On March 14, 2024, Madrigal Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Rezdiffra (resmetirom) in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), which is the first and only medication approved by the FDA for the treatment of NASH.
NASH, the advanced stage of non-alcoholic fatty liver disease (NAFLD), stands as a primary contributor to liver-related mortality, placing a growing burden on global healthcare systems. Moreover, individuals with NASH, particularly those harboring multiple metabolic risk factors (like hypertension and type 2 diabetes), face escalated risks of cardiovascular events, subsequently elevating both incidence and mortality rates. As NASH progresses to significant liver fibrosis (F2 and F3 stages), patients confront a markedly heightened risk of adverse liver outcomes.
Figure 1. The progress of NASH
Rezdiffra (Resmetirom) for NASH
Rezdiffra, developed by Madrigal Pharmaceuticals, is a once-daily oral selective agonist of the thyroid hormone receptor-beta (THR-β). THR-β is responsible for regulating metabolic pathways in the liver and is frequently impaired in NASH13. Patients with NASH have reduced levels of thyroid hormone activity in the liver with resultant impaired hepatic function.
The accelerated approval of Rezdiffra was based on results from the Phase 3 MAESTRO- NASH trial, which was recently published in the New England Journal of Medicine.
MAESTRO-NASH is an ongoing pivotal, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,759 patients with biopsy-confirmed NASH. Results showed 25.9% of patients in the resmetirom 80 mg group and 29.9% of patients in the 100 mg group achieved MASH resolution with no worsening of fibrosis compared with 9.7% of those in the placebo group. A reduction in fibrosis of at least 1 stage with no worsening of NALFD score was reported among 24.2% and 25.9% vs. 14.2%, respectively.
Figure 2. MAESTRO-NASH primary endpoints [3]
In addition to the two primary endpoints, the MAESTRO-NASH study also achieved multiple secondary endpoints, including statistically significant reductions in liver enzyme levels compared to baseline. Compared to placebo, the resmetirom treatment group observed significant decreases in various lipid and lipoprotein markers, including low-density lipoprotein cholesterol (LDL-C).
Figure 3. Resmetirom, change in lipid and lipoprotein [4]
Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to -42.1%, -51.4% and -10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by -39.6%, -41.3%, and -14.5% respectively. Liver volume dropped by -21.6% in the 80 mg group, -25.8% in the 100 mg group, compared with -1.0% in the placebo group. Spleen volume changed by -5.9%, -6.1%, and +3.2% respectively.
Figure 4. Significant effect of resmetirom in MRI-PDFF and Fibroscan CAP [4]
In terms of safety, the incidence of serious adverse events was similar across the trial groups: 11.8% for the 80 mg resmetirom group, 12.7% for the 100 mg resmetirom group, and 12.1% for the placebo group.
Figure 5. MAESTRO-NASH safety profile [3]
Other NASH Therapies in Clinical Trials
The pathways leading to NASH are complex, primarily originating from targets such as carbohydrate and lipid metabolism, lipid toxicity and cell death, inflammation, and anti-fibrosis targets associated with extracellular matrix deposition (Figure 5).
Various therapeutic approaches for NASH have been developed clinically, which can be mainly categorized based on the targets as follows: FXR agonists, THR-β agonists, GLP-1R agonists, FGF19 and FGRF21 analogs, etc.
Figure 6. Types of drugs for NASH
FXR Agonists
The development of NASH drugs has also faced challenges. Previously, several FXR agonists have failed in clinical trials, such as obeticholic acid, which was rejected by the FDA in June 2023 due to poor efficacy and significant side effects. However, there are still many FXR agonists under investigation for NASH treatment in clinical trials, such as HTD1801, TERN-101, and ASC42.
Fibroblast Growth Factors 19 and 21 Analogs
Fibroblast Growth Factors 19 and 21 (FGF19 and FGF21) are novel endocrine messengers that regulate multiple aspects of energy homeostasis. The robust effects of FGF19 and FGF21 on lipid metabolism transformed clinical emphasis for these factors toward their use for NASH.
Pegozafermin, developed by 89Bio Inc, is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) FGF21 analogue in development for NASH and severe hypertriglyceridemia. In September 2023, the Phase 2b trial results of pegozafermin were published in NEJM. Results showed that 37% of patients in the 15 mg pegozafermin treatment group met the criteria for NASH resolution, while only 2% in the placebo group. On March 12, 2024, 89bio Inc announced the initiation of the Phase 3 ENLIGHTEN Program evaluating the efficacy and safety of pegozafermin in patients with NASH. [6]
The attachment of 20 kDa linear PEG with a glycosyl moiety, significantly increases the stability and half-life of FGF21. Biopharma PEG, as a professional PEG derivative supplier, offers a broad portfolio of PEG derivatives with molecular weights up to 20 kDa for efficient PEGylations, such as mPEG-pALD-20K, etc.
Figure 7. Pegozafermin, source: 89Bio Inc official website
Efruxifermin is an Fc-FGF21 fusion protein with prolonged half-life and enhanced receptor affinity compared with native human FGF21. Efruxifermin is in clinical trials for the treatment of NASH. On March 04, 2024, Akero Therapeutics, Inc. released preliminary topline week 96 results from Phase 2b study HARMONY The study previously met its primary endpoint of ≥1 stage improvement in fibrosis with no worsening of MASH after 24 weeks of treatment for both the 50mg EFX (41%) and 28mg EFX (39%) dose groups, compared to 20% for the placebo arm. At week 96, the response rates on this endpoint increased to 75% (p<0.001) for 50mg EFX and 46% (p=0.07) for 28mg EFX, compared to 24% for placebo. [7]
Fatty Acid Synthase (FASN) Inhibitor
Denifanstat, developed by Sagimet Biosciences, is an oral, once daily pill and first-in-class fatty acid synthase (FASN) inhibitor, the key enzyme in the de novo lipogenesis (DNL) pathway that converts metabolites of dietary sugars such as fructose into palmitate, a saturated fatty acid. On 22 January 2024, Sagimet Biosciences announces positive topline results from phase 2b FASCINATE-2 clinical trial of denifanstat in biopsy-confirmed F2/F3 NASH. In this trial, denifanstat showed statistically significant improvements relative to placebo on both of the primary endpoints of NASH resolution without worsening of fibrosis with ≥2-point reduction in NAS, and ≥2-point reduction in NAS without worsening of fibrosis. Denifanstat-treated patients also showed statistically significant fibrosis improvement by ≥ 1 stage with no worsening of NASH, and a greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) ≥30% responders relative to placebo. The Phase 3 program is anticipate to begin in the second half of 2024. [8]
Figure 8. Denifanstat
GLP-1 agonists & Dual GIP/GLP-1 receptor agonists
With the significant efficacy of GLP-1 therapy in weight reduction and diabetes management, the potential of such therapy for treating NASH has garnered attention, leading to the initiation of many relevant trials.
A Phase 2 clinical trial of semaglutide for treating NASH has yielded some positive data. In a Phase 2 clinical trial involving 320 NASH patients, semaglutide demonstrated dose-dependent improvements in alleviating NASH symptoms.
In June 2023, Merck announced the results of a Phase 2a clinical trial of efinopegdutide, a GLP-1 receptor/glucagon-like peptide-1 receptor dual agonist, for treating NASH. Compared to GLP-1 receptor agonists, efinopegdutide significantly reduced liver fat levels in patients. After 24 weeks, patients in the efinopegdutide group experienced a 72.7% reduction in liver fat levels, compared to 42.3% in the active control group.
Tirzepatide, a GLP-1/GIP receptor dual agonist developed by Eli Lilly, and survodutide, a Glucagon and GLP-1 receptor dual agonist developed jointly by Boehringer Ingelheim and Zealand Pharma, both obtained preliminary positive results in Phase 2 clinical trials for treating NASH in February of 2024. Analysis revealed that among patients receiving the highest dose of tirzepatide treatment, 73.9% achieved the trial's primary endpoint, with NASH symptoms resolved and liver fibrosis not worsening after 1 year of treatment [10]. On the other hand, up to 83% of NASH adult patients receiving survodutide treatment achieved statistically significant improvement in NASH symptoms, compared to 18.2% in the placebo group. [11]
Conclusion
Despite numerous setbacks, the development of NASH medications has finally reached a turning point. With vast potential in the NASH pharmaceutical market, global pharmaceutical companies are pushing ahead relentlessly, leading to fierce competition. The FDA approval of Rezdiffra, the first NASH medication, serves as a significant boost for the market, offering fresh hope to countless patients.
References:
[1] Madrigal Pharmaceuticals Announces FDA Approval of Rezdiffra™ (resmetirom) for the Treatment of Patients with Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Moderate to Advanced Liver Fibrosis. Retrieved March 14, 2024 from https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-fda-approval-rezdiffratm
[2] Harrison et al., (2024). A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. NEJM, DOI: 10.1056/NEJMoa2309000
[3] Corporate Presentation. Retrieved March 1, 2024 from https://ir.madrigalpharma.com/static-files/cb87e7a4-4395-46a1-9a48-87496cf4e54f
[4] Primary Results From MAESTRO-NASH: A Pivotal Phase 3 52-week Serial Liver Biopsy Study in 966 Patients With NASH & Fibrosis. Retrieved March 1, 2024 from https://ir.madrigalpharma.com/static-files/e8a35f47-f841-49d4-9c21-781f41177609
[5] Madrigal Pharmaceuticals Announces Publication of the Phase 3 MAESTRO-NASH Trial of Resmetirom in the New England Journal of Medicine. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825978/0/en/Madrigal-Pharmaceuticals-Announces-Publication-of-the-Phase-3-MAESTRO-NASH-Trial-of-Resmetirom-in-the-New-England-Journal-of-Medicine.html
[6] Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH https://www.nejm.org/doi/full/10.1056/NEJMoa2304286
[7] Akero Therapeutics Reports Statistically Significant Histological Improvements at Week 96 in Phase 2b HARMONY Study https://ir.akerotx.com/news-releases/news-release-details/akero-therapeutics-reports-statistically-significant
[8] Sagimet Biosciences Announces Positive Topline Results from Phase 2b FASCINATE-2 Clinical Trial of Denifanstat in Biopsy-Confirmed F2/F3 NASH https://ir.sagimet.com/news-releases/news-release-details/sagimet-biosciences-announces-positive-topline-results-phase-2b
[9] Merck to Present Data for Efinopegdutide (MK-6024), an Investigational GLP-1/Glucagon Receptor Co-agonist, in Patients with Nonalcoholic Fatty Liver Disease (NAFLD) at EASL 2023 https://www.merck.com/news/merck-to-present-data-for-efinopegdutide-mk-6024-an-investigational-glp-1-glucagon-receptor-co-agonist-in-patients-with-nonalcoholic-fatty-liver-disease-nafld-at-easl-2023/
[10] Already rolling in diabetes and obesity, Eli Lilly touts tirzepatide's midstage MASH win https://www.fiercepharma.com/pharma/eli-lilly-touts-tirzepatide-midstage-nash-win-despite-lesser-anti-scarring-effect
[11] Survodutide Phase II trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH, with significant improvements in fibrosis https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/survodutide-top-line-results-mash-fibrosis