention strategies, the nBP field has begun to evaluate anti-HIV drugs with longer durations of action. The most advanced of these are Phase III clinical trials of a q8 weeks injection of a nanocrystal formulation of the integrase inhibitor Cabotegravir for HIV prevention in men (HPTN 083) and women (HPTN084). Although injectable prevention strategies could potentially have a significant impact on the HIV pandemic, there is still room for improvement. There are several questions that remain to be answered and capabilities that may need to be incorporated into development of sustained/extended release HIV prevention strategies. These include: impact of excess drug exposure (drug burst) after dose initiation on safety and establishment of protection; impact of periods of suboptimal drug exposure (PK tail, time during which drug drops below effective levels) on efficacy and emergence of resistance; the inability to terminate dosing if adverse events occur when deviceless (e.g. injection) DDS strategies are used; identification of optimal dosing parameters (volume of injection, size/number of devices used/implanted, user friendly durations); and methods for renewing the dose (site of drug application, surgical procedures) that facilitate sustained use of the prevention strategy. Therefore, this FOA focuses on developing the next generation of new and innovative sustained/extended release drug products that are optimized not only for delivery of HIV prevention (PK profile, DDS, etc.), but also for their interaction with the user (look, feel and use) to increase the potential for initial uptake and continued use of adherence independent strategies (implant, injection, etc.) and enhancement of adherence for user removable strategies.

Research Objectives

Sustained release for the purpose of this FOA is defined as continuous exposure to the anti-HIV drug from a DDS that is achieved using either a continuous release device or through creation of a tissue depot. Extended release is defined as providing protection from HIV infection/transmission for the minimum durations identified below. It is expected that products proposed for development will deliver active pharmaceutical ingredients (API) capable of preventing HIV replication and infection using DDSs compatible with sustained/extended HIV prevention, and achieving the minimal durations of action for the DDS below:

• IVR strategies with durations of 3 months or longer with or without removal periods for bleeding.

• Modification of licensed copper IUDs to release an antiviral drug(s) with a projected duration of at least 3 years.

• Implants or Injectable prevention strategies with a minimal duration of 6 months.

• Novel DDS with a minimum of 1-month duration, e.g. fast dissolve inserts or films, transdermal patch, etc.

Responsive DDS administration strategies include, but are not limited to, injection (depot and non-depot forming), implant (non-biodegradable or biodegradable), transdermal (continuous use or short exposure depot-forming), depot or nondepot forming mucosal intravaginal/intrarectal DDS, and other systems which may or may not be enabled using nanotechnology and engineering solutions to achieve the required minimal durations of action. Strategies/development which may enable self-administration are of interest also.

If the strategy is composed of a combination of antiviral drugs, all components must be delivered simultaneously. DDS which compartmentalize the drugs to address drug-drug interactions (DDI) and/or create different release rates are responsive, if delivered simultaneously from a single DDS.

The following areas of preclinical and behavioral research may be proposed to achieve the objective of creating the next generation of sustained/extended release candidates:

• Development of new and innovative DDS which can deliver sustained/extended HIV prevention products composed of either a single antiviral or combinations of HIV antivirals.

• Understanding the potential for and identifying/characterizing drug-drug interactions (DDI) that could compromise antiviral effectiveness.

• Understanding the PK of sustained/extended release products by mapping the characteristics of the antiviral release including, drug bursts (initial and during biodegradation), lag period (time to establish effective concentrations), PK tails (time to loss of effective concentrations) and forgiveness intervals (dosing intervals during which the drug/DDS must be renewed to maintain efficacy).

• Understanding the impact of continuous antiviral drug delivery on tissue depot sites which might alter drug effectiveness (activation of drug transporters, metabolism and excretion), foreign body reactions (wound healing, encapsulation of implants, etc.) and/or local and systemic distribution of drug to HIV target tissues.

• Understanding the ability of the sustained/extended release strategies to deliver antiviral concentrations to both the female reproductive tract (FRT), male genitourinary system (MGS), and/or gastrointestinal (GI) tract of men and women.

• Understanding Preferred User Characteristics (PUC), which will govern decisions made by individuals to use the sustained /extended release strategy (look and feel), and whether to adopt and maintain use of longer duration strategies. For this FOA, PUCs are defined as the rheological/biophysical properties of the sustained/extended release DDS that invoke user judgments, leading to decisions for first, subsequent use or non-use and/or early termination.

• Advancing the sustained/extended release candidate in the clinical pipeline by performing studies which position the drug/DDS at the end of five years to either advance to clinical testing, undergo further iterative development or terminate its development.
  

Responsive Areas of Research Interest

Examples of the types of studies responsive to this FOA include, but are not limited to:

• Research designed to identify an optimal DDS for delivery of a single or combination of anti-HIV small chemically-defined molecule(s) and/or protein(s), such as broadly neutralizing antibodies or non-antiretroviral (non-ARV) HIV inhibitors.

• Development of longer duration sustained/extended release strategies that protect both the FRT, MGS, and/or GI tract of men and women.

• Sustained/extended release strategies incorporating PK studies with activities critical to characterizing the DDS sustained/extended release characteristics and capacity such as:

• Characterization of the PK tail sufficiently to allow selection of the dosing regimen with such factors as lag, duration and forgiveness interval taken into account

• Optimizing to achieve forgiveness intervals for of no more than 1/3 of the proposed duration of action of the DDS, e.g. Forgiveness interval is defined as the interval in which redosing is recommended to avoid delivering drug below the effective concentration.

• Studies of PK lag periods (time before establishment of real or predicted effective drug concentrations).

• Characterizing and minimization of the interval between DDS drug exhaustion and full degradation of the DDS for biodegradable DDS.

• In vitro or in vivo animal PK, pharmacodynamic (PD) and toxicokinetic (TK) studies to support the proposed duration of use and PK parameters. Of significant interest are PK studies that establish relationships between plasma and GI, MGS, and FRT (upper and lower) tissues/secretions, lymphoid tissues, and implant/dosing site drug concentrations. Understanding the impact of timely or delayed re-dosing (forgiveness) on efficacy and emergence of viral resistance is also of interest.

• Nanotechnology approaches to solve specific problems related to the sustained/extended release DDS, candidate duration of action, tissue/systemic distribution, safety, and/or efficacy.

• Hypothesis-driven studies focused on the impact of the sustained/extended release drug on the genital/GI tract and tissue at the site of dosing, specifically on mucosal barrier and immune function as it relates to the safety/efficacy of the proposed sustained/extended release drug product and its use. This may include impact on drug transporters, inducible and non-inducible cellular drug-degradation and metabolism pathways, as well as the impact of the DDS/drug on epithelial cell function, mucosal wound repair, and immune cell trafficking. Understanding the impact of prolonged exposure of the drug on innate, adaptive and cellular immunity, which may control susceptibility to HIV infection is also of interest.

• Assessments of PUCs for sustained/extended release strategy rheological/biophysical attribute selection. Studies using established behavioral and social sciences tools associated with user look and feel optimization, such as ethnographic studies, perceptibility assessments, mental modeling, user journeys, discrete choice studies and conjoint analysis. Approaches will focus on identifying factors which may influence an individual’s choice to use. Studies involving potential prescribing physicians/Health givers in the U.S. that result in identification of physical and rheological/biophysical attributes of the sustained/extended release DDS, such as implant size, location and placement that could influence user perceptions of the product. PUC research using artificial tissue models to provide kinesic experience to enhance user experience with the DDS is encouraged. PUC studies should be designed and implemented to inform on the rheological and biophysical property (ies) choices made for the sustained/extended release strategy.

• Limited clinical research focused on obtaining PUC information is allowable, if the proposed research meets the criteria outlined below.
  

Industry Partner(s)

Applications submitted to the FOA must demonstrate substantial collaboration by at least one industrial partner. An industrial partner/collaborator is broadly defined as participation in the application of an individual, group, or unit from a for-profit or not-for-profit pharmaceutical, biotechnology, bioengineering, or chemical company that is large or small, domestic or foreign with an established record in product development. Substantive collaboration is defined as a significant commitment of one or more resources to the project including, but not limited to: research and development plan support/guidance, product development support/guidance, personnel, provision and testing in animal or other laboratory models for evaluation, data management resources and/or regulatory support. Inclusion of a commercial regulatory advisory group or consultants from outside the applicant’s organization to assist in preparation of the pre-IND package meets this requirement. However, inclusion of a Contract Research Organization (CRO) to provide fee-for-service deliverables without significant participation/scientific collaboration in the research agenda does not meet the definition of an industry partner.

Industry applicants are not required to involve collaborators from academic and/or non-profit research organizations, but are encouraged to do so, where appropriate.

Animal Models for Efficacy and PK Determinations

For the purposes of this FOA, animal antiviral efficacy studies are divided into two categories. The first category includes hypothesis-driven studies that are supportive of sustained/extended release drug development and address the impact of the product or strategy on the FRT, MGS, and GI track as part of a safety determination. The second category includes animal models for screening/testing sustained/extended release candidates to understand overall PK (e.g. PK tail, forgiveness and duration), antiviral activity (e.g. Pharmacodynamics, PD), safety and/or DDI.

Clinical Trials and Clinical Studies

This FOA will only support clinical research and trials for assessing PUCs at a U.S. site. To meet the objectives of the FOA it is critical that PUC study outcomes are linked to selection of sustained/extended release drug product rheological/biophysical (look and feel) properties as part of the development process. The outcome from the PUC studies should support/guide the rheological and biophysical property (ies) choices made for the sustained/extended release strategy.

Products for testing in PUC assessment must be managed for low potential risk when study participants are required to handle them during PUC studies. A mano studies (handled during the study) with commercial or licensed products may be carried out if all label contraindications and potential allergic reactions associated with handling of the product are managed.

A low risk placebo DDS or prototype may be developed and employed in studies where the device is used only for examination purposes, e.g. a mano studies. Human vaginal/rectal, parental dosing or implantation will not be supported. Any prototype or placebo manufactured specifically for use in a PUC study must be manufactured under Good Manufacturing Practices (GMP) with appropriate stability and sterility testing post-manufacture. Skin/dermal animal irritation/sensitization studies should be performed to confirm safety. For some placebo DDS there may be sufficient use of their components (excipients) in humans to justify forgoing specific skin/dermal sensitization/irritation testing, e.g. drug-free silicone and ethylene-vinyl acetate (EVA) IVRs and implants.

Handling of vaginal over-the-counter (OTC) products as surrogate products by study participants is allowed, if there are no documented handling safety risks and potential allergic reactions are managed. Use of nonoxynol-9 (N-9) based or containing products will not be supported for PUC assessments. To maintain low-risk, repackaged OTC products will not be supported.unless the appropriate package compatibility, stability and sterility studies have been performed on the repackaged product. Care should be taken when using OTC products, manufactured placebos or prototype sustained/extended release devices in PUC studies that the rheological/biophysical properties of products either span a range of potential user perceptions or match the biophysical and rheological properties of the proposed DDS.

Non-responsive Areas of Research

Applications proposing the following areas of research will be considered non-responsive and will NOT be reviewed:

• Phase I, II, III clinical trials, except for clinical research involving a mano PUC studies.

• Conduct of clinical research/trial to assess PUC at a non-U.S. site.

• Applications proposing development of sustained/extended release strategies with durations of action that do not meet the minimal durations defined in the FOA.

• Strategies or antiviral candidates without demonstrated antiviral activity to HIV. Although anti-HIV antivirals identified for development as sustained/extended release strategies may have activity against other sexually transmitted infections (STI), the objective of this FOA is the development of sustained/extended release anti-HIV products, not sustained/extended release products with activity against additional/other STIs. Strategies targeting multiple pathogens (HSV, HCV, HPV, bacterial, yeast, mycoplasma, etc.) are acceptable but should be justified and described solely for their development to prevent HIV infection. Inclusion of additional agents (other than excipients and carriers) without a significant contribution to anti-HIV activity is highly discouraged.

• Random, bulk or high-throughput screening of chemical or natural product libraries or collections to discover anti-HIV candidates (discrete inhibitors or natural product mixtures) for incorporation into sustained/extended release DDS. This includes medicinal chemistry efforts on screening leads or characterized anti-HIV active pharmaceutical ingredients (API) designed to create new anti-HIV compounds. Chemical modification of anti-HIV APIs may only be used to facilitate incorporation into and release from the proposed DDS.

• Broad, generalized global assessments in animal models or humans to identify biomarkers of sustained/extended release drug/DDS impact on the FRT, MGS, or GI tract using genomic, proteomic, scriptomic, metabolomic, and/or microbiome analysis/technologies that do not directly support the development or characterization of the impact of a sustained/extended release candidate/product.

• Intravenous infusion of any component of the sustained/extended release drug.

• Cure or amelioration of bacterial vaginosis (BV) or vaginal dysbiosis by any chemical or biological means to reduce HIV susceptibility as part of a sustained/extended release strategy.

• Sustained/extended release strategies employing a female or male condom, diaphragm or hormone containing IUD as the DDS.

• Use of any live biotherapeutic or vector system (viral, bacterial, fungal, etc.) to produce/deliver the anti-HIV component of the proposed drug product.

• Development or optimization of a Genetically Modified Organism (GMO) as a part of a sustained/extended release DDS or incorporation of bacteria selected or engineered for specific characteristics designed to create a "hostile microenvironment" for HIV. This restriction includes replacement of abnormal microbiomes with "normal" bacteria by supplementation or transplantation as a method to modulate genital or GI micro- or macro-environments as the anti-HIV strategy.

• Use of non-specific agents/products/drugs/candidates as the anti-HIV component(s). For this FOA non-specific agents are defined as agents that display broad anti-microbial activity (nonspecific killing of viruses, parasites, yeast, and pathogenic and beneficial bacteria) and/or do not have a defined anti-HIV target. Non-specific anti-HIV inhibitors may be chemically characterized as detergents or sulfonated polymers that act as either virucidal agents or inhibitors of HIV entry. Examples include, but are not limited to, N-9, BZK, C31G, and high molecular weight sulfonated polymers such as carrageenan, dextran sulfate, cellulose sulfate, and some dendrimers.

• Development of an uncharacterized or a complex-mixture natural product as the antiviral component of a strategy.

• Further development of an OTC product or a non-specific vaginal female health product, including OTC lubricants and sexual pleasure products as the DDS for the sustained/extended release strategy, or as the anti-HIV component. This does not preclude developing a strategy with rheological/biophysical properties that can act as a sexual lubricant or pleasure product.

• Development of sustained/extended release products incorporating the following HIV antiretrovirals:

• Sustained/extended release products composed solely of or combinations of Tenofovir (TFV, PMPA, (R)-9-(2-Phosphonoylmethoxypropyl) adenine), Tenofovir Disoproxil Fumarate (TDF or Viread ) and/or Tenofovir Alafenamide fumarate (TAF),

• The non-nucleoside reverse transcriptase inhibitor dapivirine as a single agent or in combination with TFV, TDF, TAF or Emtricitabine (FTC),

• Development of the following combination antiretrovirals as the anti-HIV component of a sustained/extended release strategy: TFV, TDF or TAF combined with Emtricitabine (FTC),

• Incorporation of Rilpivirine (TMC-278) or Cabotegravir (GSK-744, GSK/S 1265744) singly or in combination as the anti-HIV component in an injectable or implantable DDS. Development of combinations of these drugs with other active pharmaceutical ingredients (APIs), except as noted above, is responsive.

• Vaccine development of any form (new mucosal vaccine, vector, insert, or delivery system) and/or use of a vaccine as the antiviral or efficacy-enhancing element of a sustained/extended release prevention strategy.

• Basic behavioral research designed to develop and inform on broad issues of sustained/extended release product use as a generalized intervention to reduce HIV incidence. Surveys and studies designed to provide information on specific groups/ community/ individual attitudes/acceptability using hypothetical, conceptual or theoretical products. Education programs focused on any potential stakeholder population to support introduction of a sustained/extended release product. Structural and/or behavioral interventions to enhance projected product use or prepare for product roll-out, implementation or introduction. Epidemiologic studies targeting individuals other than product users, such as healthcare providers, policymakers, government officials or any non-user stakeholder to determine general enthusiasm/ openness to the product or concept of sustained/extended release.

• Activities that are intended solely for enabling/facilitating clinical studies to be conducted with non-SRI funds. This restriction includes GMP production of clinical supplies for use other than PUC or IND-enabling studies, and regulatory submissions other than the milestone required pre-IND and production of clinical supplies for future trials.

Applicants are encouraged to contact the Scientific/Research Contact(s) located at the end of this FOA to discuss planned strategies for developing an application.