A novel clinical trial for primary sclerosing cholangitis from Asia: All regional endeavors should improve global management of primary sclerosing cholangitis: Editorial on “Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial”

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Clin Mol Hepatol. 2025;31(2):584-588

Publication date (electronic) : 2024 November 6

doi : https://doi.org/10.3350/cmh.2024.0945

Atsumasa Komori^,1,2

¹Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan

²Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan

Corresponding author : Atsumasa Komori Clinical Research Center, NHO Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Kubara 2-1001-1, Omura city, Nagasaki 856-8562, Japan Tel: +81-957-52-3121, Fax: +81-957-53-6675, E-mail: komori.atsumasa.qr@mail.hosp.go.jp

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

Received 2024 October 25; Accepted 2024 November 1.

Primary sclerosing cholangitis (PSC) has no known specific etiologies, whether obstructive, immune-mediated, infectious, ischemic, hereditary, or toxicological [1]. Its hallmark clinical features are intractable fibrosis and strictures of intra-and extrahepatic bile ducts, often accompanied by complications related to bile duct obstruction, and eventually progressing to cholestatic liver cirrhosis [2]. Due to the high prevalence of co-occurrence with inflammatory bowel disease, the common cause of disease pathophysiology may lie within the perturbed gut–liver–biliary axis. In fact, a novel autoantibody against anti–integrinαvβ6 was detected prevalently in the sera of both ulcerative colitis [3] and PSC patients [4], suggesting converging mechanisms of tissue injury via integrinαvβ6 that exhibit shared expression in colonic and bile duct epithelial cells. Moreover, the specific pathobiont Klebsiella pneumonia, equipped not only with epithelial-damaging properties but also with the ability to induce T helper 17 cell responses in the liver, was identified in the microbiota of patients with PSC [5]. Though such progress in translational research may lead to the development of pathogenesis-oriented therapy for PSC in the future, there are still no the US FDA-approved pharmacotherapies for PSC that would ameliorate inflammation and fibrosis to prevent progression to liver-related outcomes (cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death) [2].

Experimental agents in past and present clinical trials for PSC range from bile acid (BA)-targeting drugs (ursodeoxycholic acid: UDCA and farnesoid X receptor: FXR agonists) and immunomodulators to fecal microbiota transplantations, with varying primary endpoints ranging from surrogate serum biochemistry (i.e., a reduction of alkaline phosphatase: ALP) and pathological progression to fibrosis to liver-related outcomes (Tables 1, 2). Trial history, albeit being terminated due to futility, provided relevant evidence and implications for disease pathophysiological endpoints. A notable trial of high-dose UDCA documented higher rates of serious adverse events with no improvement in survival, prompting us to reconsider the appropriateness of using UDCA in clinical practice [6]. Even the very recent disappointing results of a phase 3 PRIMIS study with another BA-targeting drug, the non-steroidal FXR agonist cilofexor (CILO) [7], which failed to meet the primary endpoint in the proportion of patients with fibrosis progression, demonstrating some reversibility of PSC fibrosis; the rate of ≥1-stage decrease in Batts–Ludwig stage at week 96 was 17.2% in a placebo group and 25.6% in a CILO 100 mg/day group [8]. Patients and hepatologists definitely need challenging clinical trials, not only with drugs featuring new mechanisms of action but also with translatable endpoints to achieve breakthroughs in pharmacotherapies for PSC.

Table 1.

Clinical trials for primary sclerosing cholangitis (recruiting and active, not recruiting)

Table 2.

Clinical trials for primary sclerosing cholangitis (completed)

In this issue, Paik et al. [9] report the results of a multicenter, randomized, double-blind, placebo-controlled phase 2 feasibility trial of HK-660S. This synthetic beta-lapachone compound enhances intracellular NAD+ pools, thereby activating the NAD-dependent sirtuin family for PSC [10]. The treatment protocol was 100 mg HK-660S (n=16) or placebo (n=7) twice daily for 12 weeks. The primary endpoints were the reduction of ALP and the improvement of PSC severity, determined by a combinatorial formulation of the results of magnetic resonance (MR) imaging with gadolinium enhancement and cholangiopancreatography (CP), called the modified Anali score (mAnali). In the efficacy analysis for the full analysis set (n=21), improvement of mAnali was observed in 13.3% of the HK-660S group, whereas no improvement was observed in the placebo group, with an enhancing trend of ALP reduction at week 12. Moreover, secondary outcomes, consisting of improvements in bile duct strictures on MRCP and non-invasive liver elasticity prediction (ELF score), were met in 26.7% of participants for each of those outcomes, only in the HK-660S group. Though none of comparisons above were statistically significant, a good safety profile was documented throughout the trial period.

What are the implications of this small-scale feasibility analysis for PSC? At least three remarkable points should be considered. First, it was a trial employing a novel pharmacological approach with HK-660S. In the chemically induced PSC mouse model, HK-660S ameliorated key PSC features, reducing serum hepatobiliary enzymes, hepatic inflammatory and fibrosis-associated gene expression, and peri-ductal fibrosis [10]. Plausible mechanisms of the beneficial effect of HK-660S on PSC model include prevention of mitochondria dysfunction through NAD+-mediated upregulation of Sirt1/3 and mitigation of BA toxicity by inducing multidrug-resistant P-glycoprotein 2 [10]. Sirt-1 and Sirt-6 activation reportedly suppressed BA synthesis through FXR activation [11] and the destabilization of estrogen receptor [12], respectively. Taken together, the past and present results suggest that activation of the NAD-dependent sirtuin family, leading to pleiotropic beneficial effects on BA metabolism, is likely a promising pharmaceutical target for PSC.

The second insight resulting from the small-scale feasibility analysis for PSC is that it was the first-ever trial to implement prognostic subjective scores of MRI imaging to be evaluated by expert radiologists, with the results calculated as the Anali score [13], serving as the primary endpoint. A comprehensive surrogate evaluation of disease status by noninvasive biomarkers, in conjunction with imaging studies, is needed not only for clinical practice but also for drug development in PSC. Even though it is subjective in nature and lacks sufficient inter-reader agreement [14], the application of the Anali score—formulated by the presence of biliary strictures, portal hypertension, and liver dysmorphy in MRI to this trial is challenging [15] but strategically appropriate for evaluating the eligibility of experimental drugs for the next phase of clinical trials. Recently, using quantitative MRCP metrics automatically provided by a software tool called MRCP+^TM, the median duct diameter was validated to be associated significantly with the survival of PSC patients [16]. The Anali score, MRCP+^TM, and ideally AI-guided multiparametric quantification of MRI may enhance the quality of PSC staging in future feasibility trials.

The third implication is that it was the trial in which improvement in bile duct strictures was documented even after a rather short duration (12 weeks) of exposure to the experimental drug. Could patho-heterogeneity of PSC patients explain such rapid resolution? In other words, similar to the mostly favorable treatment response to prednisolone observed in IgG4-related sclerosing cholangitis [17]—characterized by the reversible and curable obstruction of bile ducts—might anti-inflammatory agents reverse the peri-ductal inflammatory strictures in a small number of significant subgroups of PSC patients? The more exploratory trials that are performed with innovative scheduling of examinations, the better we hepatologists will understand the whole spectrum of PSC phenotypes.

There are substantial limitations in the study by Paik et al. [9]. First and foremost is the methodological appropriateness for evaluating the improvement of MRI imaging. Information about the precise conditions for MRI measurements is lacking, and the legitimacy of mAnali, which is the sum of the original Anali with and without gadolinium [13], has not been pre-evaluated in relation to the conceptual targets of treatment. Does the weighting analysis of liver dysmorphy by MRI, with and without gadolinium, ranging from 0 to 3 out of a maximum of 7 points for mAnali, make sense or have special significance for the pharmaceutical efficacy of HK-660S? It may be not, because patients with a decrease in mAnali exhibit improved bile duct strictures but likely not parenchymal dysmorphy. Nevertheless, apart from the nature of feasibility studies, mAnali might be a suitable endpoint in later clinical trials with longer study durations where the treatment target is the improvement of cholestatic fibrosis in the liver.

To the best of my knowledge, this Korean multicenter PSC trial is the first reported from Asia, where epidemiological studies are few, but the disease prevalence is believed to be lower than in western countries. More studies outside the USA and European countries that are not limited to observational ones but rather extend to interventional trials will better elucidate and improve management of global PSC in the future.

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