D1 MMA Stability Testing and regulatory support SOW 18MAR2025.docx

STATEMENT OF WORK

MMA-101 Stability and Compatibility Studies and CMC March 20, 2025

A. BACKGROUND AND INTRODUCTION

The National Center for Advancing Translational Sciences (NCATS) 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).

Background: 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 MMA-101 (AAV8-MMUT) to replace the MMUT gene would be desirable because it avoids the surgical and lifelong immunosuppression risks associated with liver transplant.

An open-label, single-center, first-in-human trial will evaluate the AAV8-MMUT gene therapy. Two cGMP/clinical lots of MMA-101 (AAV8-MMUT), G-NORMA-030 and G-NORMA-057, and two cGMP/clinical lots of diluent/formulation buffer (FFB-G-004 and FFB-G-023) have been manufactured by Viralgen. The products met all the release acceptance criteria for clinical use. Viralgen performed stability testing up to 36M on the cGMP lots and a compatibility study of AAV8-MMUT gene therapy with a limited number of clinical devices to deliver the product to research subjects.

B. SCOPE AND OBJECTIVES

The overall objectives of this order are for the contractor: a) to extend the stability testing of the cGMP lots for additional time points up to 48 months; b) provide Chemistry Manufacturing and Controls (CMC) regulatory support for the investigational product; and c) to perform a compatibility study of cGMP material with devices used in the clinical trial of MMA-101.

C. GENERAL REQUIREMENTS

1. Stability Testing Using the already existing stability testing protocol, the Contractor shall perform testing on the cGMP material, and analyze the data generated on the quality attributes for MMA-101 and diluent. The final protocol will be reviewed by the government prior to study start. The Contractor shall compare these data with the historical lot release results and provide a quality report that will used to support the use of MMA-101 and the diluent in clinical trial testing.

2. Record Retention and regulatory support 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, and Biologics License applications. The contractor shall provide subject matter expertise (SME) support, as needed during the submissions. Government assumes no more than 100 hours of such SME support.

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.

3. Compatibility of delivery devices used for administration of MMA-101 Using the already existing compatibility protocol and the MMA-101 product-specific assays as a reference, the Contractor shall perform a compatibility study of MMA-101 with the new devices that will be used to deliver this gene therapy in the clinical trial that will be performed at the NIH Clinical Center (CC). The protocol design shall be finalized after discussions with the Government and final protocol will be reviewed by the government prior to study start. At the end of the study, the Contractor shall prepare a compatibility study report with the data generated on the quality attributes for MMA-101. The report shall be in IND format and will be used to support the use of the devices to deliver MMA-101 in the clinical trial.

The study must include up to 4 devices (government will share details of these devices planned to be used in the clinical study), one dose of MMA-101, and the same number of timepoints and controls as used for the compatibility study previously performed (Selecta-sponsored study).

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.

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.

The overall objectives of this task order are for the contractor: a) to extend the stability testing of the cGMP material (see Table 1 below for details), to analyze the data generated on the quality attributes, to compare these data to the historical lot release results, and to ascertain if the MMA-101 material meets acceptance quality criteria for testing in clinical trials; b) to provide Chemistry Manufacturing and Controls (CMC) regulatory support; and c) to perform a compatibility study of cGMP material with devices that will be used in the clinical trial of MMA-101, using the same protocol and assays previously performed for the same product and a different set of devices (Selecta-sponsored clinical trial).

Table 1: 48-month extended stability plan, up to Month 84 (product is currently under a 36-month stability testing plan)

1. The contractor shall analyze the data generated on the quality attributes for MMA-101 clinical lot G-NORMA-30 and diluent/formulation buffer lot FFB-G-004, and clinical lot G-NORMA-57 and diluent/formulation buffer lot FFB-G-023.

2. The contractor shall compare these data to the historical lot release results and ascertain if the MMA-101 material meets acceptance quality criteria for testing in clinical trials.

3. The Contractor shall prepare stability Study Reports for MMA101 and diluent at the specified timepoints and deliver to the government.

4. The contractor shall review and/ or provide IND related documentation for the MMA101 product, as requested by the government.

5. The Contractor shall test up to 4 more devices that are planned to be used to deliver MMA-101 to research subjects.

6. The Contractor shall prepare a Compatibility Study Report in IND-ready format and deliver to the government.

E. DELIVERABLES

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

1. Stability data analysis report for the two clinical lots of MMA-101 and two lots of diluent/formulation buffer, along with the underlying datasets

2. Executive summary on Contractor’s recommendations for suitability and compliance of the product for clinical use

3. IND related documentation

4. Compatibility study report

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).

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