D.1. SOW.pdf

STATEMENT OF WORK (SOW)

General Information

Title of Project:

Testing of compounds in rat pharmacokinetic experiments

Project Purpose or Objectives:

This requirement is for the testing of 20 (twenty) small molecule compounds in rat pharmacokinetic studies. These compounds are drug molecules being evaluated for a kinase inhibitor program. Testing of the compounds for their pharmacokinetic properties in rat will provide critical information on compound clearance, exposure, and bioavailability.

Background Information:

The National Institutes of Health (NIH) is the nation’s leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability, conducting, supporting and making medical discoveries that improve people’s health and save lives. The National Center for Advancing Translational

Sciences (NCATS) is a translational science center that prides itself on its productive pipeline and is innovative in a number of ways. NCATS brings together a diverse range of scientists, including medicinal chemists, biologists, toxicologists, and engineers, in order to ultimately translate basic science into real products and services that help improve people’s lives. Included in this process is the development of unique small molecules as potential anticancer agents.

Prior work at NCATS has produced a series of small molecule inhibitors, including

NCGC00371481 and its structural analogs. Compounds such as ‘1481 have shown promising results in cellular and mouse models of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Further optimization of the biochemical, physiochemical and pharmacokinetic properties of these compounds is required, and may eventually produce a clinical candidate that could be used to treat cancers such as MDS and / or AML.

In order for a candidate compound to advance into clinical trials, it must display a wide range of acceptable properties. For this program, a potential clinical candidate must display potent inhibition of the desired targets. It must also display suitable pharmacokinetic (PK) properties in a range of preclinical species, including at least one rodent species (mouse or rat), as well as at least one higher preclinical species (dog or monkey). Good PK profiles in these species are required 1) in order to build models that predict good pharmacokinetic properties in humans, and 2) so that compounds can be given at high doses and high plasma exposure levels in preclinical safety studies.

In order to characterize and optimize the pharmacokinetic properties of our compounds in rat, we need to run a series of rat pharmacokinetic experiments. Testing a set of 20 small molecule compounds in rat PK experiments will provide critical data that identify the strengths and weaknesses of our current compounds’ PK profiles, and will help us optimize those profiles so that we can identify a suitable candidate for clinical trials.

Period of Performance:

The period of performance is 12 months from the date of contract award.

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:

Specific Requirements:

Contractor will:

1. Test each of 20 small molecule compounds in rat pharmacokinetic studies comprised of two dosing arms (one oral, one IV, n = 3 rats per arm). Test compounds will be administered as a single doses (either oral or IV, depending on the study arm), and in each study arm, 8 serial blood draws will be taken at 8 different time points covering a range of at least 8 hours, and up to 24 hours, post-dose. Plasma samples will be analyzed by LCMS to determine the concentration of test compound at each time point.

2. Provide one comprehensive report for each of the 20 compounds detailing results from the pharmacokinetic experiment. The reports must contain the following:

- A graphical plot of plasma concentration of test compound vs. time

- A table of raw data showing the plasma concentration of test compound at each time point in each rat, as well as the average or mean concentration across all 3 rats, and the standard deviation or standard error for each mean value.

- Calculated oral bioavailability (F%), clearance rate (Clp), half-life (t1/2), area under the curve (AUC), maximal concentration (Cmax), and volume of distribution (Vd) for the compound.

Government Responsibilities:

Government will not furnish property, facilities, workspace, computers, or other equipment.

Contractor will not use federal facilities. Government will have the responsibility to review and approve the final report. Government will have the responsibility to provide sufficient quantities of the lead compound in order to contractor to accomplish the necessary work.

The Government anticipates, but does not guarantee, sending these compounds in 3 (three) to

6 (six) batches, with the first batch being sent shortly after contract award and each subsequent batch being sent after the other, during the performance of the contract with reasonable time for the contractor to perform the services.

Delivery or Deliverables:

Contractor will provide the data analysis and 1 (one) report for the 20 compounds detailing results from the pharmacokinetic studies provided in the content of this statement of work.

Reporting Requirements:

Contractor will provide monthly updates on the progress of the project, or more often as appropriate. Updates shall be provided electronically to Scott Hoyt at scott.hoyt@nih.gov.

Other Considerations:

Data Rights:

FAR Clause 52.227-14, Rights in Data-General (May 2014) is included in the solicitation and resultant award. Under 52.227-14(c)(1), the contractor must obtain approval from the contracting officer to assert copyright in any data first produced in performance of this contract and published in academic, technical or professional journals, symposia proceedings, or similar works. Under 52.227-14(d)(2), the contractor must obtain approval from the contracting officer to use, release to others, reproduce, distribute, or publish any data first produced or specifically used by the contractor in the performance of this contract.

In addition, the contractor will keep the results of the acquisition confidential.

Evaluating Factors:

Notwithstanding the evaluating factors provided in the solicitation, the following relevant experience shall be addressed by the contractor on its quote:

- Contractor shall run the assays using scientists that have significant experience (>3 years) in the testing of small molecule compounds in rat pharmacokinetic experiments;

and

- Contractor shall have significant experience (>3 years) in running rat pharmacokinetic experiments.

mailto:scott.hoyt@nih.gov