[Translation] A randomized, double-blind, placebo-controlled phase Ⅱb clinical study of ZSP1601 tablets in the treatment of nonalcoholic steatohepatitis

评价ZSP1601片治疗非酒精性脂肪性肝炎（NASH）患者的安全性和有效性。

[Translation]

To evaluate the safety and efficacy of ZSP1601 tablets in the treatment of patients with nonalcoholic steatohepatitis (NASH).

Start Date13 Mar 2023

Sponsor / Collaborator

Guangdong Zhongsheng Pharmaceutical Co., Ltd.

NCT04140123

/ CompletedPhase 1/2

A Multi-center, Randomized, Double-blind, Dose-increasing, Placebo-controlled，Multi-dose, 28-day Continuous Administration Phase Ib/IIa Clinical Trial to Evaluate the Tolerability, Efficacy, and PK of ZSP1601 in Patients With Nonalcoholic Steatohepatitis

Double-blind, randomized, placebo-controlled study to explore the safety, tolerability PK characteristics and early efficacy of ZSP1601 tablets in patients with non-alcoholic steatohepatitis (NASH).

Start Date23 Jun 2020

Sponsor / Collaborator

RAYNOVENT Co., Ltd.

100 Clinical Results associated with ZSP-1601

100 Translational Medicine associated with ZSP-1601

100 Patents (Medical) associated with ZSP-1601

Literatures (Medical) associated with ZSP-1601

01 Aug 2024·EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

Dose finding for ZSP1601 in patients with nonalcoholic steatohepatitis using population pharmacokinetics and exposure–response approach

Article

Author: Li, Haijun ; Chen, Xiaoxin ; Xu, Fengyan ; Sun, Zhongyi ; Wang, Kun ; Yang, Yuting ; Hu, Yue ; Huang, Jufang

INTRODUCTION:

ZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD).

AIM:

The aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure-response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials.

METHODS:

Analysis of pooled concentration-time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored.

RESULTS:

A two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601's pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure-response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUC_ss) on the 29th day. ZSP1601 exposure levels (C_max1) exhibited a significant exposure-response relationship with headaches (p < 0.001).

CONCLUSION:

The PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601's pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations.

31 Jul 2024·Journal of Clinical and Translational Hepatology

Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease

Review

Author: Fan, Jian-Gao ; Hu, Ye ; Liu, Yu-Dong ; Sun, Chao ; Chen, Ying

Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), the absence of licensed medications is striking. A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications. MASLD therapies center on four major pathways. Considering the close relationship between MASLD and type 2 diabetes, the first approach involves antidiabetic medications, including incretins, thiazolidinedione insulin sensitizers, and sodium-glucose cotransporter 2 inhibitors. The second approach targets hepatic lipid accumulation and the resultant metabolic stress. Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs. The third approach focuses on targeting oxidative stress, inflammation, and fibrosis. Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications.

04 May 2021·Expert opinion on investigational drugsQ2 · MEDICINE

Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study

Q2 · MEDICINE

Article

Author: Lin, Junjie ; Wang, Hong ; Li, Cuiyun ; Ding, Yanhua ; Zhu, Xiaoxue ; Li, Haijun ; Peng, Yun ; Wu, Min ; Hu, Yue

Background: The pharmacokinetics (PK), safety, and tolerability profiles of ZSP1601, a first-in-class pan-phosphodiesterase (PDE) inhibitor, were evaluated in healthy Chinese volunteers.Research design and methods: This Phase 1a study consisted of a double-blinded, randomized, placebo-controlled single ascending dose (SAD) (25 to 350 mg), multiple ascending doses (MAD) (50 or 100 mg QD), and a two-period crossover food effect study (100 mg).Results: ZSP1601 was quickly absorbed, with maximum plasma concentrations (C_max) reached at 1.25 to 2.50 h (median T_max). The exposures exhibited dose-proportional increases, while the mean half-life (t1/2) ranged from 6.34-8.64 h. Steady-state was reached within seven days in the MAD study. The mean steady trough concentrations were 423 and 588 ng/mL, respectively. ZSP1601 accumulation was low, with ratios ≤ 1.5. The bioavailability of ZSP1601 was equivalent under fasted and fed states. All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study.Conclusions: The safety and PK profiles of ZSP1601 support further efficacy evaluation in nonalcoholic steatohepatitis patients.Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).

News (Medical) associated with ZSP-1601

12 Dec 2022

·www.prnewswire.com

Propulsion of Nonalcoholic Steatohepatitis Pipeline as Novel and Extensive 150+ Therapies Likely to Enter in the Treatment Domain | DelveInsight

The prevalence of nonalcoholic steatohepatitis has been rising since the past few years, which prompts the growing demand for treatment options. The increasing prevalence of Nonalcoholic Steatohepatitis and the growing research and development activities drive the market. The Companies developing the potential therapies in the last stage of development include Madrigal Pharmaceuticals, Inventiva, Boehringer Ingelheim, and several others. LAS VEGAS, Dec. 12, 2022 /PRNewswire/ -- DelveInsight's ' Nonalcoholic Steatohepatitis Pipeline Insight – 2022 ' report provides comprehensive global coverage of available, marketed, and pipeline nonalcoholic steatohepatitis therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the nonalcoholic steatohepatitis pipeline domain. Key Takeaways from the Nonalcoholic Steatohepatitis Pipeline Report DelveInsight's nonalcoholic steatohepatitis pipeline report depicts a robust space with 130+ active players working to develop 150+ pipeline therapies for nonalcoholic steatohepatitis treatment. Key nonalcoholic steatohepatitis companies such as Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma, Chemomab Therapeutics, NuSirt Biopharma, HK inno. N, Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Merck Sharp & Dohme LLC, Cascade Pharmaceuticals, Hepion Pharmaceuticals, Chipscreen Biosciences, Boston Pharmaceuticals, Bristol-Myers Squibb, Sunshine Lake Pharma, GSK plc., Future Medicine, Gilead Sciences, ENYO Pharma, Histogen, and others are evaluating nonalcoholic steatohepatitis drugs to improve the treatment landscape. Promising nonalcoholic steatohepatitis pipeline therapies in various stages of development include TERN-101, SNP-610, LJN452 (tropifexor + licogliflozin), PXL065, ALS-L1023, PF-06865571 + PF-05221304, PF-06835919, PF-06865571, ORMD-0801, Norucholic acid, NNC0194-0499, MN-001, MK-3655, MET642, MET409, LPCN 1144, LIK066, Leronlimab, ALN-HSD, MT-3995, CM101, Leu-Mit-Sil (NS-0200), IN-A010, Efruxifermin (EFX), Efinopegdutide, EDP-305, JKB-122, CS0159 (Linafexor), CRV431, Chiglitazar sodium, BOS-580, BMS-986263, HEC96719, GSK4532990, FM101, Firsocostat, EPY001a, Emricasan, BMS-986036, BIO89-100, BI 456906, BFKB8488A, AXA1125, ASC 41, GS-9674 (Cilofexor), ZSP1601, and others. In November 2022, Sagimet Biosciences announced positive interim data from its Phase IIb clinical trial (FASCINATE-2) with denifanstat, a fatty acid synthase (FASN) inhibitor, in non-alcoholic steatohepatitis patients. Data showed statistically significant improvements across key markers of NASH, reinforcing results observed in earlier studies, including statistically significant reductions in markers of liver fat, inflammation, and fibrosis. There were no treatment-related serious adverse events, with the majority of adverse events mild to moderate in nature (Grade 1 and 2). Additional interim data are expected in early 2023. In November 2022, Inventiva announced that the United States Patent and Trademark Office granted a patent (U.S. Patent No. 11,504,380) that protects the use of lanifibranor for the treatment of cirrhotic patients at risk of progressing from compensated stage to decompensated stage. This patent will expire on November 8, 2039. This patent further expands the intellectual property protection of lanifibranor in the United States for use in patients with cirrhotic NASH. In October 2022, Galectin Therapeutics, Inc. reported the positive outcome of its second data and safety monitoring board (DSMB) meeting for NAVIGATE, its seamless, adaptive, phase IIb/III study of belapectin in patients with liver cirrhosis caused by non-alcoholic steatohepatitis (NASH). The objective of this second independent DSMB was further to review the emerging tolerance and safety profiles of belapectin. Based on its deliberation, the DSMB concluded that NAVIGATE could continue as designed, without modifications. In September 2022, Inventiva and Chia Tai-Tianqing Pharmaceutical Group entered into a licensing and collaboration agreement to develop and commercialize lanifibranor, if approved, for the treatment of nonalcoholic steatohepatitis and potentially other metabolic diseases in mainland China, Hong Kong, Macau, and Taiwan. In June 2022, Poxel SA announced that the U.S. Patent and Trademark Office (PTO) has issued to Poxel US Patent No. 11319313, which represents a new patent for PXL065, a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone which is being investigated in Phase II stage of clinical trial evaluation for the treatment of Nonalcoholic steatohepatitis (NASH). In May 2022, Pfizer Inc. announced the U.S. Food and Drug Administration (FDA) had granted Fast Track designation to Pfizer's investigational combination therapy for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis: ervogastat (PF-06865571, a diacylglycerol O-acyltransferase 2 inhibitor, or DGAT2i) and clesacostat (PF-05221304, an acetyl-CoA carboxylase inhibitor, or ACCi). In May 2022, Hepion Pharmaceuticals, Inc. announced that it has entered into a clinical collaboration with HepQuant, a Denver-based, privately held company with novel, proprietary investigational technology for evaluating liver function and health in patients with chronic liver diseases. Hepion will incorporate the HepQuant 'SHUNT' test into a dedicated Phase IIb clinical trial in presumed NASH F3 subjects. In February 2022, the US Food and Drug Administration (FDA) granted a Fast-Track Designation to Axcella Therapeutics' AXA1125 to treat non-alcoholic steatohepatitis (NASH) with liver fibrosis. In January 2022, LISCure Biosciences announced that it had executed a research collaboration agreement with Mayo Clinic for new drug development for rare liver diseases. LISCure Biosciences Inc. has executed a research collaboration agreement with US based-Mayo Clinic for new drug development for rare liver diseases. Request a sample and discover the nash drugs in development 2022 @ Nonalcoholic Steatohepatitis Pipeline 2022 Report The nonalcoholic steatohepatitis pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage nonalcoholic steatohepatitis drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the nonalcoholic steatohepatitis clinical trial landscape. Nonalcoholic Steatohepatitis Overview Nonalcoholic steatohepatitis (NASH) is a type of liver inflammation and damage caused by fat buildup. It is one of several conditions known as nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease is classified into two types: isolated fatty liver, in which only fat accumulates, and nonalcoholic steatohepatitis, in which fat, inflammation, and liver cell damage occur. NASH does not usually cause symptoms. Most people with NASH feel fine and are unaware that they have it. As NASH progresses and liver damage worsens, a patient may experience fatigue, weight loss, general weakness, and acne in the upper right part of the belly. Screening for nonalcoholic fatty liver disease in the general population is not advised. It is usually considered after discovering unexplained liver enzyme levels, or imaging reveals hepatic steatosis. A patient's medical history, a physical exam, and tests for nonalcoholic steatohepatitis are used by doctors. Want to discover how the Nash treatment pipeline will look like? Request for sample @ NASH Drug Pipeline 2022 A snapshot of the Nonalcoholic Steatohepatitis Pipeline Drugs mentioned in the report: Want to know how nash dash the pipeline race is for new agents? Download the sample page @ NASH Clinical Trials Nonalcoholic Steatohepatitis Therapeutics Assessment The nonalcoholic steatohepatitis pipeline report proffers an integral view of nonalcoholic steatohepatitis emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Nonalcoholic Steatohepatitis Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Intravenous, Parenteral, Oral, Subcutaneous Therapeutics Assessment By Molecule Type: Antibody, Biologic, Cell therapy, Peptide, Protein, Small molecule Therapeutics Assessment By Mechanism of Action: Adiponutrin inhibitor, Diacylglycerol O acyltransferase inhibitor, Adiponutrin modulator, RNA interference, Glucagon like peptide 1 receptor agonist, Ornithine decarboxylase stimulant, Farnesoid X-activated receptor agonist, Thyroid hormone receptor beta agonist, Mitochondrial membrane transport protein modulator, Thyroid hormone receptor beta agonists, Peroxisome proliferator-activated receptor alpha agonist Key Nonalcoholic Steatohepatitis Companies:Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma, Chemomab Therapeutics, NuSirt Biopharma, HK inno. N, Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Merck Sharp & Dohme LLC, Cascade Pharmaceuticals, Hepion Pharmaceuticals, Chipscreen Biosciences, Boston Pharmaceuticals, Bristol-Myers Squibb, Sunshine Lake Pharma, GSK plc., Future Medicine, Gilead Sciences, ENYO Pharma, Histogen, and others. Key Nonalcoholic Steatohepatitis Pipeline Therapies: TERN-101, SNP-610, LJN452(tropifexor + licogliflozin), PXL065, ALS-L1023, PF-06865571 + PF-05221304, PF-06835919, PF-06865571, ORMD-0801, Norucholic acid, NNC0194-0499, MN-001, MK-3655, MET642, MET409, LPCN 1144, LIK066, Leronlimab, ALN-HSD, MT-3995, CM101, Leu-Mit-Sil (NS-0200), IN-A010, Efruxifermin (EFX), Efinopegdutide, EDP-305, JKB-122, CS0159 (Linafexor), CRV431, Chiglitazar sodium, BOS-580, BMS-986263, HEC96719, GSK4532990, FM101, Firsocostat, EPY001a, Emricasan, BMS-986036, BIO89-100, BI 456906, BFKB8488A, AXA1125, ASC 41, GS-9674 (Cilofexor), ZSP1601, and others. Dive deep into rich insights for nonalcoholic steatohepatitis research; visit @ NASH Treatment Pipeline Table of Contents For further information on the most promising nash drugs, reach out @ NASH Medication Pipeline Related Reports Nonalcoholic Steatohepatitis Epidemiology Nonalcoholic Steatohepatitis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted nonalcoholic steatohepatitis epidemiology in the 7MM. Nonalcoholic Steatohepatitis Market Nonalcoholic Steatohepatitis Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key nonalcoholic steatohepatitis companies, including Boehringer Ingelheim, Oramed Pharmaceuticals, ENYO Pharma, Terns Pharmaceuticals, Cirius Therapeutics, among others. Non-Alcoholic Fatty Liver Disease Market Non-Alcoholic Fatty Liver Disease Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key non-alcoholic fatty liver disease companies including AstraZeneca, Novartis, Pfizer, Roche, among others. Non-Alcoholic Fatty Liver Disease Pipeline Non-Alcoholic Fatty Liver Disease Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key advanced non-alcoholic fatty liver disease companies, including AstraZeneca, Novartis, Pfizer, Roche, among others. Non-Alcoholic Fatty Liver Disease Epidemiology Non-Alcoholic Fatty Liver Disease Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted non-alcoholic fatty liver disease epidemiology in the 7MM. Other Trending Reports Alcohol Use Disorder Market | Liver Cancer Market | Alcoholic Hepatitis - Market | Acute Liver Failure - Market | Liver Angiosarcoma - Market | Liver Cirrhosis - Market | Chronic Liver Disease - Market | Advanced Liver Cancer - Market | Acute On Chronic Liver Failure (ACLF) Market Related Healthcare Services Healthcare Business Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. Connect with us at LinkedIn Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research LLP

Phase 2License out/inFast Track

100 Deals associated with ZSP-1601

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	China	Guangdong Zhongsheng Pharmaceutical Co., Ltd.	13 Mar 2023

Clinical Result

Indication

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04140123 (phase Ib study, EASL2022)	Phase 1	Nonalcoholic Steatohepatitis ALT \| BMI \| MRI-PDFF	36	ZSP1601 50 mg QD	qjxgaljhvl(pxyvyjddql) = yngjomdsay ytfsgzroot (vmajeilwcn ) View more	Positive	25 Jun 2022
				ZSP1601 50 mg BID	qjxgaljhvl(pxyvyjddql) = nmqchhzsxh ytfsgzroot (vmajeilwcn ) View more
NCT03392779 (Pubmed \| Expert Opin Investig Drugs)	Phase 1	-	-	ZSP1601	xlowoygbki(itojlnqnhb) = All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study. oekeslpoal (eftfomwbvz ) View more	-	04 May 2021
				Placebo

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