Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial

Abstract

Background/aims: A clinical unmet need persists for medications capable of modulating the progression of primary sclerosing cholangitis (PSC). This study aimed to assess the clinical feasibility of HK-660S (beta-lapachone) in PSC.

Methods: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 trial, participants were assigned in a 2:1 ratio to receive either 100 mg of HK-660S or a placebo twice daily for 12 weeks. The primary outcomes were the reduction in serum alkaline phosphatase (ALP) levels and the percentage of participants showing improvements in PSC severity, as determined by magnetic resonance cholangiopancreatography with the Anali score. Secondary endpoints included changes in liver stiffness and adverse events.

Results: The analysis included 21 patients, 15 receiving HK-660S, and six receiving a placebo. Improvements in the Anali score were observed in 13.3% of the HK-660S group, with no improvements in the placebo group. HK-660S treatment resulted in a 15.2% reduction in mean ALP levels, compared to a 6.6% reduction in the placebo group. A stratified ad-hoc analysis based on baseline ALP levels showed a statistically significant response in the HK-660S group among those with ALP levels greater than twice the upper limit of normal, with a 50% responder rate (p=0.05). Additionally, 26.7% of the HK-660S group showed improvements in the enhanced liver fibrosis score, with no improvements in the placebo group. HK-660S was generally well tolerated.

Conclusion: HK-660S is well tolerated among patients with PSC and may improve bile duct strictures, decrease serum ALP levels, and reduce liver fibrosis (cris.nih.go.kr, Number KCT0006590).

Keywords: Alkaline phosphatase; Cholangiopancreatography, magnetic resonance; Lapachone; Nicotinamide adenine dinucleotide; Primary sclerosing cholangitis.

Figure 1.

Patient disposition. Nine of 32 patients were excluded for the following reasons. Participants who have T/T type as determined by NQO1 genotyping assays (n=5) (exclusion criteria before protocol change), participants who have ALT or AST >5 times the upper limit of normal (ULN) (n=2), serum ALP of <1.5 times the ULN at screening (n=1), and expiration of screening period (n=1). NQO1, NAD(P)H quinone dehydrogenase 1; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FAS, full analysis set; PPS, per protocol set. ^*Four participants were excluded from the FAS due to the administration of herbal medicine.

Figure 2.

(A) Improvement rate of PSC severity based on MRCP Anali scores in the FAS and (B) PPS population. (C) Improvement of biliary strictures after HK-660S treatment in MRCP images. PSC, primary sclerosing cholangitis; MRCP, magnetic resonance cholangiopancreatography; FAS, full analysis set; PPS, per protocol set.

Figure 3.

(A, B) Mean change in ALP from baseline and at 4, 8, 12, and 16 weeks (FAS) and (PPS). (C) Percent change in ALP from baseline and responder ad-hoc analysis. ALP, alkaline phosphatase; BL, baseline; FAS, full analysis set; PPS, per protocol set; ULN, upper limit of normal.