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cGMP Production, IND-enabling studies, and Phase I Clinical Studies to Test a Novel siRNA drug product for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Award Number: R44DK129102
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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cGMP Production, IND-enabling studies, and Phase I Clinical Studies to Test a Novel siRNA drug product for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) - SUMMARY Metabolic dysfunction-associated steatohepatitis (MASH), formerly called non-alcoholic steatohepatitis (NASH) is a form of non-alcohol fatty liver disease (MAFLD) and results from a pathological accumulation of fat in the liver. Approximately 5 million people in the United States are diagnosed each year, being more common in those with co-morbidities such as obesity, diabetes, and/or hyperlipidemia. MASH can lead to cirrhosis, followed by liver failure or hepatocellular carcinoma. Resmetirom was granted conditional approval by the FDA in March 2024 for treating MASH contingent upon verification and description of clinical benefit in ongoing confirmatory clinical trials. While this is likely an important step forward, a need exists for drugs that can further reduce liver fat, fibrosis, and inflammation. To address this medical need, we have taken the innovative approach of treating MASH and related liver diseases by increasing mitochondrial metabolism in the liver to boost the degradation of fatty acids and prevent their accumulation in the liver. Our target is MCJ (Methylation-Controlled J protein encoded by the DnaJC15 gene), an endogenous negative regulator of the ETC and mitochondrial respiration. MCJ is expressed in the hepatocytes and its expression is upregulated in the liver of MASH patients. We have shown that removal of MCJ in the liver is safe and results in increased mitochondrial respiration without increasing the generation of reactive oxygen species (ROS). Our therapeutic approach for MASH is to silence MCJ expression in hepatocytes using siRNA technology (five siRNA-based drugs are approved by FDA for treatment of different genetic diseases). Our lead drug candidate (MITO-1041) uses a proprietary siRNA for human MCJ (siMCJ) conjugated to our proprietary GalNAc (N-acetylgalactosamine), currently the preferred chronic siRNA delivery vehicle for hepatocytes. We have shown that MITO-1041 significantly reduces liver steatosis and lipid accumulation (55- 65% reduction) and fibrosis (75-85% reduction) in multiple mouse models of MASH. We have demonstrated PK/PD properties and safety in animal based non-GLP pre-clinical studies. Moving forward with MITO-1041 to MASH patients and following the recommendations from a pre-IND FDA meeting, in this application we propose to: Task 1: manufacturing cGMP material (our drug MITO-1041); Task 2: develop and validate assays for quantification of drug and metabolites in human, NHP, and rat sera; Task 3: IND enabling studies: 90 day rat and NHP tox studies and in vitro studies requested by FDA; Task 4: IND submission and conduct of a Phase 1 clinical study.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $996,169 )
2026	2026	MITOTHERAPEUTIX, LLC	4 RESEARCH DR	WOODBRIDGE	CT	06525	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/17/2026	COMPETING CONTINUATION	$996,169
														Subtotal = $996,169

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	MITOTHERAPEUTIX, LLC	4 RESEARCH DR	WOODBRIDGE	CT	06525	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,008,980 )
2023	2023	MITOTHERAPEUTIX LLC	400 FARMINGTON AVE	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$1,008,980
														Subtotal = $1,008,980

Issue Date FY: 2022 ( Subtotal = $860,261 )
2022	2022	MITOTHERAPEUTIX LLC	400 FARMINGTON AVE	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/28/2022	EXTENSION WITH OR WITHOUT FUNDS	$860,261
2022	2021	MITOTHERAPEUTIX LLC	400 FARMINGTON AVE	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/15/2021	NEW	$0
														Subtotal = $860,261

Issue Date FY: 2021 ( Subtotal = $253,050 )
2021	2021	MITOTHERAPEUTIX LLC	400 FARMINGTON AVE	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/26/2021	NEW	$253,050
														Subtotal = $253,050

Grand Total All Awards = $3,118,460

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cGMP Production, IND-enabling studies, and Phase I Clinical Studies to Test a Novel siRNA drug product for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Award Number: R44DK129102

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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