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A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis

Award Number: U01AA028951
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Alcoholic hepatitis (AH) is characterized by inflammatory liver injury with impaired hepatocyte regeneration, with high rates of morbidity and mortality. Currently, steroids are the only treatment option for patients with severe AH, however, they have limited efficacy (no treatment benefit demonstrated beyond 28 days) and many patients have contra-indications to steroid use (e.g. active infections) and cannot be treated. There is a clear unmet need for new therapeutic approaches in AH. Wnt signaling plays an important role in liver development, metabolic zonation, homeostatic turnover of hepatocytes, hepatocyte differentiation and maturation, and normal function and regulation of hepatocytes. Furthermore, Wnt/β-catenin signaling is critical to hepatocyte regeneration following various forms of liver injury. Deletion or overactivation of β-catenin has been shown to have a key impact on hepatocyte regeneration following partial hepatectomy, acetaminophen, CCl4, or alcohol-induced injuries in animal models. R-spondins (RSPOs) play an important role in liver homeostasis and hepatocyte regeneration following injury such as partial hepatectomy. RSPOs enhance Wnt signaling, and RSPO function depends on the presence of endogenous Wnt ligands; endogenous Wnt ligands tend to be upregulated and localized in injured tissues. Importantly in human AH patients, lack of hepatocyte regeneration and maturation is a major issue. Surrozen has developed SZN-043, a bi-specific fusion protein which is an R-spondin mimetic targeted to the hepatocyte receptor ASGR1 for liver-specific enhancement of Wnt signaling and tissue regeneration and repair. Our studies suggest that the effects of SZN-043, in contrast to RSPO2, are highly specific to hepatocytes, and can improve liver function and reduce fibrosis in rodent disease models. Our preclinical studies in mice and non-human primates have demonstrated that SZN-043 induces Wnt-target gene activation in the liver and selectively stimulates proliferation and maturation of hepatocytes. We are interested in exploring whether SZN-043 is capable of improving liver function and/or fibrosis in AH. In this grant, we propose first moving forward to develop cell line and material manufacturing process for SZN-043. This will be followed by IND-enabling studies, including, pharmacology, toxicology, pharmacokinetics, and biomarker information to inform and enable safe and effective administration of SZN-043 for testing in humans. We will then conduct Phase 1 single- and multiple-ascending dose studies in human patients to assess pharmacokinetics, pharmacodynamics, and safety of SZN-043 for the treatment of AH.


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: 2024 ( Subtotal = $0 )
2024	2023	SURROZEN OPERATING INC	171 OYSTER POINT BLVD	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	002	4	6/19/2024	NON-COMPETING CONTINUATION	$0
2024	2022	SURROZEN OPERATING INC	171 OYSTER POINT BLVD	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	001	3	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$500,000
2024	2021	SURROZEN INC	171 OYSTER POINT BLVD #400	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	000	2	12/5/2023	NON-COMPETING CONTINUATION	-$500,000
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $505,000 )
2023	2023	SURROZEN OPERATING, INC.	171 OYSTER POINT BLVD	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	000	4	9/22/2023	NON-COMPETING CONTINUATION	$505,000
														Subtotal = $505,000

Issue Date FY: 2022 ( Subtotal = $505,000 )
2022	2022	SURROZEN OPERATING, INC.	171 OYSTER POINT BLVD	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	001	3	9/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$505,000
2022	2021	SURROZEN INC	171 OYSTER POINT BLVD #400	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	000	2	9/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $505,000

Issue Date FY: 2021 ( Subtotal = $502,500 )
2021	2021	SURROZEN INC	171 OYSTER POINT BLVD #400	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	001	2	9/10/2021	NON-COMPETING CONTINUATION	$502,500
2021	2020	SURROZEN INC	171 OYSTER POINT BLVD #400	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	000	1	8/17/2021	NEW	$0
														Subtotal = $502,500

Issue Date FY: 2020 ( Subtotal = $1,005,000 )
2020	2020	SURROZEN INC	171 OYSTER POINT BLVD #400	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	Alcohol Research Programs	000	1	9/25/2020	NEW	$1,005,000
														Subtotal = $1,005,000

Grand Total All Awards = $2,517,500

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A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis

Award Number: U01AA028951

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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