SZN-043 Demonstrates Safety, Pharmacodynamic Effect for Cirrhosis in Phase 1a Trial

Craig Parker

Credit: Surrozen

Surrozen has announced safety and pharmacodynamic activity data from its phase 1a clinical trial of SZN-043 in healthy volunteers and patients with cirrhosis, a pivotal first step in its development for severe liver diseases.¹

According to the April 1, 2024, release, results showed SZN-043 demonstrated acceptable safety and tolerability in all study participants with evidence of target engagement, Wnt signal activation, and effects on liver function. Of note, these data serve as the basis for Surrozen’s initiation of enrollment in a phase 1b study in alcohol-associated hepatitis.¹

”We are excited to have observed activation of Wnt signaling, target engagement and improvement in markers of liver function during the Phase 1a studies and are pleased to advance SZN-043 into the Phase 1b clinical trial in severe alcohol-associated hepatitis. We look forward to presenting the encouraging Phase 1a data at an upcoming medical conference - the first clinical data for this innovative antibody-based approach to modulating the Wnt pathway,” Craig Parker, president and chief executive officer of Surrozen, said in a press release.¹ “Progress with our platform technologies supports our belief that modulation of the Wnt pathway has the potential to provide important new therapeutic options through targeted tissue regeneration.”

A bi-specific antibody targeting Fzd4-mediated Wnt signaling, SZN-043 is the first development candidate using Surrozen’s hepatocyte-targeted R-spondin-mimetic (SWEETS) technology and is in development for the treatment of severe liver diseases and retinal vascular-associated diseases.² In addition to phase 1a data for chronic liver disease, data generated in preclinical models of retinopathy suggest SZN-043 could potently stimulate Wnt signaling in the eye, induce normal retinal vessel regrowth, suppress pathological vessel growth, and reduce vascular leakage. The release noted in the fourth quarter of 2022, Surrozen entered into a strategic partnership with Boehringer Ingelheim for the research and development of SZN-413 for the treatment of retinal diseases.¹

For severe liver diseases, Surrozen is initially focusing on the use of SZN-043 in alcohol-associated hepatitis following the completion of a phase 1a study in February 2024. The trial enrolled a total of 48 patients, including 40 healthy volunteers and 8 patients with cirrhosis and a history of liver disease, who received single or multiple IV doses administered in doses ranging from 0.5mg/kg to 3 mg/kg.¹

According to the release, no serious adverse events or infusion reactions were observed. Of note, in the planned phase 1b trial dose range of 0.5mg/kg to 1.5 mg/kg, adverse events deemed to be drug-related were mild to moderate and all resolved during the study period.¹

In healthy volunteers, investigators observed multiple asymptomatic and transient transaminase elevations that resolved without intervention or clinical sequelae. There were no drug-related adverse events reported in patients with cirrhosis at any dose. Investigators also noted the pharmacokinetics of SZN-043 were consistent with expectations and supportive of the planned doses, schedule, and route of administration for alcohol-associated hepatitis.¹

In patients with cirrhosis and a history of liver disease, the phase 1a study also demonstrated dose-dependent pharmacodynamic activity through activation of Wnt signaling as assessed by the methacetin breath test, which measures activation of the Wnt pathway via the metabolism of a Wnt target gene (CYP1A2) substrate. Target engagement was confirmed via transient increases in alkaline phosphatase (ALP), indicative of SZN-043 binding to its targeting receptor ASGR1 and reduction in its capacity to clear ALP, consistent with observations in other ASGR1 binding agents. Patients with cirrhosis also showed evidence of liver function effects after treatment with SZN-043 as measured by HepQuant, a test that measures cholate clearance.¹

As noted in the release, Surrozen is initiating a multi-center, open-label phase 1b clinical trial in patients with severe alcohol-associated hepatitis in multiple countries. Safety, pharmacokinetics, immunogenicity, and multiple efficacy endpoints including MELD score, Lille score, and survival will be evaluated, with proof-of-concept data expected to be available in the first half of 2025.¹

References:

1. ^{Surrozen. Surrozen Announces Safety, Pharmacodynamic and Liver Function Data for SZN-043. News. April 1, 2024. Accessed April 1, 2024. https://investors.surrozen.com/news-releases/news-release-details/surrozen-announces-safety-pharmacodynamic-and-liver-function}
2. ^{Surrozen. SZN-043 SWEETS for Liver Disease. Programs. Accessed April 1, 2024. https://www.surrozen.com/programs/szn-043}