D1 SOW_MMA BioA Statement of Work 9DEC2024_LC241209215110 edited 25MAR2025.docx

STATEMENT OF WORK

Bioanalytical Assay Methods Development and Performance for the Evaluation of Safety and Efficacy of an AAV-Based Gene Therapy Candidate in Methyl Malonic Acidemia (MMA) disease December 9, 2024

A. BACKGROUND AND INTRODUCTION

The National Center for Advancing Translational Sciences (NCATS), through its Therapeutics for Rare and Neglected Diseases (TRND) program, is collaborating with the National Human Genome Institute (NHGRI) to advance an adeno-associated virus gene therapy candidate as possible treatment for isolated methyl malonic acidemia (MMA). The overall objective of this task order is for the contractor to develop bioanalytical assays suitable for the testing of the AAV transgene gene therapy candidate AAV8-MMUT (MMA-101) in clinical trials and to evaluate clinical samples using these assays and others previously developed for the same AAV gene therapy.

Disease Background: Isolated methylmalonic acidemia (MMA) is a serious, life-threatening inherited metabolic disorder that is caused most frequently by biallelic pathogenic variants in the gene coding for the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT). Patients who harbor variants in MMUT resulting in very low or absent MMUT enzymatic activity are the most severely affected (mut0 subtype), while those with partial deficiency (mut – ) are associated with markedly milder phenotypes and improved survival. For mut0 patients, mortality remains high and is estimated at 40-47% in different case series, despite newborn screening and advanced care. Gene therapy with AAV8-MMUT to replace the MMUT gene would be desirable because it avoids the surgical and lifelong immunosuppression risks associated with liver transplant.

Clinical Evaluation of AAV8-MMUT based gene therapy: An open-label, single-center, first-in-human trial will evaluate the gene therapy. The study will treat less than 10 subjects with MMA. The primary objectives of this study are: 1) to evaluate the safety and tolerability of AAV8-MMUT delivered intravenously; and 2) to evaluate the pharmacodynamic (PD) response to the gene therapy as assessed via identified biomarkers. In addition, the study proposes to evaluate antibodies against AAV8 and MMUT, neutralizing antibodies to AAV8, T-cell responses to AAV8 and MMUT, as well as viral shedding of the AAV-based gene therapy in body fluids.

B. SCOPE AND OBJECTIVES

The scope of this task order is the development of qualified bioanalytical assay methods and testing of clinical samples collected before and after administration of the AAV gene therapy product. The results of the testing will be indicative of the safety and efficacy of the gene therapy product for MMA.

C. GENERAL REQUIREMENTS

1. Project Management The Contractor shall provide project management for its own core team to ensure planning, execution, delivery of reports, and accurate and timely communication with the Contracting Officer’s Representative (COR), Contracting Officer (CO), and other stakeholders. The Contractor shall immediately (within 1 working day) contact the COR if there are any adverse results or difficulties with the study that would impact the project or timeline. The communications shall include proposed solutions. The Contractor shall immediately (within 1 working day) respond to any email communications sent by the Government and flagged as important.

The Contractor shall manage bi-weekly teleconference meetings to keep the COR and the project team apprised of project progress. At the discretion of the COR, the frequency or method of meetings may be changed. It is expected that during each task initiation and study protocol development, communication will be more frequent. The Contractor shall communicate via e-mail when teleconferences are cancelled as agreed upon by the Government. The Contractor shall also manage ad hoc meetings as requested by COR, which shall be scheduled by the Contractor within 48 hours of request. The Contractor shall be responsible for setting up the meeting with technology that enables screen sharing (ex. Teams, Zoom, etc.), including a call-in number and passcode for the relevant participants and be responsible for moderating and participating in the meeting.

The Contractor shall submit Pre-Meeting Status Updates/Agendas, and Post-Meeting Minutes, as described in Paragraphs E and F below. The Contractor shall provide any CRO Standard Operating Procedures, protocols, and methods within forty-eight (48) hours upon request as outlined in Paragraph F below. Status updates and progress of experiments including new preliminary data generated between meetings will be reviewed and discussed at each teleconference meeting.

2. Standard Operating Procedures The Contractor shall follow all site-specific standard operating procedures (SOPs); or if a deviation from an SOP is required, notify the COR of the deviation and document as appropriate. At the request of the COR, the Contractor shall submit to the Government any SOPs, method descriptions, and references used in the implementation of studies. The Government will treat Contractor SOPs as confidential.

3. Record Retention The Contractor shall provide all data, information, and records required for the writing and submission of regulatory documentation including but not limited to Investigator’s Brochures and Investigational New Drug, New Drug, and Biologics License applications.

Upon study completion, the Government may require all study documentation to be placed in secure storage for a period of up to seven years. During this period, the Contractor shall be responsible for the integrity and organization of the material and its confidentiality. At the end of the period, all such documentation will be transferred or disposed at the direction of the COR.

4. Government-Furnished Data The Contractor will have access to any data available at NCATS or the NCATS partner related to each task order that the Government deems necessary to successfully perform under the task order.

The Government will ensure all candidate therapeutics and any known safety data for storage and handling are supplied to the Contractor.

5. Research Involving Live Vertebrate Animals There is no research involving live animals.

D. TECHNICAL 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 tasks described below. Successful execution of the tasks will be dependent on communication between the Contractor and the Government as detailed in “Task Order Delivery and Report Schedule” found in this document, and an open dialog between the Contractor and the Government is expected.

Contractor must perform method development and qualification or validation as well as sample analysis for methods to be conducted in compliance with Good Clinical Practice (GCP), International Council for Harmonization (ICH), or Clinical Laboratory Improvement Amendments (CLIA), as required.

The Contractor shall perform the following tasks (and options, if exercised):

Task A (Base): to provide a qualified assay for the measurement of T-cell responses to AAV8 and MMUT in clinical samples collected before and after administration of AAV8-MMUT gene therapy The contractor shall:

1. Establish and qualify an immunological Elispot assay to quantitate T-cell responses to AAV8 (capsid) and MMUT (transgene) in clinical samples from patients receiving AAV gene therapy in the clinical trial.

2. Provide a complete separate qualification report (IND and cGCP format) for the assay, including all data for assay qualification, calibration standards, and QCs.

Task B (Option): to provide a validated qPCR assay for the measurement of viral shedding in clinical samples collected after administration of AAV8-MMUT gene therapy The contractor shall:

1. Establish and validate a qPCR assay for viral shedding to quantitate the AAV8-MMUT vector shed into the saliva of patients receiving AAV gene therapy in the clinical trial

2. Provide a complete separate validation report (IND format) for the assay, including all data for assay validation, calibration standards, and QCs.

Task C (Option): set-up of AAV8 and MMUT antibody IgG/IgM assay and AAV8 neutralizing antibody assay performance for testing of clinical trial samples The Contractor shall:

1. Get ready and set up the existing AAV8 and MMUT antibody (IgG and IgM) assay and the AAV8 neutralizing antibodies assay previously developed for this investigational product in order to initiate testing of clinical samples from the planned Phase 1/2 clinical trial.

Task D (Option): perform AAV8 and MMUT immunological testing and viral shedding on clinical samples collected before and after administration of AAV8-MMUT gene therapy The Contractor shall:

1. Evaluate AAV8 neutralizing antibodies using a CLIA AAV8 Neutralizing Antibody assay in clinical samples from screening of research participants for eligibility and transmit results to the IND Sponsor of the clinical trial in compliance with ICH, GCP and CLIA to determine participant eligibility

2. Evaluate anti-AAV8 and anti-MMUT antibodies (IgG and IgM) in clinical samples using validated assays, prepare report with the results, and submit report to IND sponsor of the clinical trial

3. Evaluate anti-AAV8 and anti-MMUT T-cell responses in clinical samples using the Elispot assay developed in Task A, prepare report with the results, and submit report to IND sponsor of the clinical trial, in compliance with ICH and GCP

4. Evaluate viral shedding in human saliva using the assay developed in Task B, prepare report with the results, and submit report to IND sponsor of the clinical trial, in compliance with ICH and GCP

E. DELIVERABLES

Contractor shall prepare and submit the following deliverables in accordance with the below and Section F.

1. Pre-Meeting Status Report/Agenda A Pre-meeting Status Report/Agena that documents the efforts performed in the completion of each task and highlights updates that occur between teleconference meetings. The Pre-meeting Status Reports shall include, at a minimum, the following information:

· Program status, to include objectives met, work completed, data generated, and outstanding work

· Notable achievements, and a review of data generated through visualization (ex. tables, graphs, images, figures, spreadsheets)

· Issues or obstacles impeding progress and recommended solutions

· Description of work completed and plans for next reporting period

· Agenda for corresponding team meeting

· Status of deliverables/milestones

· Issues and resolutions

· Resource planning/status

2. Qualified of Elispot assay to detect T-cell responses to AAV8 and MMUT The report of assay development and qualification for the assay must meet ICH standards mentioned in the SOW requirements and will be finalized in communication with the government.

3. Validated viral shedding assay for AAV gene therapy The report of assay development and validation for the assay must meet ICH standards mentioned in the SOW requirements. The validation report will need to be approved prior to execution.

4. Clinical sample analysis for samples of research participants enrolled and treated in the clinical trial of AAV8-MMUT

· Assays already validated for AAV8 and MMUT antibodies (IgG/IgM) and AAV8 Neutralizing antibodies assays will be restarted to be used in the AAV8-MMUT clinical trial for sample analysis

· Analyze clinical samples for AAV8 neutralizing antibodies (n=50-80)and provide reports according to the CLIA standards

· Analyze clinical samples for anti-AAV8 and anti-MMUT total antibodies (IgG/IgM) (n=~50-80), T-cell responses to AAV8 and MMUT (n= ~40) and provide reports according to ICH and GCP standards, for research use only. Samples can be analyzed in batches.

· Analyze clinical samples for AAV8-MMUT viral shedding (n=~60-80) and provide reports according to ICH and GCP standards, for research use only. Samples can be analyzed in batches.

5. Transition Plan A proposed Transition Plan for an orderly and complete transition/relocation of the task order resources to a successor Contractor or to the Government. The plan shall include details on the relocation/disposition of: unused materials and supplies; manuals and directories developed by the Contractor; and all other government property not listed. The Transition Plan shall specify that all raw data will be transferred to the Government. The Transition Plan shall also specify that unused test agents will be returned to the submitter at the submitter’s expense or destroyed at the conclusion of the task order, as determined by the Government, and a cumulative list of test samples disposed and the method of disposition will be provided to the Government. Upon written direction by the Government, the Contractor shall transfer all Government property as directed, and fully cooperate with any successor Contractor and the Government to ensure an efficient transfer.

F. 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. The deliverables shall be delivered F.o.b. Destination as set forth in FAR Clause 52.247-35, F.o.b. DESTINATION, WITHIN CONSIGNESES PREMISES (APRIL 1984).

*The completion status of a task will be determined in the biweekly teleconference.

G. Period of Performance:

This is intended to be awarded as One (12-month) Base and Four (12-month) Option Periods.

Base (Task A) Option Year 1 (Tasks B, C and D) Option Year 2 (Task D) Option Year 3 (Task D) Option Year 4 (Task D)