75N95023R00004_Att. 4_Sample TORFP Technical Area 1.pdf

SAMPLE TASK ORDER REQUEST FOR PROPOSAL FOR TECHNICAL AREA 1

I. Task Order Information

A. Task Order Title: Generation and characterization of a mouse model for Farber disease, including pharmacological assessment of a candidate enzyme replacement therapy

B. Task Order Period of Performance: 36 months

C. Task Order Type: Cost plus Fixed Fee or Firm Fixed Price

D. Task Order Technical Area(s): Technical Area 1

II. Task Order Proposal Instructions

See Section L – Instructions to Offerors of Request for Proposals No. 75N95023R00004 for proposal instructions.

III. Task Order Technical Requirements

A. TASK DESCRIPTION: The following study involves work described in Technical Area 1 of the Statement of Work.

The Government seeks to develop an enzyme replacement therapy to treat a rare, inherited lysosomal storage disease (Farber disease, FD) caused by mutations in ASAH1, the gene that encodes the acid ceramidase enzyme. It presents in infants, affecting multiple organs, including the liver, spleen, lung and musculoskeletal system. The goal of this therapy is to resolve the hepatosplenomegaly, arthritis and inflammatory lung disease characteristic of FD.

The objectives of this SOW are to generate a mouse model for Farber disease; to breed live animals to assess viability and characterize and validate the phenotype in a longitudinal study; to develop bioanalytical methods and conduct biodistribution studies of the lead candidate, including enzyme activity; and to perform an efficacy study.

Comprehensive reporting will be required in the Common Technical Document (CTD) format sufficient for use in a regulatory submission to FDA.

Task 1. Generation and characterization of the Farber disease mouse model

Various mutations to the human ASAH1 gene have been described associated with acid ceramidase deficiency, and it has been shown that homozygous deletion of Asah1 gene (Asah1-/-) in mice leads to embryonic lethality.

For this study, the Contractor is to generate a mouse line bearing the murine Asah1 (Proline [P] 361 to Arginine [R]) mutation, using the genetic manipulation techniques of the Contractor’s choosing. The Contractor will establish a colony of mice that includes animals (1) homozygous and (2) heterozygous for the mutation and (3) wild-type controls for a longitudinal natural history study of disease. This will include molecular, biochemical, histopathological and phenotypic characterization.

Reference for specified mutation: Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med (2013) 5:827-842. https://doi.org/10.1002/emmm.201202301.

Task 2. Development of bioanalytical methods and conduct of biodistribution and enzyme activity studies Monocytes and macrophages are the primary target cells for FD treatment; are present in the systemic

RFP No. 75N95023R00004 Attachment 4 https://doi.org/10.1002/emmm.201202301 circulation and in key target organs; and readily take up exogenous enzyme. The Contractor will propose, establish and perform bioanalytical assays to measure the biodistribution and activity of rhAC in relevant tissue compartments after tail vein injection. Both male and female rodents should be used.

Task 3. Efficacy study of rhAC in FD mice to measure breakdown of accumulated ceramide

The therapeutic agent, a recombinant human acid ceramidase (rhAC) enzyme, will be supplied by the Government.

The Contractor will:

1. Breed homozygous and heterozygous mice established in Task 1, including wild type controls. The number of animals of each type used for the studies will be calculated to achieve sufficient statistical power, and both male and female animals are to be used.

2. Perform genotyping of all pups, including any that die during the efficacy study.

3. Treat mice of all genotypes with five (5) doses of the rhAC, administered once weekly by tail vein injection, beginning at 1 week of age.

4. Record body weight measurements of all pups.

5. Observe pups daily until weaning and if any pups die, preserve tissues for subsequent analysis (per 7-9, below).

6. Wean animals and maintain weaned animals on a regular diet according to the standard IACUC animal protocol.

7. Euthanize animals from all cohorts (dosed and control) at week 6 (one week after the final injection).

Perform a terminal bleed and collect blood at the time of necropsy. Measure liver ceramide levels.

8. Measure a standard panel of clinical pathology parameters and harvest and preserve a standard list of tissues (as collected in GLP-toxicology studies).

9. Preserve a portion of each tissue in formalin for histopathology and ship part of the formalin blocks to the Government.

10. Snap-freeze the remainder of each tissue on dry ice and store at -80°C.

Assumptions, Constraints, Clarifications and Qualifications

1. The Contractor is to assume that the required genetically modified mouse lines must be generated de novo, and that neither live Asah1 mutant animals, previously modified cell lines nor other genetic material can be obtained from other researchers or commercial suppliers.

B. TASK ORDER REPORT, DELIVERY SCHEDULE AND REPORTING REQUIREMENTS: Satisfactory performance of the task order shall be deemed to occur upon performance of the work described in the TO award, and upon completion, delivery, and acceptance by the Contracting Officer, or duly authorized representative, the below listed deliverables.

Technical Reports

1. Monthly Progress Report

This report shall include a description of the activities during the reporting period, and the activities planned for the ensuing reporting period. The first reporting period consists of the first full month of performance plus any fractional part of the initial month. Thereafter, the reporting period shall consist of each calendar month.

RFP No. 75N95023R00004 Attachment 4

Reporting shall be due on or before the 10th calendar day following each reporting period. A monthly report will not be required for the final month covered by the last Final Study Report.

2. Final Study Report

The Final Study Report shall accurately and completely describe the study design, procedures, and findings;

and present an analysis and summary of the data followed by the conclusions derived from the analyses. The report shall also include: (i) a cover page that includes the task order title, contract and task order numbers, report authors, laboratory addresses, dates of study initiation and completion, and sponsor; (ii) an abstract at the beginning of the report; (iii) a summary that follows the abstract; (iv) the signature of the study director;

(v) a table of contents; and (vi) a statement prepared and signed by the Quality Assurance Unit that refers to all phases of the study and to where the raw data, records, reports, and samples are stored.

Task Order Deliveries

Item Description Delivery Delivery Schedule

1 Monthly Progress Report Electronically to COR & CO

Due on the 10th calendar day following each reporting period.

2 Draft Study Protocol - for review (Task 1)

Electronically to COR & CO

At least 3 weeks prior to the start of the study. Government can take up to 2 weeks to review

3 Final Study Protocol (Task 1) Electronically to COR & CO

No Later Than (NTL) 1 week after receipt of Government’s Draft Study Protocol review comments

Draft Report of Completed Technical Requirements - for review (Task 1)

Electronically to COR & CO

NLT one (1) month after the technical requirements are completed

5 Final Report of Completed Technical Requirements (Task 1)

Electronically to COR & CO

NLT 1 month after receipt of Government’s Draft Report review comments

6 Draft Study Protocol - for review (Task 2)

Electronically to COR & CO

At least 3 weeks prior to the start of the study. Government can take up to 2 weeks to review

7 Final Study Protocol (Task 2) Electronically to COR & CO

No Later Than (NTL) 1 week after receipt of Government’s Draft Study Protocol review comments

Draft Report of Completed Technical Requirements - for review (Task 2)

Electronically to COR & CO

NLT one (1) month after the technical requirements are completed

9 Final Report of Completed Technical Requirements (Task 2)

Electronically to COR & CO

NLT 1 month after receipt of Government’s Draft Report review comments

10 Draft Study Protocol - for review (Task 3)

Electronically to COR & CO

At least 3 weeks prior to the start of the study. Government can take up to 2 weeks to review

11 Final Study Protocol (Task 3) Electronically to COR & CO

No Later Than (NTL) 1 week after receipt of Government’s Draft Study Protocol review comments

Draft Report of Completed Technical Requirements - for review (Task 3)

Electronically to COR & CO

NLT two (2) months after the technical requirements are completed

13 Final Report of Completed Technical Requirements (Task 3)

Electronically to COR & CO

NLT 1 month after receipt of Government’s Draft Report review comments

14 Final Study Report Electronically to COR & CO

Due on or before Task Order expiration date