An Adaptive Two-Part Phase 2, Multi-Center, Randomized, Double Blind, Placebo-Controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 Administered Once Monthly in Adult Subjects With Confirmed Non-Alcoholic Steatohepatitis

The purpose of this study is to assess the effect of multiple ION224 doses when administered by subcutaneous (SC) injection for 49 weeks (end of the treatment [EOT]) on non-alcoholic steatohepatitis (NASH) histologic improvement and to assess the effect on liver steatosis by magnetic resonance imaging-determined proton density fat fraction (MRI-PDFF), additional changes in NASH histologic features, liver biochemistry tests, and plasma lipid profile.

Start Date17 Jun 2021

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

NCT03334214

/ CompletedPhase 2

A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Pharmacodynamics of ISIS 484137 (IONIS-DGAT2Rx, an Antisense Inhibitor of Diacylglycerol Acyltransferase 2) Administered Once-Weekly for 13 Weeks in Adult Patients With Type 2 Diabetes

The purpose is to assess the Safety, Tolerability, and Pharmacodynamics effect of IONIS DGAT2Rx in up to 45 Adult Patients with Type 2 Diabetes.

Start Date03 Nov 2017

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

100 Clinical Results associated with IONIS-DGAT2Rx

100 Translational Medicine associated with IONIS-DGAT2Rx

100 Patents (Medical) associated with IONIS-DGAT2Rx

Literatures (Medical) associated with IONIS-DGAT2Rx

01 Sep 2020·The lancet. Gastroenterology & hepatologyQ1 · MEDICINE

Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial

Q1 · MEDICINE

Article

Author: Baker, Brenda F ; Loomba, Rohit ; Bhanot, Sanjay ; Geary, Richard S ; Watts, Lynnetta ; Hannan, Lisa A ; Xia, Shuting ; Morgan, Erin

BACKGROUND:

Diacylglycerol-O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2_Rx is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2_Rx versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD.

METHODS:

This double-blind, randomised, placebo-controlled, phase 2 study consisted of a 2-week screening period, a run-in period of up to 4 weeks, a 13-week treatment period of once-weekly dosing, and a 13-week post-treatment follow-up period. The study was done at 16 clinical research sites in Canada, Poland, and Hungary. Eligible participants were aged 18-75 years, had a body-mass index at screening between 27 kg/m² and 39 kg/m², haemoglobin A_1c (HbA_1c) levels from 7·3% to 9·5%, and liver fat content 10% or greater before randomisation, and agreed to maintain a stable diet and exercise routine throughout the study. Enrolled participants were stratified on the basis of liver fat content during the run-in period (<20% or ≥20%) and then centrally randomised (2:1) to receive once weekly subcutaneous injection of 250 mg IONIS-DGAT2_Rx or placebo for 13 weeks. Participants, investigators, funder personnel, and the clinical research organisation staff, including central readers of MRI scans, were all masked to treatment identity. The primary endpoints were the safety, tolerability, and pharmacodynamic effect of IONIS-DGAT2_Rx on hepatic steatosis, according to absolute reduction from baseline in liver fat percentage as quantified by MRI-estimated proton density fat fraction and assessed in the per-protocol population. Pharmacodynamic performance was determined in the per-protocol population by the change in liver fat content from baseline to 2 weeks after the last dose. The per-protocol population included all randomised participants who received at least ten doses of study drug, with the first four doses administered in the first 5 weeks, did not miss more than three consecutive weekly doses, and who had no protocol deviations that might affect efficacy. All randomised participants who received at least one dose of study drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT03334214.

FINDINGS:

Between Nov 3, 2017, and Nov 28, 2018, we screened 173 people for eligibility. 44 were enrolled and randomly assigned to receive either IONIS-DGAT2_Rx (29 participants) or placebo (15 participants). After 13 weeks of treatment, the mean absolute reduction from baseline was -5·2% (SD 5·4) in the IONIS-DGAT2_Rx group compared with -0·6% (6·1) in the placebo group (treatment difference -4·2%, 95% CI -7·8 to -0·5, p=0·026). Reductions in liver fat were not accompanied by hyperlipidaemia, elevations in serum aminotransferases or plasma glucose, changes in bodyweight, or gastrointestinal side-effects compared with placebo. Six serious adverse events occurred in four patients treated with IONIS-DGAT2_Rx. No serious adverse events were reported in the placebo group. One of four patients reported three serious adverse events: acute exacerbation of chronic obstructive pulmonary disease, cardiac arrest, and ischaemic cerebral infarction, each considered severe and not related to study drug. Three of four patients reported one serious adverse event of increased blood triglycerides (severe, unrelated to study drug), deep-vein thrombosis (severe, unlikely to be related to study drug), and acute pancreatitis (mild, unrelated to study drug).

INTERPRETATION:

Our results suggest that DGAT2 antisense inhibition could be a safe and efficacious strategy for treatment of NAFLD and support further investigation in patients with biopsy-proven NASH. Based on the pharmacological target, the response to treatment observed in this study population could extend to the broader population of patients with NAFLD.

FUNDING:

Ionis Pharmaceuticals.

Cardiovascular diabetology

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7

Review

Author: Wang, Yanhong ; Zhang, Shuangshuang ; Zhu, Meng ; Hu, Weichao ; Wang, Jie ; Hu, Jianxia ; Wu, Xiaolin ; Xing, Dongming ; Liu, Xiaolei ; Chen, Wujun ; Wu, Jianfeng ; Shao, Yingchun ; Wang, Chao ; Guo, Zhu ; Hao, Minglu ; Zhang, Miao ; Wu, Yudong

Abstract:

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

News (Medical) associated with IONIS-DGAT2Rx

30 Jan 2025

·www.prnewswire.com

Metabolic Dysfunction-Associated Steatohepatitis Market to Register Stunning Growth at a CAGR of 17.9% in the US by 2034 | DelveInsight

The MASH treatment landscape is evolving rapidly, driven by a diverse array of therapeutic classes, each with unique mechanisms and potential impacts. The forecast period reveals significant shifts and emerging trends that will shape future market dynamics. LAS VEGAS, Jan. 30, 2025 /PRNewswire/ -- DelveInsight's Metabolic Dysfunction-Associated Steatohepatitis Market Insights report includes a comprehensive understanding of current treatment practices, MASH emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan]. Key Takeaways from the Metabolic Dysfunction-Associated Steatohepatitis Market Report According to DelveInsight's analysis, the market size for MASH was found to be USD 2.1 billion in the 7MM in 2023. In 2023, there were an estimated 42 million prevalent cases of MASH in the 7MM. Out of these, a total of ~15 million cases were diagnosed, and this number is projected to increase by the end of 2034 in the 7MM. Leading MASH companies such as Inventiva Pharma, Novo Nordisk A/S, Cirius Therapeutics, Akero Therapeutics, 89bio, Boehringer Ingelheim, Zealand Pharma, Galectin Therapeutics, Lipocine, Viking Therapeutics, Eli Lilly and Company, Boston Pharmaceuticals, Pfizer, HighTide Biopharma, CytoDyn, Merck & Co., Hanmi Pharmaceutical, Hepagene (Shanghai), Hepion Pharmaceuticals, Enyo Pharmaceuticals, Gilead Sciences, Poxel SA, Zydus Therapeutics, Sagimet Biosciences, Ionis Pharmaceuticals, Corcept Therapeutics, and others are developing novel MASH drugs that can be available in the MASH market in the coming years. The promising MASH therapies in the pipeline include Lanifibranor (IVA337), Semaglutide, Azemiglitazone (MSDC-0602K), Efruxifermin (EFX), BIO89-100 (Pegozafermin), Survodutide (BI 456906), GR-MD-02 (Belapectin), LPCN1144, VK2809, Tirzepatide, BOS-580, Ervogastat (PF-06865571) + Clesacostat (PF-05221304), HTD1801, Leronlimab (PRO 140), Efinopegdutide, HPG1860, Rencofilstat (CRV431), EYP001 (Vonafexor), Semaglutide/Cilofexor/Firsocostat, PXL065, Saroglitazar Magnesium, Denifanstat (TVB-2640), ION224, Miricorilant (CORT118335), and others. In March 2024, Madrigal Pharmaceuticals' groundbreaking product, REZDIFFRA (resmetirom), a once-daily, oral THR-ß agonist, received accelerated endorsement from the US FDA based on results from the Phase III MAESTRO-NASH trial. This approval marks a significant stride in the medical landscape, as REZDIFFRA becomes the inaugural and sole FDA-sanctioned therapy for adults afflicted with non-cirrhotic MASH, accompanied by moderate to advanced liver scarring (fibrosis) corresponding to stages F2–F3 fibrosis. Discover which therapies are expected to grab the major MASH market share @ Metabolic Dysfunction-Associated Steatohepatitis Market Report Metabolic Dysfunction-Associated Steatohepatitis Overview Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that stems from metabolic dysfunction, often linked to obesity, diabetes, and other conditions of metabolic syndrome. MASH is characterized by the accumulation of fat in liver cells, accompanied by inflammation and liver cell injury, which can progress to fibrosis, cirrhosis, or even liver cancer. The primary drivers of MASH include insulin resistance, obesity, type 2 diabetes, and dyslipidemia. Genetic predisposition and a sedentary lifestyle also play significant roles. Environmental factors, such as a poor diet high in sugars and fats, exacerbate the condition. MASH is often asymptomatic in its early stages. When symptoms occur, they can include fatigue, vague abdominal discomfort, or pain in the upper right quadrant. In advanced stages, signs of liver dysfunction such as jaundice, swelling of the abdomen or legs, and confusion may arise. Diagnosis involves a combination of clinical history, physical examination, and diagnostic tests. Blood tests measuring liver enzymes (ALT, AST) often indicate liver inflammation. Imaging techniques like ultrasound, MRI, or FibroScan can identify liver fat and fibrosis. In some cases, a liver biopsy is required to confirm the diagnosis and assess disease severity. Metabolic Dysfunction-Associated Steatohepatitis Epidemiology Segmentation The MASH epidemiology section provides insights into the historical and current MASH patient pool and forecasted trends for the 7MM. It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders. The MASH market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Prevalent Cases of MASH Diagnosed Prevalent Cases of MASH Gender-specific Diagnosed Prevalent Cases of MASH Severity-specific Diagnosed Prevalent Cases of MASH Metabolic Dysfunction-Associated Steatohepatitis Treatment Market The approval of REZDIFFRA (resmetirom) in March 2024 represents a pivotal achievement in medical innovation, transforming the treatment landscape for MASH disease. This groundbreaking therapy addresses the root causes of MASH, offering renewed hope to patients grappling with this challenging condition. Clinical trials have shown impressive results, with REZDIFFRA effectively reducing symptoms like inflammation and fibrosis, enhancing liver function, and improving patients' quality of life. By providing healthcare professionals with a robust treatment option, this approval addresses a critical unmet need and has the potential to significantly alleviate the complications linked to advanced liver disease. The prevalence of MASLD is strongly linked to type 2 diabetes mellitus and obesity, particularly in individuals with a higher body mass index. However, MASLD occurrence is reduced in T2DM patients receiving treatments such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, GLP-1 receptor agonists, and insulin. Vitamin E, with its antioxidant properties, is regarded as a first-line pharmacological option for managing MASH, especially when dietary and lifestyle interventions are insufficient. Antifibrotic agents can help prevent the progression of liver fibrosis and MASLD into fibrotic MASH. The role of pioglitazone, an anti-diabetic medication, in improving MASH histology in T2DM patients is well-documented, but concerns remain regarding potential side effects like weight gain, fluid retention, cancer risk, and bone fractures. Additional therapeutic targets for MASLD and MASH include G protein-coupled receptors (GPCRs), estrogen-related receptor alpha (ERRα), bone morphogenetic proteins (BMPs), and KLFs. Bariatric surgery, or weight loss surgery, is the most effective intervention for treating obesity and diabetes, as it reduces food absorption while influencing gut hormone secretion and metabolic function. To know more about MASH treatment guidelines, visit @ Metabolic Dysfunction-Associated Steatohepatitis Management Metabolic Dysfunction-Associated Steatohepatitis Pipeline Therapies and Key Companies Lanifibranor (IVA337): Inventiva Pharma Semaglutide: Novo Nordisk A/S Azemiglitazone (MSDC-0602K): Cirius Therapeutics Efruxifermin (EFX): Akero Therapeutics BIO89-100 (Pegozafermin): 89bio Survodutide (BI 456906): Boehringer Ingelheim/Zealand Pharma GR-MD-02 (Belapectin): Galectin Therapeutics LPCN1144: Lipocine VK2809: Viking Therapeutics Tirzepatide: Eli Lilly and Company BOS-580: Boston Pharmaceuticals Ervogastat (PF-06865571) + Clesacostat (PF-05221304): Pfizer HTD1801: HighTide Biopharma Leronlimab (PRO 140): CytoDyn Efinopegdutide: Merck & Co./Hanmi Pharmaceutical HPG1860: Hepagene (Shanghai) Rencofilstat (CRV431): Hepion Pharmaceuticals EYP001 (Vonafexor): Enyo Pharmaceuticals Semaglutide/ Cilofexor/ Firsocostat: Gilead Sciences PXL065: Poxel SA Saroglitazar Magnesium: Zydus Therapeutics Denifanstat (TVB-2640): Sagimet Biosciences ION224: Ionis Pharmaceuticals Miricorilant (CORT118335): Corcept Therapeutics Discover more about MASH drugs in development @ Metabolic Dysfunction-Associated Steatohepatitis Clinical Trials Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics The MASH market dynamics are expected to change in the coming years. Growing research activities and multiple clinical trials for MASH, driven by the rapid surge in its prevalence due to rising obesity and type 2 diabetes rates, highlight an active drug development pipeline and an expanding market size. The large pool of patients and lucrative growth opportunities present attractive prospects for key players, further supported by ongoing preclinical studies aimed at advancing imaging techniques for MASH diagnosis, potentially eliminating the need for invasive biopsy-based histopathological confirmation. Furthermore, potential therapies are being investigated for the treatment of MASH, and it is safe to predict that the treatment space will significantly impact the MASH market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the MASH market in the 7MM. However, several factors may impede the growth of the MASH market. Lack of awareness and negligence in the early stages of MASH by physicians often lead to disease progression, culminating in irreversible damage where liver transplantation becomes the only viable option. Diagnosing advanced MASH typically requires procedures like liver biopsy, which are costly, invasive, and risky. Regulatory challenges also pose hurdles, as the FDA mandates achieving one MASH endpoint for approval, while the EMA's draft guidance requires efficacy in both endpoints, potentially delaying first-mover approvals in major European markets. Additionally, access to expensive MASH treatments may be limited in certain regions, further hindering patient adoption. Moreover, MASH treatment poses a significant economic burden and disrupts patients' overall well-being and QOL. Furthermore, MASH market growth may be offset by failures and discontinuation of emerging therapies, unaffordable pricing, market access and reimbursement issues, and a shortage of healthcare specialists. In addition, the undiagnosed, unreported cases and the unawareness about the disease may also impact MASH market growth. Scope of the Metabolic Dysfunction-Associated Steatohepatitis Market Report Therapeutic Assessment: Metabolic Dysfunction-Associated Steatohepatitis current marketed and emerging therapies Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics: Key Market Forecast Assumptions of Emerging Metabolic Dysfunction-Associated Steatohepatitis Drugs and Market Outlook Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's views, Analyst's views, Metabolic Dysfunction-Associated Steatohepatitis Market Access and Reimbursement Download the report to understand which factors are driving MASH market trends @ Metabolic Dysfunction-Associated Steatohepatitis Market Trends Table of Contents Related Reports Non-Alcoholic Steatohepatitis Epidemiology Forecast Non-Alcoholic Steatohepatitis Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted NASH epidemiology in the 7MM, i.e., the United States, EU4 (Germany, France, Italy, Spain), the United Kingdom, and Japan. Nonalcoholic Steatohepatitis Pipeline Nonalcoholic Steatohepatitis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key nonalcoholic steatohepatitis companies, including Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Inventiva, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, 89bio, Inc., Eccogene, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, Arrowhead Pharma, LG Chem, Redx Pharma, Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Chemomab Therapeutics, NuSirt Biopharma, HK inno. N, Aligos Therapeutics, Altimmune, Inc., 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, among others. Non-Alcoholic Fatty Liver Disease Market Non-Alcoholic Fatty Liver Disease Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key NAFLD companies, including MediciNova, Eli Lilly and Company, AstraZeneca, Inventiva Pharma, Oasis Pharmaceuticals, LLC, Madrigal Pharmaceuticals, Inc., BioMarin Pharmaceutical, GlaxoSmithKline, Zydus Therapeutics Inc., Akero Therapeutics, Inc, Pfizer, Boehringer Ingelheim, Neuraly, Inc., Merck Sharp & Dohme LLC, Rivus Pharmaceuticals, Inc., Hepion Pharmaceuticals, Inc. , among others. Non-Alcoholic Fatty Liver Disease Pipeline Non-Alcoholic Fatty Liver Disease Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key NAFLD companies, including BeiGene, Inventiva Pharma, Cirius Therapeutics, Madrigal Pharma, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Dr. Falk Pharma GmbH, Sagimet Biosciences, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Afimmune, Poxel SA, AngioLab, Pfizer, Oramed Pharmaceuticals, Can Fite Biopharma, MediciNova, Metacrine, Inc., 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, Enanta Pharmaceuticals, Cascade Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 3

15 Apr 2024

·www.biospace.com

5 Promising MASH Therapies That Could Follow Madrigal’s Rezdiffra

Pictured: A collage containing a fatty liver over blood vessels/Taylor Tieden for BioSpace When Madrigal Pharmaceuticals’ Rezdiffra was approved last month as the first-ever treatment for metabolic dysfunction-associated steatohepatitis, experts hailed the drug as an “important first.” However, the consensus among experts is that Rezdiffra is just the beginning for a disease that has been notoriously difficult to treat. Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cells, which can lead to progressive fibrosis and cirrhosis of the liver. “[Rezdiffra] is the first oral drug that’s been demonstrated to show reversal of fibrosis in Phase III clinical studies,” said Lawrence Blatt, CEO of Aligos Therapeutics, which is also developing a candidate for MASH. “If you look at the magnitude of the impact of Madrigal’s drug, it’s good for patients,” he told BioSpace. “I don’t want to downplay what they’ve achieved . . . but there’s a lot of room for improvement.” About a quarter of patients treated with Rezdiffra have an improvement in fibrosis, he noted. “That leaves 75% of patients with the need for better therapies.” A day before Rezdiffra’s approval, Ionis Pharmaceuticals announced that its own metabolic dysfunction-associated steatohepatitis (MASH) candidate hit the primary endpoint in a Phase II trial, showing significant improvement in steatohepatitis without worsening fibrosis, according to the company. And this is only the tip of the iceberg. Here, BioSpace looks at five mid- to late-stage investigational MASH drugs. Ionis’s ION224 The FDA asks MASH drug developers to show in Phase III clinical trials a one-stage improvement in fibrosis (ranked on a scale from F0, or the absence of fibrosis, to F4, full-blown cirrhosis) with no worsening of MASH, or the resolution of MASH with no worsening of fibrosis. Ionis appears to be well on its way to this metric, as 32% of people in the high dose arm of its Phase II trial of ION224 had at least a one-stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of patients in the placebo cohort. The drug was safe and well-tolerated in the trial, Ionis stated, and there was a lower rate of early termination in the ION224 study arms compared to placebo. ION224 is designed to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. The Phase II trial “is the first to demonstrate clinical evidence that the reduction of hepatic fat after DGAT2 inhibition correlates with improvements in MASH histological endpoints,” Rohit Loomba, a professor of medicine and chief of the division of gastroenterology and hepatology at the University of California San Diego, said in a company statement. Altimmune’s Pemvidutide Pemvidutide, developed by Altimmune and currently entering Phase IIb trials, is a peptide-based GLP-1/glucagon dual receptor agonist. While activation of the GLP-1 receptors leads to appetite suppression, activation of glucagon increases energy expenditure, both of which are important for weight loss. Glucagon is also believed to have direct effects on hepatic fat metabolism, leading to rapid reductions in levels of liver fat and serum lipids, according to Altimmune. Mayank Mamtani, head of healthcare research at B. Riley Securities, is bullish on therapies targeting the glucagon receptor to treat MASH. In addition to pemvidutide, he cited Eli Lilly’s retatrutide and Boehringer Ingelheim’s survodutide. “If you look at [these programs], they’re telling you that this is the drug class that’s going to win in MASH.” On top of a “profound” lowering of liver fat, he said there are other benefits with this drug class, including lowering of liver enzymes and cholesterol, “that you’re not getting from Madrigal.” Boehringer Ingelheim reported positive data from its own Phase II trial in February. So far in clinical trials, once weekly pemvidutide has shown “compelling weight loss, robust reductions in triglycerides, LDL cholesterol, liver fat content and blood pressure,” and a clean safety profile, according to Altimmune. Topline 24-week data from the Phase II IMPACT trial is due in the first quarter of 2025. 89bio’s Pegozafermin San Francisco–based 89bio is one of a handful of companies developing an analog of FGF21, a hormone that may address underlying metabolic issues that drive liver and cardiometabolic diseases, including MASH. The primary unmet need in MASH is in more advanced disease, Mamtani said. “Something that works in F4 is obviously the holy grail,” he said, adding that analogs of fibroblast growth factor 21 (FGF21) could have potential here. In November 2023, 89bio announced positive topline data from its Phase IIb trial of pegozafermin. After 48 weeks, MASH patients with stage F2 or F3 fibrosis treated with the candidate saw sustained, statistically significant improvements across liver fat and noninvasive tests of liver injury/inflammation and fibrosis. Pegozafermin is “the first FGF21 analog candidate to demonstrate positive, sustained benefits over a 48-week period in patients with advanced NASH,” Hank Mansbach, the company’s chief medical officer, said in a statement at the time. (MASH used to be known by the name nonalcoholic steatohepatitis, or NASH.) Patients with stage F2 and F3 fibrosis are at high risk of progression to cirrhosis and increased risk of liver cancer, liver decompensation and death. Viking Therapeutics’ VK2809 Currently in Phase IIb trials, Viking Therapeutics’ VK2809 belongs to the same thyroid hormone receptor beta (THR-β) class as Rezdiffra. William Blair analysts Andy Hsieh and Alexandra Ramsey wrote in a March 2024 note that the drug could “potentially outshine Rezdiffra’s clinical profile.” Topline data presented in May 2023 showed VK2809 cleared the trial’s primary endpoint, significantly reducing liver fat in patients with biopsy-confirmed MASH. After 12 weeks, patients treated with 2.5 mg of Viking’s candidate saw a 45.3% decrease in liver fat content, compared to 3.7% in placebo comparators. Updated results from the Phase IIb study demonstrated “robust and comparable liver fat reductions among patients with or without type II diabetes, as well as patients with either F2 or F3 fibrosis,” Viking reported in November 2023. Viking expects 52-week biopsy results during the first half of this year. Aligos Therapeutics’ ALG-055009 Earlier this month, Aligos initiated dosing in the Phase IIa HERALD study of ALG-055009, also a THR-ß agonist. The placebo-controlled trial will enroll approximately 100 individuals with presumed MASH and F1–F3 fibrosis. So far in clinical trials, Blatt said ALG-055009 is showing up to 100-fold more potency than Rezdiffra. He added that, in contrast to Rezdiffra, the drug has linear and non-variable pharmacokinetics, “so it’s very well controlled.” With Rezdiffra, “the variation they see among these individuals is highly variable, so some people are getting the optimal dose, some people are getting underdosed [and] some people might be getting overdosed,” Blatt explained, even though they all got the same amount of the drug. He added that only about 25% of patients taking Rezdiffra had improvement in fibrosis because “you have a lot of patients who were underexposed to the drug, and they weren’t receiving the amount of drug that they needed.” Topline safety and efficacy data from the HERALD trial are expected in Q4, 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Phase 2Clinical ResultDrug ApprovalPhase 3

18 Mar 2024

·firstwordpharma.com

Chipscreen says MASH candidate chiglitazar succeeds in Phase II

Shenzhen Chipscreen Biosciences Co. is the latest company to report positive data for a metabolic dysfunction-associated steatohepatitis (MASH) drug candidate. On Monday, the Chinese biotech said its PPAR pan-agonist chiglitazar cleared a key hurdle, meeting the primary efficacy endpoint of a Phase II study.The trial win comes on the heels of the FDA's approval last week of Madrigal Pharmaceuticals' THR-β selective agonist Rezdiffra (resmetirom), the first drug waved through by US regulators to treat the liver disease. Cleared via the FDA's accelerated pathway, Rezdiffra is indicated for adult patients with non-cirrhotic MASH and moderate-to-advanced liver fibrosis consistent with stages F2 to F3 fibrosis. The drug hits the market next month at a US list price of $47,400 per year.Chiglitazar, also known as carfloglitazar, has been approved in China since 2021 under the brand name Bilessglu to treat type 2 diabetes.The current trial, dubbed CGZ203, tested two doses of chiglitazar monotherapy or placebo given once daily for 18 weeks to patients diagnosed with MASH. Chipscreen said the primary endpoint was met at both dose levels, producing "significant and dose-dependent reductions" in liver fat content compared to placebo after 18 weeks, based on MRI-proton density fat fraction (MRI-PDFF).Both dose groups also showed "significant or dose-dependent trend of improvements" on secondary measures such as the proportion of patients achieving a >30% decrease in liver fat content, non-invasive indicators related to hepatocyte damage, inflammation, and fibrosis, the company said. Chipscreen said "overall safety is good," and that further data analyses are underway.Other MASH drug hopefuls with recent positive readouts include Akero Therapeutics' efruxifermin, engineered to mimic the FGF21 hepatic hormone; Ionis Pharmaceuticals' antisense inhibitor ION224; Sagimet Biosciences' FASN inhibitor denifanstat; the dual GLP-1 and glucagon agonist survodutide being co-developed by Boehringer Ingelheim and Zealand Pharma; as well as Viking Therapeutics' VK2809, which like Rezdiffra also targets thyroid hormone receptor beta.

Drug ApprovalPhase 2Clinical Result

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	United States	Ionis Pharmaceuticals, Inc.	17 Jun 2021
Nonalcoholic Steatohepatitis	Phase 2	Puerto Rico	Ionis Pharmaceuticals, Inc.	17 Jun 2021
Fatty Liver	Phase 2	Canada	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Fatty Liver	Phase 2	Hungary	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Fatty Liver	Phase 2	Poland	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Fatty Liver	Phase 2	United Kingdom	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Diabetes Mellitus, Type 2	Phase 2	Canada	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Diabetes Mellitus, Type 2	Phase 2	Hungary	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Diabetes Mellitus, Type 2	Phase 2	Poland	Ionis Pharmaceuticals, Inc.	03 Nov 2017
Diabetes Mellitus, Type 2	Phase 2	United Kingdom	Ionis Pharmaceuticals, Inc.	03 Nov 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04932512 (ION224-CS2, Corporate Publications) Manual	Phase 2	Nonalcoholic Steatohepatitis	160	ION224 60mg	dozuzxoewy(xtubgajwlj) = ION224 achieved statistically significant MASH resolution without worsening of fibrosis, as measured by biopsy (p=0.039). opytquvnml (kiblzfzowi ) View more	Positive	13 Mar 2024
				ION224 90mg
NCT03334214 (Pubmed) Manual	Phase 2	Metabolic dysfunction-associated steatotic liver disease	44	IONIS-DGAT2Rx	cbmhozyckc(dsgwxnstgz) = jqxoijxrhz pgjcbjzktg (oirfxihhga, 5.4) View more	Positive	01 Sep 2020
				Placebo	cbmhozyckc(dsgwxnstgz) = hyldjbfqwq pgjcbjzktg (oirfxihhga, 6.1) View more

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