official website and that any information you provide is encrypted . Obeticholic acid (Ocaliva) is a semisynthetic analog of the bile acid, chenodeoxycholic acid, and acts as a Farnesoid X receptor (FXR) agonist (Figure 2). Expert Opin Investig Drugs. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Front Med (Lausanne). Serum chemokines unchanged at 4 weeks but increased after 14 weeks of CVC therapy. The 1-year results of a 2-year phase IIb study showed that CVC treatment for nonalcoholic steatohepatitis (NASH) in patients with fibrosis appears to be safe and effective in reducing fibrosis: Twice as many patients on CVC had 1-stage improvement in fibrosis than those . In this review, we have summarized the complex therapeutic landscape of NAFLD/NASH and compared the different drug classes and pathway targets, focusing on those compounds that are in late-stage clinical development and by definition are better placed to succeed in the race for the first FDA-approved and specific therapeutic option against NASH. After one year, the experimental arm continued receiving the drug while the control arm split in two, with one piece switching to cenicriviroc. doi: 10.7759/cureus.12713. Colca JR, McDonald WG, McCommis KS, Finck BN. The .gov means its official. In addition, an increase in low-density lipoprotein cholesterol and total cholesterol has been observed after treatment with Obeticholic acid in the Phase 2 FLINT clinical trial (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01265498","term_id":"NCT01265498"}}NCT01265498).15 Undeterred by this initial set-back, Intercept Pharmaceuticals are also sponsoring another Phase 3 REVERSE clinical trial (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03439254","term_id":"NCT03439254"}}NCT03439254) to evaluate the efficacy and safety of Obeticholic acid in patients with compensated cirrhosis due to NASH. In a phase 2b clinical trial on 289 patients with NASH and fibrosis, Cenicriviroc consistently demonstrated liver fibrosis improvement after 1 year . Lanifibranor is an oral small molecule that activates all three PPAR isoforms (PPAR, PPAR and PPAR), inducing anti-fibrotic, anti-inflammatory and other beneficial metabolic changes in the body, and delivers these outcomes by decreasing triglyceride levels and increasing high-density lipoprotein cholesterol levels and insulin sensitization (Figure 2). This trial is divided into two different arms. PMC Only patients with stage 2 or 3 fibrosis levels were assessed in this cohort (230 individuals). To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease . Julia M Fraile reports being a Knowledge Transfer Partnership-Associate (Innovate UK) between the University of Aberdeen and Elasmogen Ltd, during the conduct of the study. Importantly, Allergan has a deal with Novartis AG pairing CVC with the Swiss pharma's LJN452 in a Phase 2 study for NASH, and that's where investors should be paying attention, according to Raffat. Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%). Cenicriviroc reduced fibrosis in the same study by only 31.9% (p=0.00032). In another Phase 2 clinical trial, EVIDENCES I, Saroglitazar showed improvement measured as a reduction in liver enzymes and lipid values in NAFLD patients. HHS Vulnerability Disclosure, Help Core tip: Macrophages appear to play an important role in the development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Furthermore, Pfizer has recently included a Phase 1 clinical trial in their pipeline to evaluate PF-06865571 in combination with PF-06882961 (Danuglipron), a GLP-1R agonist, for the treatment of NASH. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial, Nonalcoholic fatty liver disease and type 2 diabetes mellitus. However, it delivered on one of two key secondary endpoints . Hopefully, these next-generation mAbs from Genentech and Merck with boosted specificity and potency will succeed where others have failed, and we may also see the first-approved antibodies for the treatment of metabolic diseases such as NASH. The Tobira deal was especially important to any dreams Allergan had for securing its spot at the top of the space, as it provided the company with two investigational therapies, CVC and evogliptin. a The number of animals at the start of the study is indicated, with the number of animals at the end of the study on which analyses were conducted indicated in brackets; b Vehicle control: 0.5% [w/v] methylcellulose + 1% Tween -80.BID, twice daily; CVC, cenicriviroc; DEX, dexamethasone; IP, intraperitoneal; NASH, non-alcoholic steatohepatitis; PBS, phosphate . The company has not indicated future plans for CVC yet, but the termination of the AURORA study sows a seed of doubt about its efficacy as a monotherapy. The study is expected to start in Q3 2021 and will enroll patients with liver-biopsy confirmed NASH (CRN stage 2 or 3). Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti-inflammatory macrophages in the high-dose CVC group. HHS Vulnerability Disclosure, Help Still, new biotech companies continue to emerge, as private investors have billions of available dollars to put to use. The company's lead product candidate, cenicriviroc (CVC), is a first-in-class immunomodulator and dual inhibitor of CCR2 and CCR5 being evaluated for the treatment of non-alcoholic steatohepatitis . (A) Monocyte chemotactic protein 1/chemokine ligand 2. Would you like email updates of new search results? sharing sensitive information, make sure youre on a federal Although Obeticholic acid had been heralded as the most advanced drug for the treatment of NASH, the FDA response to their NDA, together with the potential for liver toxicity problems, was encouraging enough for Intercepts competitors to continue playing their part in this drug race. JAMA 2015;313:22632273. Due to the lack of a cost-effective and minimally invasive diagnostic test, the prevalence of this disease can only be estimated. 2 The term nonalcoholic steatohepatitis (NASH) was coined almost 4 decades ago. Epub 2018 Feb 22. Many later phase drugs have already failed to meet key endpoints. In addition to liver-specific pathology, a diagnosis of NASH is also associated with increased cardiometabolic risk and represents the leading cause of death for these patients.3 Last year, a group of experts started a new debate on the best terminology for NAFLD and proposed Metabolic Associated Fatty Liver Disease (MAFLD) as a more appropriate term to reflect the heterogeneity of this disease.4 Although the incorporation of this new term leads to a change in the diagnostic criteria, it does not affect the prevalence of the condition in the population.5 Since no decision regarding which term should be used had been made by the time of writing this revision, we decided to maintain NAFLD in this article. Hopefully, this situation is about to change, as several drug candidates are in late-stage clinical trials.8, The histological evidence for a NASH diagnosis is determined by the NAFLD activity score (NAS), which is a composite of steatosis, inflammation and hepatocyte ballooning and represents a measure of disease activity. 2022 Jun 13;13:874408. doi: 10.3389/fphar.2022.874408. Cenicriviroc mechanism of action. government site. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases, Non-alcoholic steatohepatitis (NASH) opportunity analysis and forecasts to 2029. Herein, we report the final data from Year 2 exploratory analyses. (PPAR)-/ agonist elafibranor 75 failed to show efficiency on NASH resolution (NCT02704403). 8600 Rockville Pike -. Chalasani N, Younossi Z, Lavine JE, et al. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Both studies enrolled over 1600 patients in total and were designed to evaluate the safety and efficacy of Selonsertib when used to treat NASH patients with stage 3 fibrosis (STELLAR-3) or compensated cirrhosis, stage 4 fibrosis (STELLAR-4). At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. The combinations of Semaglutide/Cilofexor/Firsocostat (Novo Nordisk and Gilead), Tropifexor/CVC (Allergan and Novartis) and Selonsertib/Cilofexor/Firsocostat (Gilead, now discontinued) have all been discussed in more detail above. AURORA: A Study for the Efficacy and Safety of Cenicriviroc (CVC) for the Treatment of Liver Fibrosis in Adults With Nonalcoholic Steatohepatitis (NASH) (AURORA) . and transmitted securely. An Update on the Chemokine System in the Development of NAFLD. On Friday, the drugmaker unveiled new follow-on data reinforcing that benefit. The https:// ensures that you are connecting to the Keywords: PMC legacy view Am J Gastroenterol 2017;112:581587. All combinations were well tolerated, and a statistically significant improvement in hepatic steatosis and liver injury was observed in the combination arms compared to Semaglutide alone (at 24 weeks in post-hoc analysis). This one-year study demonstrated liver fat reduction, biochemical improvement and both NASH and fibrosis resolution, with favorable safety and tolerability profiles. doi:10.1002/hep4.1134 A 2021 Update. Cenicriviroc, a dual CCR2 and CCR5 antagonist leads to a reduction in plasma fibrotic biomarkers in persons living with HIV on antiretroviral therapy Louie Gangcuangco 2019, HIV Research & Clinical Practice Arch Pharm Res. Selonsertib is an oral small molecule inhibitor of the apoptosis signal-regulating kinase 1 (ASK1) and eventually failed in two different Phase 3 trials, STELLAR-3 (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03053050","term_id":"NCT03053050"}}NCT03053050) and STELLAR-4 (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03053063","term_id":"NCT03053063"}}NCT03053063). Therapeutic landscape for NAFLD/NASH with targeted pathways. Cenicriviroc treatment has no notable effect on body or liver . (A) Eotaxin; (B) macrophagederived chemokine; (C) macrophage inflammatory protein1; (D) monocyte induced by gamma interferon. 2016 Jun 27;11(6):e0158156. NGMBios Phase 1b clinical study demonstrated that a single subcutaneous dose of this antibody significantly reduced liver fat content and improved multiple metabolic parameters in obese, insulin-resistant subjects with NAFLD. Cenicriviroc (CVC) is a dual antagonist of CCR2 and CCR5 (Lefebvre et al., 2016) which has antiinflammatory and antifibrotic properties mediated by CCR2/CCR5 blockade based on evidence from preclinical and clinical data. An investigator-led Phase II trial investigating AbbVie's nonalcoholic steatohepatitis (NASH) asset cenicriviroc in hospitalised Covid-19 patients has so far recruited 45 patients of its 183-participant target, said principal investigator Dr Frank Tacke, professor of medicine, Department of Hepatology and Gastroenterology at the Charit Universittsmedizin Berlin, Germany. AIDS Dementia Complex +2 more; cenicriviroc . 1999;116(6):14131419. Trials per page: STUDY. Free Whitepaper Would you like email updates of new search results? Andrew J Porter reports personal fees from Elasmogen Ltd, during the conduct of the study. It is noteworthy that Aldafermin has recently failed a Phase 2b ALPINE 2/3 study for NASH patients with stage 2 or 3 of liver fibrosis, but NGM Biopharmaceuticals are still evaluating this drug in a Phase 2b ALPINE 4 trial in NASH patients with severe fibrosis and compensated fibrosis. 2018;2(2):199210. 2020 Aug 13; 12:115-123. . 8600 Rockville Pike The company expects to release data from this study by the end of 2021. Chemomab has recently started enrolling patients in a Phase 2a SPLASH clinical trial that will evaluate the effects of CM-101 in 40 NASH patients with fibrosis stage 2 or 3 (Figure 2 and Table 1). Nonalcoholic steatohepatitis, or NASH, is related to an accumulation of fat in the liver, leading to fibrosis, or scarring of the liver, eventually resulting in cirrhosis, liver cancer or liver failure. Epub 2018 Feb 22. 26 One-year follow-up results were available for 252 participants which confirmed that CVS failed to demonstrate a statistically significant improvement in the primary endpoint of NASH resolution . A public market downturn has extended through 2022, forcing venture firms to build their drug startups more cautiously. Thus, Efruxifermin (Akero), Pegbelfermin (Ambrx Inc/Bristol Myers Squibb), BFKB8488A (Genentech), Aldafermin (NGM Biopharmaceuticals) and MK-3655 (Merck & Co) are currently being studied in Phase 2b development (Figure 2). 2016 Mar;47:356-65. doi: 10.1016/j.cct.2016.02.012. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis, Current and future treatments in the fight against non-alcoholic fatty liver disease. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. P30 DK043351/DK/NIDDK NIH HHS/United States, Rinella ME. Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, Liepelt A, Lefebvre E, Luedde T, Hellerbrand C, Weiskirchen R, Longerich T, Costa IG, Anstee QM, Trautwein C, Tacke F. Hepatology. As such, the inconsistent results raise concern over the strength of the signal. Clinical trials involving monotherapies are still much higher in number than combination studies and are typically further in their clinical drug journey than most combination studies. 2018;67(1):328357. Cenicriviroc ( INN, [1] code names TAK-652, TBR-652, commonly abbreviated as CVC) is an experimental drug candidate for the treatment of HIV infection [2] and in combination with Tropifexor for non-alcoholic steatohepatitis. It is scheduled to be annotated soon. Company, drug name and targets are indicated for each clinical therapy. Role of aramchol in steatohepatitis and fibrosis in mice. The authors report no other potential conflicts of interest in this work. CENTAUR ( NCT02217475) is a phase 2 trial that evaluated CVC in noncirrhotic patients with NASH who have NAS 4, and NASH . Bril F, Biernacki DM, Kalavalapalli S, et al. MAESTRO-NASH began in 2019 and is expected to enroll up to 2000 NASH patients with fibrosis (CRN stage 2 or 3). Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. government site. This strategy delivers the promise of increasing potency still further through the combination of biologic and small molecule drugs as a single targeted therapy. At a much earlier point in their development (late stage pre-clinical) than any of the studies described above, companies such as Elasmogen Ltd are using the power and flexibility of their soloMER drug discovery platforms to produce smaller antibody-like biologics for the treatment of later stage liver disease, and fibrosis in particular. Di Lella S, Sundblad V, Cerliani JP, et al. On Friday, the drugmaker unveiled new follow-on data reinforcing that benefit. FOIA Cenicriviroc (CVC) is a CCR2/5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). The authors report no other conflicts of interest in this work. Cenicriviroc | C41H52N4O4S | CID 11285792 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities . By Allie Nawrat. Over the last few years, several pharmaceutical companies have failed to find a drug for the treatment of NASH typically because of a lack of efficacy, toxicity or elements of both. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Vitamin E . Several drugs that modulate the activity of these nuclear receptors have been investigated as treatments for NASH in patients (Figure 2). and transmitted securely. 1 The pooled prevalence of NAFLD in Asia is 30% (95% confidence interval [CI]: 28.13-31.15). This bi-specific capability can aid therapeutic potency, specificity and reduce off-target side effects. Role of bile acids and bile acid receptors in metabolic regulation, Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. However, what has changed in the last decade is the development of numerous therapies in later stage clinical trials that could offer real hope, and soon, to patients struggling with metabolic liver diseases, such as NASH and NAFLD. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. "We have gained important insights from this analysis which will further support our progress with CVC. Accessibility Clinical intervention is woefully inadequate and is still often limited to changes in life-style advice, a situation that has altered little in over 10 years. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Bethesda, MD 20894, Web Policies Federal government websites often end in .gov or .mil. Conclusion: CVC is a novel therapeutic agent that is associated with reduced fibrosis despite ongoing steatohepatitis. Of those molecules that appear to be progressing well, Dapagliflozin, developed by Bristol-Myers Squibb and AstraZeneca Ltd, is currently in Phase 3 and is an inhibitor of SGLT2, which in turn impedes glucose reabsorption in the proximal tubule leading to glucosuria and plasma glucose reduction (Figure 1). (CENTAUR) and it failed phase III (AURORA) clinical trial. The decision to continue EFX development in 2020 was taken after positive histological results demonstrated a reduction in liver fat and improvement in liver fibrosis, obtained in a 16-week Phase 2a BALANCED study in NASH patients.28 Akero now intends to evaluate the efficacy of EFX in NASH patients in a Phase 2b/3 adaptive clinical trial.
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