Inipharm Commences Dosing in INI-822 Trial for MASH

Inipharm Begins Dosing for Oral MASH Drug INI-822

Inipharm has initiated dosing in a 12-week, placebo-controlled, double-blind proof-of-concept clinical study for its oral drug, INI-822, targeting metabolic dysfunction-associated steatohepatitis (MASH). The trial aims to enroll approximately 50 MASH patients to evaluate safety, pharmacokinetics, tolerability, and changes in MASH-related biomarkers and fibrosis using FibroScan. INI-822 is a hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) inhibitor, a target supported by genetic studies showing reduced risk of fibrotic liver diseases with decreased HSD17B13 activity. This study builds on prior encouraging biomarker data and is designed to pave the way for Phase IIb studies.

• Inipharm's 12-week proof-of-concept study for INI-822 is a placebo-controlled, double-blind trial enrolling approximately 50 MASH patients. Its primary objectives include assessing the drug's safety, pharmacokinetics, and tolerability. Additionally, the study will evaluate changes in key MASH-related biomarkers and fibrosis, utilizing FibroScan technology to provide comprehensive data on the drug's impact on liver health.
• INI-822 is an oral small-molecule inhibitor of hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13), making it the sole such inhibitor in clinical development. This target is validated by genetic studies demonstrating that variants reducing HSD17B13 enzyme activity significantly lower the risk of progressive fibrotic liver diseases, including a 50% to 60% reduction in the transition from fatty liver to fibrotic MASH or cirrhosis.
• The current study builds upon previous encouraging biomarker and target engagement data observed in MASH patients after 28 days of dosing. The results from this 12-week trial are crucial for providing deeper insights into INI-822's potential to address MASH features like fibrosis, strategically positioning Inipharm for advancement into subsequent Phase IIb studies. The company believes an oral small molecule approach may better reflect natural protective variants compared to RNAi-based methods.

HSD17B13: A Genetically Validated Target for MASH

Cholesterol accumulation in liver lipid droplets emerges as a critical mediator of MASH and fibrosis progression. Studies demonstrate increased cholesterol content within liver lipid droplets occurs as early as 5 days in murine models fed choline-deficient L-amino acid-defined high-fat diet, with similar elevations observed in humans with MASH and liver fibrosis. Notably, cholesterol accumulation is higher in individuals carrying PNPLA3 I148M variants compared to HSD17B13 variants. Defective lipid metabolism further drives disease progression through phosphatidylserine accumulation and impaired very-low-density lipoprotein lipidome remodeling, while autophagy dysfunction leads to disrupted lipid homeostasis through impaired function of key proteins including Beclin1, LC3A, SQSTM1, CD36, and Perilipin 3.

Mitochondrial dysfunction represents a fundamental mechanism underlying MASH pathogenesis, characterized by pathological alterations in inner mitochondrial membrane lipid composition that directly promote electron transfer inefficiency and oxidative stress. Cardiolipin downregulation in hepatocytes disrupts respiratory supercomplex formation and increases electron leak at sites II and III of the electron transport chain, while paradoxically increasing respiratory capacity. The SPHK1-mitochondrial dynamics axis further exacerbates hepatic stellate cell activation through impaired mitochondrial fusion and altered sphingosine-1-phosphate signaling. Additionally, dysregulation of the AMPK/mTORC1 pathway, where AMPK activity decreases while mTORC1 increases, disrupts cellular energy homeostasis and contributes to decreased fumarate levels that impair cholesterol clearance through the AMPK-FOXO3a-PCSK9-LDLR signaling pathway.

Inflammatory signaling cascades drive MASH progression through multiple interconnected pathways, including macrophage β-catenin-Ihh axis activation that promotes hepatic stellate cell activation and fibrosis. The NLRP3 inflammasome becomes activated through endoplasmic reticulum stress, leading to increased IL-1β release and caspase-1 cleavage, while TLR4/MyD88/NF-κB pathway activation enhances expression of pro-inflammatory cytokines including TNF-α, IL-6, and MCP1. Adipose tissue-derived MFG-E8 infiltrates the liver to promote macrophage-hepatocyte interactions, contributing to hepatic inflammation independently of fatty liver development. These inflammatory mechanisms converge with oxidative stress pathways, where hepatic glutathione depletion and lipid peroxidation products directly mediate hepatic stellate cell activation and collagen gene expression.

HSD17B13: A Genetically Validated Target Advancing in MASH

Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant global health challenge, characterized by its complex, multifactorial pathogenesis and a pressing need for more effective treatments beyond the single approved therapy. The initiation of a proof-of-concept study for Inipharm's oral drug, INI-822, targeting hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13), represents a promising advance in this landscape.

The scientific rationale for targeting HSD17B13 is robust, grounded in compelling human genetic evidence. Studies consistently show that loss-of-function variants in HSD17B13 are associated with a reduced risk of MASH progression, fibrosis, cirrhosis, and hepatocellular carcinoma. This strong genetic validation provides a solid foundation for INI-822, potentially de-risking its development compared to targets lacking such clear human genetic support. As a liver-specific, lipid droplet-associated protein, HSD17B13 plays a critical role in hepatic lipid homeostasis and inflammation, suggesting that its inhibition could offer a novel mechanism to attenuate steatosis and fibrosis.

However, the path forward is not without considerations. While human genetics are encouraging, some preclinical murine models have shown inconsistent results regarding HSD17B13's protective effects, highlighting a potential translational challenge that underscores the importance of robust human clinical data. Furthermore, the HSD17B13 target is becoming increasingly competitive, with other companies developing RNA interference therapeutics and small molecule inhibitors, including dual modulators. INI-822 will need to demonstrate a clear differentiation in efficacy, safety, or patient profile to carve out its market share. Additionally, the efficacy of HSD17B13 inhibition might vary across the diverse MASH patient population, particularly in lean MASH patients where genetic associations with HSD17B13 variants are less consistently observed. The focus on MASH-related biomarkers and FibroScan in this early study is a strategic move to identify early signals of efficacy and potentially guide patient selection for future trials, paving the way for more tailored and effective MASH treatments.