Breakthrough Clinical Results
CureGene Pharmaceuticals announced preclinical data for its investigational drug, CG-0416, a liver-targeted thyroid hormone receptor beta (THR-β) prodrug. The data, presented at the EASL Congress, showed CG-0416 to be effective in reducing hepatic lipid accumulation (58%), improving weight loss (66%), and lowering muscle loss (50%) compared to standard therapies in murine models. This dual-action mechanism targets both obesity and metabolic dysfunction-associated steatohepatitis (MASH). The drug's liver-specific activation minimizes systemic side effects, and its high oral bioavailability suggests potential for oral combination therapy with GLP-1 agonists.
Key Highlights
- 58% reduction in hepatic lipid accumulation
- 66% improvement in weight loss efficacy
- 50% lower muscle loss rate compared to standard therapies
- High oral bioavailability (92%)
Incidence and Prevalence
Global MASH Burden:
The prevalence of Metabolic dysfunction-associated steatotic liver disease (MASLD), including its progressive form MASH, is increasing globally. Pinpointing exact global incidence and prevalence of MASH specifically is challenging due to variations in diagnostic criteria, study populations, and data collection methods across research. Many studies focus on MASLD as a whole or provide regional rather than global MASH data. Furthermore, the recent name change from non-alcoholic steatohepatitis (NASH) to MASH adds complexity to tracking historical trends.
Prevalence Estimates:
- A 2021 study using Global Burden of Disease data estimated the global age-standardized point prevalence of MASLD (including MASH) at 15,018.1 cases per 100,000 population. This study did not separate out MASH specifically. The highest prevalence rates were in Kuwait (32,312.2 cases per 100,000), Egypt (31,668.8 cases per 100,000), and Qatar (31,327.5 cases per 100,000).
- A systematic review and meta-analysis from 2024 found a pooled prevalence of MASH in US Hispanic adults of 61%. This study focused on a specific population within the US and did not provide global estimates.
- Another 2024 study projected a steady increase in the prevalence of MASLD in US adults from 33.7% (86.3 million people) in 2020 to 41.4% (121.9 million people) by 2050. This study focused on the US and did not provide global MASH-specific prevalence.
- A 2020 systematic review and meta-analysis estimated a global MAFLD (including MASH) prevalence of 50.7% among overweight/obese adults. This study did not separate out MASH specifically.
Incidence Estimates:
- The 2021 Global Burden of Disease study mentioned above estimated the global age-standardized annual incidence rate of MASLD (including MASH) at 608.5 cases per 100,000 population. This study did not separate out MASH specifically.
- A 2024 study using GBD data found that MASH-associated primary liver cancer (PLC) incidence increased by 98% globally between 2000 and 2021. While this provides insight into a severe consequence of MASH, it does not directly reflect MASH incidence.
- A 2024 study found that among 2378 patients with MASH in the US, the incidence of all-cause mortality increased with disease severity, ranging from 0.14/100 person-months at fibrosis stage 0-1 to 4.62/100 person-months with decompensated cirrhosis. This study focused on mortality within a specific MASH cohort and did not provide global incidence data.
Challenges in Estimation:
The lack of standardized diagnostic criteria and global surveillance systems for MASH makes precise global estimates difficult. Liver biopsy, the gold standard for diagnosis, is not feasible for large-scale epidemiological studies. Non-invasive tests are improving but still lack widespread validation and standardization. Furthermore, the interplay of various metabolic factors in MASH adds complexity to defining and identifying cases consistently across populations.
Future Directions:
Continued research and improved surveillance are needed to better characterize the global burden of MASH. Standardization of non-invasive diagnostic tools and the development of global registries will be crucial for generating more accurate and comparable data on MASH incidence and prevalence worldwide.
Economic Burden
MASH Economic Burden
The economic burden of MASH is substantial and rising, impacting both the United States and Europe. Several studies using different data sources and methodologies have quantified this burden, focusing on direct medical costs, indirect costs (e.g., productivity losses), and overall societal costs.
United States:
- A 2023 study using the Healthcare Integrated Research Database (HIRD) found significantly higher all-cause, cardiovascular-related, and liver-related hospitalization rates and medical costs in patients with MASH compared to a matched non-MASH cohort. Specifically, MASH patients had 1.22 times higher all-cause hospitalization rates, 1.13 times higher CV-related hospitalization rates, and 7.22 times higher liver-related hospitalization rates. All-cause medical costs were 1.26 times higher, CV-related costs were 1.66 times higher, and liver-related costs were a staggering 7.79 times higher in the MASH cohort.
- Another 2023 study using HIRD data examined the cost of MASH by disease severity based on the FIB-4 score. All-cause hospitalization was significantly higher in the high FIB-4 group. While CV-related hospitalization rates were similar across FIB-4 scores, CV-related costs were higher in the indeterminate (1.26 times) and high (2.15 times) FIB-4 groups compared to the low FIB-4 group. Liver-related hospitalization rates were dramatically higher in the indeterminate (2.97 times) and high (12.08 times) FIB-4 groups, with liver-related costs also significantly elevated (3.68 times and 33.73 times higher, respectively).
- A 2024 study using the Optum Clinformatics Data Mart Database found that MASH patients with cirrhosis at baseline had significantly higher mean healthcare costs per person per year ($110,403) compared to those without cirrhosis ($28,340). Among patients without cirrhosis at baseline, those who progressed to cirrhosis during follow-up also had higher costs ($58,128) compared to those who did not progress ($20,031). Costs increased over time in all groups, with the largest increase seen in those without baseline cirrhosis who progressed (49% increase by year 6).
- A study using IQVIA Ambulatory electronic medical record data (2022) found high annual total healthcare costs in MASH patients, particularly those with cirrhosis. The study also highlighted the high prevalence of comorbidities in the MASH population and their contribution to increased costs.
Europe:
- A 2024 study in the Valencian Community region of Spain found a MASLD prevalence of 2.22%, with higher prevalence in individuals with type 2 diabetes or obesity. The study also reported high healthcare costs associated with MASLD and MASH, particularly in patients with both MASH and type 2 diabetes.
- A 2020 study estimated the global prevalence of MAFLD (a similar concept to MASLD) among overweight/obese adults to be 50.7%. While this study didn't provide specific cost data for Europe, it highlights the high prevalence of the condition, suggesting a substantial potential economic burden.
Summary:
The available data consistently demonstrate a high and increasing economic burden associated with MASH in both the US and Europe. This burden is driven by increased healthcare resource utilization, higher medical costs, and the prevalence of comorbidities. Further research is needed to fully characterize the economic impact of MASH and to evaluate the cost-effectiveness of interventions aimed at preventing and treating the disease.
Emerging Mechanism of Action
Several mechanisms of action (MoAs) are emerging as promising targets for MASH pharmacotherapy. These include:
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Thyroid hormone receptor-β (THR-β) agonists: These agents, such as resmetirom, aim to improve liver function by targeting hepatic lipid and carbohydrate metabolism. Resmetirom has shown efficacy in reducing liver fat, decreasing aminotransferases, and improving dyslipidemia, leading to its accelerated approval for MASH with fibrosis.
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Fatty acid synthase (FAS) inhibitors: FAS inhibitors like TVB-2640 aim to reduce the production of fatty acids in the liver, thereby addressing a key driver of MASH.
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Incretin analogues: These drugs, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide and tirzepatide, improve systemic metabolism, leading to weight loss and improvements in insulin resistance, which can indirectly benefit the liver and reverse MASH features. Semaglutide has shown promising results in improving liver histology in patients with MASH and fibrosis. Tirzepatide, a dual GIP and GLP-1 receptor agonist, has also demonstrated efficacy in resolving MASH and improving fibrosis in clinical trials.
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Fibroblast growth factor 21 (FGF21) analogues: FGF21 analogues have pleiotropic effects, including improving glucose and lipid metabolism and reducing liver inflammation and fibrosis. Several FGF21 analogues are in clinical development for MASH, with promising results in phase 2 and 3 trials.
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Other MoAs: Other emerging MoAs include peroxisome proliferator-activated receptor (PPAR) agonists, such as lanifibranor, which modulate lipid metabolism and inflammation; stearoyl-CoA desaturase 1 (SCD1) inhibitors, such as aramchol, which target fatty acid synthesis; and agents targeting specific genetic determinants of MASH, such as PNPLA3 and HSD17B13, using oligonucleotide-based therapies like siRNA and ASOs.
Combination therapies are also being explored to address the complex pathophysiology of MASH more effectively. For example, combining a THR-β agonist with an FAS inhibitor or a GLP-1RA could potentially provide synergistic benefits.
It is important to note that the field of MASH pharmacotherapy is rapidly evolving, and ongoing clinical trials will provide more definitive data on the efficacy and safety of these emerging therapies.
Drug used in other indications
CG-0416, also known as efruxifermin, is an FGF21 analog being investigated for various metabolic disorders beyond Metabolic dysfunction-associated steatohepatitis (MASH). While many studies focus on MASH, clinical trials are exploring its efficacy in other conditions, often in combination with existing therapies. Here's a summary based on the provided information:
1. Type 2 Diabetes (T2D) with MASH and concurrent GLP-1RA therapy:
- Trial Design: A double-blind, placebo-controlled, phase 2b study (Cohort D) evaluated the safety and efficacy of efruxifermin (50 mg once weekly for 12 weeks) in adults with T2D and MASH fibrosis (F1-F3) already receiving stable GLP-1RA therapy (semaglutide, dulaglutide, or liraglutide).
- Intervention Model: Add-on therapy with efruxifermin to existing GLP-1RA treatment.
- Key Findings: Efruxifermin, in addition to a GLP-1RA, was found to be safe and well-tolerated, significantly reducing hepatic fat fraction (HFF) and improving noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss.
2. Obesity-related metabolic comorbidities:
- Focus: While not a specific disease indication, several studies mention the potential of FGF21 analogs, including efruxifermin, for treating obesity-related metabolic issues like dyslipidemia (especially hypertriglyceridemia) and hepatic steatosis.
- Intervention Model: Likely as monotherapy or in combination with other metabolic medications.
- Key Mechanisms: FGF21 analogs exert pleiotropic effects, improving glucose and lipid metabolism and potentially resolving MASH and improving fibrosis.
3. Combination therapy with other hormones (e.g., GLP-1):
- Rationale: Emerging evidence suggests that combining FGF21 analogs with other hormones like GLP-1 may synergize their pharmacological benefits, maximizing therapeutic efficacy for obesity and related comorbidities.
- Intervention Model: Dual or triple agonist therapies targeting multiple metabolic pathways.
4. General MASH (without specific comorbidity focus):
- Trial Design: Multiple studies have investigated efruxifermin in broader MASH populations, including those without explicitly stated comorbidities like T2D.
- Intervention Model: Typically as monotherapy in placebo-controlled trials.
- Key Outcomes: These trials have demonstrated significant improvements in liver histology, including fibrosis reduction and MASH resolution, along with beneficial biochemical outcomes.
It's important to note that the provided information doesn't explicitly list separate clinical trials for efruxifermin in conditions other than MASH/T2D with concurrent GLP-1RA use. However, the mention of its potential in obesity-related comorbidities and combination therapies suggests that such trials may exist or be planned. Further research is needed to fully characterize the efficacy and safety of efruxifermin in these broader indications.