This Funding Opportunity Announcement (FOA) solicits applications that will each support the early clinical development of a single new monoclonal antibody (mAb) compound or mAb combination regimen to achieve a drug-free sustained viral remission (SVR) in HIV infected individuals.
Achieving a drug free sustained viral remission is a high priority for the NIH. HIV remains in quiescent infected CD4+ cells and re-emerges when ART is stopped even after years of suppressive therapy and in the absence of detectable HIV DNA. It is of the utmost interest to the field to test interventions that can result in a sustained drug-free remission. Preclinical studies in non-human primates (NHPs) with mAbs, including combinations of broadly neutralizing antibodies (bNAbs), engineered mAbs and an anti-a4B7 integrin, have independently demonstrated that mAbs can result in a drug-free sustained viral remission (SVR) that persists long after mAb clearance. The precise mechanisms of action of these findings are unknown at present but they support exploring the use of mAbs to achieve a drug-free SVR in HIV infected individuals. Clinical trials in HIV infected individuals using some mAbs (bNAbs, anti-a4B7 integrin, and antibodies that work by a different mechanism of action) are underway or planned. However, multiple other candidate native and engineered mAbs with similar or better potency, PK parameters, safety profiles, breadth of neutralization, enhanced Fc function, or other mechanisms of action have been identified, characterized, and evaluated in preclinical studies. The goal of this initiative is to support the clinical development of candidate mAbs, either alone or in combination, that have achieved a SVR in an appropriate animal model or clinical study.
Preclinical and clinical studies have failed to identify HIV specific immune responses or changes in the HIV reservoir that correlate to a SVR when ART is stopped. Therefore, antiretroviral treatment interruption (ATI) is a necessary component of proof-of-concept (POC) studies, in addition to assessing the impact of the mAb on the HIV reservoir and HIV-specific innate and adaptive immune responses.
This FOA will support the early clinical development of a native or engineered mAb or mAb combination that has preclinical data in an appropriate animal model or from a clinical study that would support its ability to achieve a drug-free SVR. The objective of this FOA is to rapidly assess mAb candidates and to move promising mAbs through the POC stage of clinical development.
Monoclonal antibodies used in the clinical trials must:
- Be manufactured in accordance with the U.S. FDA’s current good manufacturing practice (cGMP) regulations;
- Be available in the appropriate quantity and format when the first clinical trial opens to enrollment within 9 months of the grant award.
It is anticipated that all trials supported by this initiative will be conducted under an Investigational New Drug (IND) application. In most cases, it is expected that NIAID will NOT hold the IND. Investigators will provide all regulatory support required of an IND sponsor. NIAID reserves the right to specify the requirements for the establishment of a DSMB (Data Safety Monitoring Board) or SMC (Safety Monitoring Committee). Applicants are encouraged to discuss these issues with NIAID prior to submission of the application.
Clinical Trials
Two small pilot clinical trials in HIV infected individuals must be proposed. To facilitate rapid implementation, clinical trials are limited to one or two clinical sites located only in the U.S.
The first trial must include viremic HIV infected subjects. In most cases these trials will involve a small number of subjects (e.g., 30 participants or fewer). The first trial must evaluate the safety, PK and antiviral activity, as appropriate, of a new mAb or mAb combination that will be evaluated in a subsequent POC trail.
The second trial must be a delayed onset POC trial with a closely monitored ATI, and must include the same mAb(s) that were evaluated in the first trial. One goal for the POC trial must be to explore the ability of the mAb, alone or in combination to achieve a drug-free SVR during an ATI. Additional goals might include exploring the effects of the mAb(s) on HIV virions and on immune effector mechanisms. The second trial may be designed to:
- Extend the results of the initial trial including studies of combinations of agents;
- Evaluate the mAb intervention in a new population (e.g., pediatric) provided adequate safety data are available.
Regulatory Support
All clinical trial planning activities for the first trial must be completed by the time of the published FOA receipt date. The first trial must open to enrollment within 9 months of receiving the award to allow for an evaluation of early enrollment and the probability of successfully completing the clinical trial(s) within the five-year grant project period.
This FOA will NOT support clinical trial planning activities for the first trial, such as:
- Development of study design
- Identification of collaborators and enrollment site
- Development of the clinical protocol and informed consent
- Development of the statistical analysis plan
- Development of the data management plan
- Development of the Investigator’s Brochure
This FOA WILL support clinical trial planning activities for the second trial, such as:
- Development of the clinical protocol and informed consent
- Development of the statistical analysis plan
- Development of the data management plan
- Development of the Investigator’s Brochure
This FOA MAY support activities related to the conduct of the clinical trials, including, but not limited to:
- Regulatory activities to support implementation of the trial
- Training of study personnel related to conduct of the trial
- Enrollment and recruitment of study subjects
- Data collection, management, and quality control
- Laboratory work and data analysis
- Study management and oversight
- Establishment of committees to manage trial implementation activities
- Preparation of the final study report
- Other related post-enrollment activities
- Site monitoring
NIAID reserves the right to specify: 1) whether an IND (Investigational New Drug)/IDE (Investigational Device Exemption) application should be submitted to an appropriate regulatory agency; 2) the entity (NIAID, primary awardee, etc.) who will hold the IND/IDE; and 3) the requirements for the establishment of a DSMB (Data Safety Monitoring Board)/SMC (Safety Monitoring Committee). In most cases, it is expected that the NIAID will not hold the IND/IDE. In addition, NIAID reserves the right to review all documents and correspondence from all appropriate regulatory agencies concerning the first trial prior to making a funding decision.
Prior to award, NIAID will review the status of the product with the FDA. If the first study will be filed to an existing IND, the PD(s)/PI(s) must provide evidence that the FDA has received the protocol. If the first study proposed in the application is used to open an IND, the PD(s)/PI(s) must provide a safe to proceed letter from the FDA before NIAID will make an award. NIAID reserves the right to review the FDA’s response/comments and the IND Applicant’s response to the FDA’s comments prior to making an award decision.
Applicants should review the NIAID Clinical Terms of Award and associated guidance documents, policies, and procedures that will be made terms of an award (https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award ), and the DAIDS Clinical Research Policies and Standard Procedures Documents (https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures) that describe requirements for DAIDS-funded clinical research. Applicants are also referred to NIAID’s Clinical Research Toolkit website (https://www.niaid.nih.gov/research/trans-niaid-clinical-research-toolkit ).
Deadlines: October 10, 2018, October 9, 2019 (letters of intent due 30 days prior to deadline)
URL: https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-18-022.html
Filed Under: Funding Opportunities