Akero FGF21 drug development for NASH/MASH
The development and potential of the drug efruxifermin (EFX), previously referred to as AKR-001, for the treatment of liver diseases, particularly Nonalcoholic Steatohepatitis (NASH), is a significant advancement in the field of hepatology. Efruxifermin, developed by Akero Therapeutics, is engineered to mimic the biological activity of the endogenous hormone FGF21 (Fibroblast Growth Factor 21), which plays a crucial role in regulating metabolism and energy balance. This drug represents a novel therapeutic approach by targeting the underlying metabolic dysfunctions associated with NASH.
**Background on NASH and FGF21**
NASH is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver inflammation and damage due to fat buildup in the liver. It can progress to more severe conditions such as cirrhosis and liver cancer. The role of FGF21 in metabolism, including its effects on glucose and lipid metabolism, makes it an attractive target for NASH treatment. FGF21 regulates multiple metabolic pathways and has beneficial effects on body weight, insulin sensitivity, and lipid profiles.
Fibroblast Growth Factor 21 (FGF21) is a pivotal hormone in the regulation of metabolism and energy homeostasis, making it a prime target for therapeutic interventions in metabolic diseases such as Nonalcoholic Steatohepatitis (NASH). FGF21 is primarily produced in the liver, but also in adipose tissue and the pancreas, and it acts on various tissues throughout the body to exert its metabolic effects. The multifaceted role of FGF21 includes the regulation of carbohydrate and lipid metabolism, energy expenditure, and insulin sensitivity, which are all crucial aspects in the pathophysiology of NASH.
FGF21 exerts its effects through binding to a complex receptor system consisting of β-Klotho and FGFR1c (Fibroblast Growth Factor Receptor 1c). This interaction triggers a cascade of intracellular signaling pathways that lead to the modulation of glucose and lipid metabolism. Specifically, FGF21 has been shown to:
- Enhance insulin sensitivity and glucose uptake in adipocytes, contributing to improved glycemic control.
- Stimulate lipolysis in adipose tissue, leading to reduced lipid accumulation and amelioration of lipotoxicity, which is a critical factor in the development of NASH.
- Increase energy expenditure through promoting thermogenesis in brown adipose tissue.
- Suppress lipogenesis in the liver, thereby reducing hepatic fat accumulation.
These actions collectively contribute to the potential of FGF21 as a therapeutic target for conditions characterized by insulin resistance and metabolic dysfunction, such as NASH.
FGF21 represents a promising target for metabolic disease therapy, with its wide-ranging effects on metabolism offering a potentially comprehensive approach to treating conditions like NASH. However, ongoing research and clinical trials are crucial to fully understand its therapeutic potential and optimize treatment strategies.
**Efruxifermin (EFX) Development**
Efruxifermin has been designed to confer the therapeutic benefits of native FGF21 with improved pharmacokinetics. The engineered version of FGF21 in EFX has a half-life of three to four days, which supports once-weekly dosing, making it a convenient option for patients [1]. Akero Therapeutics has positioned EFX as its lead drug candidate for the treatment of NASH, highlighting its potential to address the multifaceted nature of the disease by improving liver health, insulin sensitivity, lipid profiles, and reducing body weight [2].
**Clinical Trials and Results**
Despite the promising mechanism of action and preclinical studies, the path to proving efruxifermin's efficacy in humans has encountered challenges. In a Phase 2b study, efruxifermin missed its primary endpoint of showing significant improvement in liver fibrosis without worsening of NASH. The mixed results from this trial led to a significant drop in Akero Therapeutics' share value, underscoring the complexities and challenges in developing effective therapies for NASH [3].
**Conclusion**
Efruxifermin represents a novel approach to treating NASH by targeting the metabolic dysfunctions at the heart of the disease. While early results have shown promise, the journey towards full approval and validation of its efficacy underscores the challenges inherent in drug development for complex diseases like NASH. Continued research and clinical trials will be crucial in determining efruxifermin's place in the treatment landscape for liver diseases.
For further information on efruxifermin and its development, visit Akero Therapeutics' official website and relevant scientific publications on NASH and FGF21-based therapies.
**References:**
1. "Akero picks up $65M to advance Amgen-licensed NASH drug." FierceBiotech. [Link](https://www.fiercebiotech.com/akero-picks-up-65m-to-advance-amgen-licensed-nash-drug)
2. "Akero Therapeutics | EFX for NASH | Fc-FGF21 Fusion Protein." AkeroTX. [Link](https://akerotx.com/efruxifermin/)
3. "Akero drug for NASH misses goal in mid-stage study." BioPharma Dive. [Link](https://www.biopharmadive.com/news/akero-nash-symmetry-trial-results-fibrosis-liver/696109/)