Comparison of the Safety and Efficacy of Newly-Developed Generic Ursodeoxycholic Acid (Cholicray^®) and Ursophar^® as Standard Drug in Patients with Non-alcoholic Fatty Liver Disease: A Phase IIa Double-Blind Randomized Controlled Clinical Trial

Chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD), have emerged as a major public health challenge worldwide over the recent decade. Epidemiological studies have estimated a significant increase in the global prevalence of NAFLD among the adult population, from 25.26% in 1990 - 2006 to 38.00% in 2016 - 2019 (1). In Iran, research suggests that approximately 30 - 40% of adults may have some degree of NAFLD (2), often associated with increasing age, obesity, type 2 diabetes, and metabolic syndrome.

The pathophysiology of NAFLD is complex and multifactorial. Key mechanisms include insulin resistance, increased peripheral lipolysis, oxidative stress, chronic inflammation, mitochondrial dysfunction, and hepatotoxicity induced by bile acids (3-8). The accumulation of hydrophobic bile acids, such as deoxycholic and lithocholic acid, within liver tissue is considered a major contributor to hepatocellular injury and chronic inflammation in these patients (9).

Among therapeutic options, ursodeoxycholic acid (UDCA), a hydrophilic bile acid, exerts hepatoprotective effects through various mechanisms. These include shifting the bile acid composition toward less toxic forms (10), reducing cholesterol absorption (11, 12), stabilizing hepatocyte membranes (13), inhibiting apoptosis (14), and modulating inflammatory signaling pathways such as NF-κB (15). Additionally, UDCA enhances bile flow and has an established role in treating cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) (16).

Numerous pieces of evidence have demonstrated the efficacy of UDCA in improving liver biochemical markers [e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), GGT, alkaline phosphatase (ALP)], reducing fibrosis, and increasing transplant-free survival in patients with PBC and NAFLD. Studies have shown that using this drug significantly reduces liver enzymes and improves liver enzyme markers in patients with NAFLD. Clinical studies indicate that daily UDCA administration, alongside lifestyle modification, leads to significant reductions in the Fatty Liver Index (FLI), triglyceride levels, LDL cholesterol, and histological liver abnormalities (17-20).

In Iran, Ursophar^® (produced by Koushan Pharmed) has long served as the reference brand for UDCA. However, the recent introduction of Cholicray^® (manufactured by Reyhaneh Pharmaceutical Company) as a generic formulation necessitates rigorous evaluation of its efficacy, safety, and tolerability in comparison with the standard. The use of domestically produced generics may help reduce treatment costs for both patients and the healthcare system.

This study was designed as a proof-of-concept, randomized, double-blind, controlled clinical, phase IIa trial to compare the safety and efficacy of Cholicray^® versus Ursophar^® in patients with grade II NAFLD. This study aimed to determine whether the new formulation provides comparable therapeutic benefits and safety profiles, thereby offering clinically relevant data to inform treatment decisions.

The present study demonstrates that Cholicray^®, a locally manufactured generic formulation of UDCA, exhibits comparable safety and efficacy to the reference drug Ursophar^® in patients with NAFLD. The decision to target patients with grade II NAFLD, rather than those with cholestatic liver diseases such as PBC or PSC, was based on scientific, methodological, and ethical considerations.

First, NAFLD has a significantly higher prevalence in the general population, both globally and in Iran, facilitating access to an adequate sample size and allowing for sufficient statistical power within a practical timeframe. In contrast, PBC and PSC are considered rare diseases, and conducting a large-scale clinical trial in these populations would require extended durations and specialized referral centers. Second, the efficacy of UDCA in treating PBC has already been well-established through multiple international trials and is recognized in clinical practice guidelines. In contrast, evidence supporting the use of UDCA in NAFLD and related metabolic liver disorders remains limited and heterogeneous, necessitating locally conducted, well-designed studies. From this standpoint, evaluating Cholicray^® in an NAFLD population provides greater scientific value than replicating existing cholestatic studies.

Furthermore, assessing the safety profile of UDCA-based therapies in patients without advanced cholestatic pathology allows for a more accurate detection of subclinical or mild adverse effects. Some adverse effects, like itching, diarrhea, and visual disturbances, are known potential side effects of UDCA-based therapies, and their documentation helps physicians weigh benefits against risks, monitor patients appropriately, and manage symptoms.

However, our findings align with those of Nakano et al. (26), who reported no statistically significant differences in biochemical response between branded and generic UDCA formulations. Similarly, the safety profile of Cholicray^® observed in our trial corresponds well with the Nakano et al. study. This study provides direct evidence of comparable safety between generic/formulated UDCA and standard branded UDCA in a controlled clinical setting (26).

Our results are also consistent with broader clinical evidence regarding UDCA’s role in NAFLD. For instance, a meta-analysis of nine randomized controlled trials (up to September 2019, n = 1106 patients) found that UDCA significantly reduced ALT levels (P = 0.07), though changes in AST, GGT, and other biochemical markers were not statistically significant. Notably, patients over 50 years old, of European ancestry, or those undergoing therapy for more than six months experienced more pronounced benefits (18). Among the enzymes secreted by the liver, ALT has the highest specificity for hepatocellular injury, surpassing the other enzymes. The lack of changes in AST and ALP may reflect their lower sensitivity in such settings. In NAFLD, hepatocytes are primarily affected, making ALT a valuable marker for assessing liver status.

The observed reduction, though modest, is clinically relevant in the context of a proof-of-concept phase IIa trial, indicating potential efficacy. The modest ALT reduction might indeed stem from the short three-month treatment duration, which may not suffice for more pronounced effects; an insufficient dose relative to disease severity; or the limited sample size, which reduces power to detect smaller changes.

An open-label, multicenter international trial with 174 NAFLD patients, receiving 15 mg/kg/day of UDCA in combination with lifestyle modification, demonstrated significant reductions in liver enzymes, FLI, triglycerides, and LDL cholesterol after 6 months, although no improvement was observed in fibrosis scores (17). A recent study on the efficacy of UDCA in NAFLD followed patients for 3 months and measured outcomes based on clinical findings and serum ALT levels, demonstrating significant reductions in liver enzymes (27). A reduction in liver enzyme levels within three months, as seen in the present study, suggests that the treatment is likely effective and impactful. However, from a clinical perspective, more invasive assessments like biopsy would provide stronger evidence of improvement, but as these were not feasible in the present and many other studies, the observed drop in hepatic enzymes serves as a practical proxy for treatment efficacy.

A 2018 systematic review of 1548 RCTs noted that approximately 85% of studies documented biochemical and histological improvements in the liver, while 15% showed no benefit. The authors highlighted the farnesoid X receptor (FXR) pathway as a potential mechanistic target of UDCA action in these outcomes (19). Another systematic review noted that UDCA monotherapy improved liver enzymes in multiple studies with follow-up periods as short as 3 - 6 months (ALT: P ≤ 0.0001, AST: P = 0.0009) (28).

In our study, both medications, Ursophar^® and Cholicray^®, demonstrated comparable effects in improving LEBs in patients with NAFLD. The reduction in liver enzymes without significant adverse events observed in both groups indicates that these two drugs exhibit efficacy in enhancing hepatic status. Although this phase IIa trial, due to its limited sample size, lacks the statistical power to draw definitive conclusions on efficacy, the results showed that the reduction in ALT levels was statistically significant in both groups. On the other hand, no statistically significant differences were observed in the mean changes before and after the intervention between the study groups.

Despite the relatively high attrition rate in the present study, the comparative analyses between completers and the subset of non-completers with available data revealed no significant differences in their baseline characteristics. This reduces concerns about the potential risk of bias related to attrition and strengthens the validity of the final findings. However, the results revealed the potential of generic medications as safe and cost-effective alternatives to branded drugs. As a generic formulation, Cholicray^® may enhance access to effective treatment options for NAFLD and reduce the economic burden on healthcare systems.