SOW Pharmacodynamic and Tolerability studies.pdf

FAR Part 11—Describing Agency Needs

STATEMENT OF WORK (SOW)

GENERAL INFORMATION

Title of Project:

Pharmacodynamic and Tolerability studies of candidate AD drugs in a transgenic AD mouse model

Statement of Need and Purpose:

There is currently a pressing need to identify effective treatments for Alzheimer’s disease (AD).

With the repeated failures of multiple pivotal phase-III clinical trials in patients with AD, it is critical to test novel methods of discovering disease-modifying AD treatments. As part of one complete study called the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study, one ongoing study called the Experimental Validation of candidate Alzheimer’s disease treatments identified by multi-omics analyses (PREVENT-AD) study, in addition to three ongoing contracts, the NIA IRP is testing the utility of commonly prescribed, FDA-approved drugs that may be repurposed as `candidate AD treatments.’ The proposed acquisition will build on this work to test 1) tolerability of two candidate AD drugs in the 5x-FAD transgenic mouse model of AD to determine their optimal dosing in efficacy studies; and 2) efficacy of two candidate AD drugs in this transgenic AD mouse model.

Background Information and Objective:

Research in the NIA IRP has identified several FDA approved drugs through the DREAM study that may target metabolic abnormalities associated with AD and be of utility as effective disease-modifying AD treatments. Repurposing of approved drugs is a promising approach that can accelerate the development of novel AD treatments.

Through ongoing contracts for ‘Phenotypic screening of candidate drugs to treat Alzheimer’s Disease’, ‘In vivo efficacy studies of a candidate Alzheimer treatment in a transgenic mouse model’, and ‘Tolerability studies of candidate AD drugs and efficacy of Poly(L-lysine succinylated)-hydroxychloroquine (PLS-HCQ) in a transgenic AD mouse model’, the NIA IRP is testing a subset of `candidate AD treatments’ in cell culture-based phenotypic screening models and in a well characterized transgenic AD mouse model. Through the recently funded PREVENT-AD study (‘Experimental validation of candidate Alzheimer’s disease treatments identified by multi-omics analyses’), the NIA IRP will be testing 11 drugs in in vivo efficacy studies in a transgenic AD mouse model and 45 drugs in cell culture models.

This acquisition has two objectives: 1) NIA IRP proposes to test the tolerability of 2 candidate drugs. These tolerability studies will determine the optimal dose to be used in the in vivo efficacy studies. 2) Based on the results of the tolerability studies, NIA IRPs propose to test the efficacy of 2 drugs in a well-characterized transgenic AD mouse model.

Anticipated Period of Performance (POP):

September 30, 2023 – September 29, 2025

SCOPE OF WORK

General Requirements:

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the Statement of Work below:

1. In vivo tolerability studies in a well characterized transgenic AD mouse model:

Perform tolerability studies of 2 FDA approved or experimental drugs. Appropriate drug doses to be tested will be derived from preliminary screening against cell viability measures in a cell culture model completed in a previous acquisition; ‘Phenotypic screening of candidate drugs to treat Alzheimer’s Disease’. Tolerability studies will be performed to determine the impact of drug administration compared to a vehicular control across multiple toxicity categories (cardiovascular, gastrointestinal, respiratory). We will specifically test the following:

- General signs of health, distress, pain, body weight, dehydration, motivation to groom

- Toxicity by visual inspection

- Cage-side observations

- Impact of the drug on overall survival

2. In vivo efficacy studies in a well characterized transgenic AD mouse model:

Perform efficacy studies of 2 FDA approved or experimental drugs. In the 5x-FAD transgenic AD mouse model we will specifically test whether the drug:

- improves cognitive performance tested by the Morris Water Maze and Y-maze

- reduces amyloid pathology, tau phosphorylation, and microglial activation measured via brain histology: quantitative immunofluorescence (4 markers, 2 areas of interest) in cortex and hippocampus using LOC antibody labeling and thioflavin S staining to label amyloid-beta fibrils and plaque cores, and AT8 antibody labeling for pSer202/pThr205 tau, and Iba1 labeling of activated microglia; includes DAPI staining

- reduces amyloid pathology and microglial activation via brain biochemical assays: MSD kit measured Aβ40 and Aβ42 and 10-plex inflammation marker panel (e.g. IFNγ, IL-1β, IL-10, IL-12p70, IL-6, TNFα)

- reduces neurodegeneration (by serial plasma assays for neurofilament light chain protein (NfL).

Specific Requirements:

LEVEL OF EFFORT:

1. Tolerability studies of 2 drugs

- Senior researcher: 100 labor hours

2. In vivo efficacy study of 2 drugs

- Senior researcher 230 labor hours

GOVERNMENT RESPONSIBILITIES

Provide a list of 2 candidate AD drugs to the contractor for testing in in vivo tolerability studies efficacy studies as described above.

DELIVERY OR DELIVERABLES

Electronic copy of excel spreadsheet including results of the drug tolerability studies and efficacy study to be delivered within 364 calendar days of receipt of the ‘candidate AD treatments.’ The timely submission of this deliverable is essential to successful completing this requirement.

REPORTING REQUIREMENTS

The contractor is required to provide written progress reports every 3 months for the contract period 09/30/23 through 09/29/25 with annual reports at the end of each year. The progress report shall cover all work completed and shall present the work to be accomplished. This report shall also identify any problems that arose and a statement explaining how the problem was resolved. This report shall also identify any problems that have arisen but have not been completely resolved and provide an explanation.

Reports shall be as follows:

1. WORD/ PDF document and summary XLS tables detailing all the technical aspects of the experimental methodology used and results of toxicity studies describing the impact of drug administration on internal organs across toxicity categories, cage-side observation, and the impact of drug administration on overall survival.

2. WORD/ PDF document and summary XLS tables detailing all the technical aspects of the experimental methodology used and results of in vivo drug efficacy study describing its effects on cognitive performance, AD pathology (histology), AD pathology and neuroinflammation (biochemical assays) and neurodegeneration (NfL assay).

OTHER CONSIDERATIONS

Data Rights:

The National Institute on Aging shall have unlimited rights to and ownership of all deliverables provided under this contract including reports, recommendations, briefings, work plans and all other deliverables. This includes the deliverables provided under the basic contract and any optional task deliverables exercised by the contracting officer. In addition, it includes any additional deliverables required by contract change. The definition of “unlimited rights” is contained in Federal Acquisition Regulation (FAR) 27.401, “Definitions.”

Section 508—Electronic and Information Technology Standards:

The contractor is not required to develop, procure, maintain, or use Electronic and Information Technology (EIT) in the performance of the SOW.

Publications and Publicity:

It is expected that the successful completion of the project and receipt of the deliverables specified above will allow investigators in the NIA IRP led by Dr. Madhav Thambisetty to include them in peer-reviewed scientific publications describing their original research carried out in the NIA IRP. At the time of drafting these scientific manuscripts, it is anticipated that Dr.

Thambisetty will consult with the contractor(s) and consider their participation as co-authors on publication(s) arising from the project.

Confidentiality of Information:

The Government will not provide to the contractor any information or data of a personal nature about individual(s) or proprietary information or data pertaining to an institution or organization which is confidential.