SZN-043 / Surrozen - LARVOL DELTA

Surrozen Announces an Oversubscribed $175 Million Private Placement of Securities to Focus on Selective Wnt Mimetic Therapeutics to Treat Serious Eye Diseases (GlobeNewswire) - "Surrozen, Inc...today announced that the company will focus its Wnt biology expertise and Wnt signal modulation antibody technologies on its ophthalmology programs including development of new treatment options for retinopathies. The Company also announced a private placement consisting of two tranches in aggregate up to $175 million in gross proceeds to fund multiple ophthalmology programs through initial Phase 1 safety, tolerability and efficacy studies...The two lead candidates for the treatment of retinopathies include SZN-8141 (Fzd4/VEGF) and SZN-8143 (Fzd4/VEGF/IL-6)...The Company will discontinue development of SZN-043 in severe alcohol associated hepatitis....The second closing is subject to the receipt of clearance from the FDA of the Company’s Investigational New Drug Application for SZN-8141, expected in 2026."

Discontinued • Financing • IND • Diabetic Macular Edema • Hepatology • Ophthalmology • Wet Age-related Macular Degeneration

A Multiple Dose Study in Participants with Severe Alcohol-Associated Hepatitis to Assess the Safety and the Way the Body Absorbs, Distributes, and Eliminates the drug SZN-043. (ANZCTR) - P1 | N=18 | Recruiting | Sponsor: Surrozen Operating, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: May 2024

Enrollment open • Trial initiation date • Hepatology • Inflammation

Preliminary results of a phase I study of SZN-043, a novel R-Spondin mimetic, in healthy volunteers and subjects with liver cirrhosis (EASL-ILC 2024) - "Administration of SZN-043 to HVs and LCs was well tolerated at doses where evidence of pharmacology was observed. Combined with the promise of the underlying biological mechanisms, the results from this study warrant further clinical investigation of SZN-043. A Phase Ib study in subjects with severe alcohol-associated hepatitis is under way."

Clinical • P1 data • Addiction (Opioid and Alcohol) • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • RSPO1 • SPON1

A Multiple Dose Study in Participants with Severe Alcohol-Associated Hepatitis to Assess the Safety and the Way the Body Absorbs, Distributes, and Eliminates the drug SZN-043. (ANZCTR) - P1 | N=18 | Not yet recruiting | Sponsor: Surrozen Operating, Inc.

New P1 trial • Hepatology • Inflammation

SZN-043, A HEPATOCYTE-TARGETED R-SPONDIN MIMETIC, STIMULATES HEPATOCYTE PROLIFERATION AND IN A HUMANIZED LIVER FRG MOUSE MODEL (AASLD 2023) - "These results show that SZN-043 can drive human hepatocyte-proliferation in humanized liver mice. This effect suggests that SZN-043 may have meaningful clinical benefit in human disease states where hepatocyte proliferation is impaired, such as in severe alcoholic hepatitis."

Preclinical • Addiction (Opioid and Alcohol) • Hepatology • Inflammation • CTNNB1 • CYP1A2 • CYP2E1 • IL2RG • LECT2 • RSPO1 • SPON1

SZN-043, AN R-SPONDIN MIMETIC IN PRECLINICAL DEVELOPMENT FOR THE TREATMENT OF LIVER DISEASE, DEMONSTRATES A STRONG SAFETY PROFILE IN NONCLINICAL TOXICOLOGY STUDIES (AASLD 2022) - "SZN-043 was well-tolerated up to 125 mg/kg twice weekly with effects limited to nonadverse, reversible changes in clinical chemistry and organ weights. There were no macroscopic or microscopic SZN-043-related observations. Based on these results, the no-observed-adverse-effect level was the highest dose of 125 mg/kg."

Preclinical • Hepatology • Liver Failure • Ophthalmology • RSPO1 • SPON1

SERUM LECT2 AS A BIOMARKER IN SUBJECTS WITH EXCESSIVE ALCOHOL USE AND ALCOHOLIC CIRRHOSIS (AASLD 2022) - "Treatment of mice with SZN-043, a hepatocyte-specific Wnt mimetic, transiently increases liver and serum LECT2 levels... Serum level of LECT2 was decreased in ED and AC patients compared to controls. This suggests that excessive alcohol use may dysregulate hepatic Wnt/ꞵ-catenin signaling and may indicate impaired liver regeneration in these patients. The prognostic implication of LECT2 in AC patients should be further explored."

Biomarker • Clinical • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Inflammation • Portal Hypertension • AFP

DELAYED TREATMENT WITH SZN-043, A HEPATOCYTE TARGETED R-SPONDIN MIMETIC, ACCELERATED TISSUE REPAIR IN AN ACUTE ACETAMINOPHEN-INDUCED LIVER INJURY MODEL (AASLD 2022) - "These results provide supporting evidence that SZN-043 can accelerate hepatocyte-specific regeneration in response to APAP overdose, even with delayed administration. This approach may be beneficial for the treatment of acute liver injury."

Hepatology • Liver Failure • CCND1 • IL1B • IL6 • RSPO1 • SPON1

THE USE OF TRANSLATIONAL PHARMACOLOGY TO ESTIMATE THE HUMAN PHARMACOLOGICALLY ACTIVE DOSE OF SZN-043, AN R-SPONDIN MIMETIC IN DEVELOPMENT FOR THE TREATMENT OF LIVER DISEASE (AASLD 2022) - "Predictions of human SZN-043 PK show that elimination will be rapid at low doses but become progressively slower as doses increase and reach the pharmacologically active range. The pharmacologically active dose of SZN-043 in humans is estimated to be in the range of ≥3 mg/kg."

Hepatology • Liver Failure • AFP • ASGR • RSPO1 • SPON1

SZN-043, AN R-SPONDIN MIMETIC IN DEVELOPMENT FOR THE TREATMENT OF LIVER DISEASE, DEMONSTRATES A STRONG SAFETY PROFILE IN NONCLINICAL TOXICOLOGY STUDIES (UEGW 2022) - "Administration of SZN-043 was well-tolerated up to 125 mg/kg twice weekly. SZN-043-related changes were considered nonadverse and limited to clinical chemistry and organ weight changes.All observations showed evidence of recovery. There were no macroscopic or microscopic SZN-043-related observations."

Clinical • Hematological Disorders • Hepatology • Liver Failure • Ophthalmology • RSPO1 • SPON1

SZN-043 INDUCED QUICK AND ROBUST HEPATOCYTE PROLIFERATION IN A 14-DAY DAILY DOSING EDU-LABELING STUDY IN SCID MICE (UEGW 2022) - "Hepatocytes responded quickly to SZN-043 treatments and underwent a limited number of proliferation cycles, despite the continued exposure to SZN-043 and β-catenin signaling induction for up to 14 days. The proliferation observed in the HNF4A-negative cells in this study was likely due to the tissue responding to the large number of proliferating hepatocytes, as we have previously shown that SZN-043 has no direct impact on cells other than hepatocytes (Surrozen data presented previously)."

Preclinical • Hepatology • Liver Failure • AXIN2 • HNF1A • PRKDC

Surrozen Presents Data on Two Lead Therapeutic Candidates at United European Gastroenterology (UEG) Week (GlobeNewswire) - "SZN-043 preclinical data shows rapid, transient increases in hepatocyte proliferation and was well tolerated in non-clinical toxicology studies; SZN-1326 preclinical data shows improved intestinal epithelial healing, restored epithelial barrier, and reduced colitis-associated collagen deposition and was well tolerated in non-clinical toxicology studies...Surrozen, Inc...announced the presentation of data supporting the continued development of its lead therapeutic programs at United European Gastroenterology Week (UEGW), being held Oct. 8-11 in Vienna."

Preclinical • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

SZN-043 INDUCED QUICK AND ROBUST HEPATOCYTE PROLIFERATION IN A 14-DAY DAILY DOSING EDU-LABELING STUDY IN SCID MICE. (DDW 2022) - "Conclusion : Hepatocytes responded quickly to SZN-043 treatments and underwent a limited number of proliferation cycles, despite the continued exposure to SZN-043 and β-catenin signaling induction for up to 14 days. The proliferation observed in the HNF4A-negative cells in this study was likely due to the tissue responding to the large number of proliferating hepatocytes, as we previously showed that SZN-043 has no direct impact on cells other than hepatocytes."

Preclinical • Hepatology • Liver Failure • AXIN2 • HNF1A • PRKDC

A Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety and Pharmacokinetics of SZN-043, a Novel Bispecific Fusion Protein Targeting ASGR1 and ZNRF3/RNF43, in Healthy Volunteers and Subjects with Liver Cirrhosis (ANZCTR) - P1 | N=40 | Not yet recruiting | Sponsor: Surrozen Operating, Inc.

New P1 trial • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis

Surrozen Presents Data Supporting Potential of SZN-043 at The Liver Meeting 2021, the Annual Meeting of the American Association for the Study of Liver Diseases (GlobeNewswire) - '"The data presented at the AASLD conference represent important developments in Surrozen's liver research program for SZN-043,' said Scott Friedman, MD...'These preclinical studies are encouraging and demonstrate progress in identifying and measuring non-invasive serum markers that have the potential to provide an early assessment of Wnt signal activation and restoration of liver function as the program advances toward Phase 1 clinical trials.'"

Media quote

[VIRTUAL] SZN-043 IMPROVES LIVER METABOLIC FUNCTION IN A MOUSE PRECLINICAL MODEL (AASLD 2021) - "CYP1A2 converts orally administered 13C-methacetin via O-dealkylation to acetaminophen and 13CO2 . These results show that this method can be used to show that SZN-043 can increase liver function in small animals, and that the duration of this effect can last beyond effects on gene regulation ."

Preclinical • Hepatology • Liver Failure • CYP1A2 • RSPO1 • SPON1

[VIRTUAL] NON-INVASIVE PHARMACODYNAMIC MARKERS OF SZN-043 TARGET ENGAGEMENT AND WNT PATHWAY ACTIVATION (AASLD 2021) - "Serum ALP concentrations can be used as a non-invasive and dose-dependent pharmacodynamic marker of SZN-043 target occupancy while serum LECT2 concentrations can be used as a pharmacodynamic marker of Wnt activation ."

PK/PD data • Addiction (Opioid and Alcohol) • Hepatology • Liver Failure • ASGR • MUC4 • RSPO1 • SPON1

[VIRTUAL] TRANSCRIPTOME ANALYSIS OF HUMAN LIVERS EXPLANTS FROM ALCOHOL-ASSOCIATED LIVER DISEASES HIGHLIGHTS A LOSS OF PERICENTRAL AND PROLIFERATION GENE EXPRESSION (UEGW 2021) - "The following genes encoding Wnt and RSPO ligands, FZD receptors, RSPO and SZN-043 target receptors, Wnt target genes were analyzed by qPCR: AFP, ANG, ASGR1, ASGR2, AXIN2, CYP1A2, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 AND FZD10, LECT2, LGR5, NOTUM, RSPO-1, RSPO-2, RSPO-3, RNF43, RSPO-4, WNT1, WNT2, WNT2b, WNT3, WNT4, WNT5a, WNT5b, WNT7a, WNT7b, WNT8b WNT9a, WNT9b, WNT11 and ZNFR3. This transcriptome analysis illustrates a loss of pericentral gene expression, including enzymes involved in the metabolism of xenobiotics such as CYP1A2 and CYP2E1, and impaired hepatocyte proliferation in patients with alcohol-associated liver disease. These results suggest that a molecule which induces pericentral gene expression and hepatocyte proliferation, such as SZN-043, a bispecific fusion protein and hepatocyte-specific R-spondin mimetic, could be beneficial for the treatment of alcohol-associated liver disease."

Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Oncology • ASGR • CYP1A2 • CYP2E1 • HNF1A • RNF43 • RSPO1 • SPON1 • WNT5B • WNT7A

[VIRTUAL] SZN-043, a Hepatocyte-targeted-R-spondin mimetic, stimulates hepatocyte proliferation in an acute alcoholic hepatitis model (EASL-ILC 2021) - "These results show that SZN-043 can stimulate hepatocyte-specific cell regeneration in this commonly used AH- induced liver injury model. SZN-043 may have meaningful clinical benefit in human disease states where hepatocyte proliferation is impaired, such as in severe AH."

Hepatology • Immunology • Inflammation • Liver Failure • CCND1 • IL1B • IL6 • RSPO1 • SPON1

[VIRTUAL] SZN-043, a hepatocyte-targeted R-spondin mimetic, promotes robust hepatocyte proliferation and zonal gene expression changes in mice (EASL-ILC 2021) - "SZN-043 induces a transient increase in the number of proliferating hepatocytes and a transient shift in zonal metabolic gene expression, and both changes normalizewithin 7 days of dosing cessation. The ability of SZN-043 to target hepatocytes and promote their proliferation suggests its utility as a regenerative therapy for liver diseases."

Preclinical • Hepatology • Liver Failure • RSPO1 • SPON1

[VIRTUAL] SZN-043, a Hepatocyte-targeted-R-spondin mimetic, stimulates hepatocyte proliferation in an acute alcoholic hepatitis model (EASL-ILC 2021) - "These results show that SZN-043 can stimulate hepatocyte-specific cell regeneration in this commonly used AH- induced liver injury model. SZN-043 may have meaningful clinical benefit in human disease states where hepatocyte proliferation is impaired, such as in severe AH."

Hepatology • Inflammation • Liver Failure • CCND1 • IL1B • IL6 • RSPO1 • SPON1

[VIRTUAL] Pharmacokinetics, Pharmacodynamics, and toxicology of SZN-043, a hepatocyte-targeted Wnt potentiator, in nonhuman primates (EASL-ILC 2021) - "The data from these studies indicate that SZN-043 can be safety administered to NHPs, with PK suitable for use in humans, and support further investigation of this molecule in settings of severe hepatocyte loss where SZN-043 may have a rapid impact on hepatocyte regeneration, as well as in cirrhosis."

PK/PD data • Fibrosis • Hepatology • Immunology • Liver Failure • ASGR

[VIRTUAL] SZN-043, a hepatocyte targeted R-spondin mimetic, induces hepatocyte proliferation in acute acetaminophen-induced liver injury model (EASL-ILC 2021) - "These results provide supporting evidence that SZN-043 can induce hepatocyte specific regeneration in response to APAP overdose. This approach may be beneficial for the treatment of liver diseases."

Hepatology • Liver Failure • CCND1 • RSPO1 • SPON1

[VIRTUAL] SZN-043, A HEPATOCYTE-TARGETED R-SPONDIN MIMETIC, STIMULATES HEPATOCYTE PROLIFERATION IN AN ACUTE ALCOHOLIC HEPATITIS MODEL (DDW 2021) - "These results show that SZN-043 can stimulate hepatocyte-specific cell regeneration in this commonly used AH-induced liver injury model. SZN-043 may have meaningful clinical benefit in human disease states where hepatocyte proliferation is impaired, such as in severe AH."

Hepatology • Immunology • Inflammation • Liver Failure • CCND1 • IL1B • IL6 • RSPO1 • SPON1

[VIRTUAL] PHARMACOKINETICS, PHARMACODYNAMICS, AND TOXICOLOGY OF SZN-043, A HEPATOCYTE-TARGETED WNT-POTENTIATOR, IN NONHUMAN PRIMATES (DDW 2021) - "The data from these studies indicate that SZN-043 can be safety administered to NHPs, with PK suitable for use in humans, and support further investigation of this molecule in settings of severe hepatocyte loss where SZN-043 may have a rapid impact on hepatocyte regeneration, as well as in cirrhosis."

PK/PD data • Fibrosis • Hepatology • Immunology • Liver Failure • ASGR