MASLD and MASH Therapeutics

CE / CME

Advances in MASLD/MASH Therapeutics and Updates to the Development Pipeline

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurses: 0.50 Nursing contact hour

Physicians: maximum of 0.50 AMA PRA Category 1 Credit

Released: March 13, 2024

Expiration: March 12, 2025

Mazen Noureddin
Mazen Noureddin, MD, MHSc

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Mechanisms of Action of Hepatic Drugs

I am going to end this module by discussing new attractive mechanisms such as the mitochondrial uncoupler HU6. HU6 is a controlled metabolic accelerator that leads to increased fatty acid oxidation and decreased oxidative stress to reduce body fat. It is worth pointing out the tremendous progress with GLP-1 RAs combined with other therapies. I want to mention that drugs such as efinopegdutide, survodutide, semaglutide, and tirzepatide are all currently under investigation for use in patients with MASH, with promising data so far.2

Phase IIa Trial of HU6 vs Placebo: Absolute % Change in Liver Fat From BL to Day 61

In this short 61-day study, patients achieved a remarkable absolute and relative reduction in MRI- PDFF with every dose level of HU6.2

Phase IIa Trial of HU6 vs Placebo: Relative % Change in Liver Fat in Patients With Normal and Elevated A1C

These graphs show weight loss in the overall study population with normal A1C (left) vs elevated A1C (right). In patients with normal A1C, there was a remarkable improvement in MRI-PDFF, reaching up to 72% response in the 300-mg and 450-mg subgroups. In patients with elevated A1C, weight loss was achieved in up to 86% of patients in the 300-mg and 450-mg subgroups—one of the best improvements we have seen thus far.2

Weight Loss: Overall and High A1C Group

The combination of weight loss and improvement of A1C currently makes this drug very attractive for further evaluation in future studies.

Summary of MASH Drugs Field

In summary, we have a huge improvement in the MASH pipeline, with the potential of first drug approval in 2024. GLP-1 RAs and FGF-21 analogues are very promising, and there are newer promising medications such as HU6. The GLP-1 RAs and the combination therapies have the advantage of targeting the body holistically to increase weight loss and improve cardiovascular outcomes; data to study their effect on liver fibrosis are still ongoing. Combination therapy trials are ongoing, and the medical community believes that is where the future is. Cirrhosis trials are being explored, which is remarkable in such a difficult disease stage, and the future seems bright as we look forward to the readout for these trials.

A 55-year-old patient with obesity (BMI 33.5 kg/m2) and type 2 diabetes (T2D) (controlled on maximum dose of metformin) presents for follow-up. He has MASLD with a FIB-4 score of 2.0 and a liver stiffness measurement of 10 kPa. According to the American Gastroenterological Association (AGA) clinical care pathway, this patient should:

A 60-year-old patient is diagnosed with MASLD after a liver biopsy. Her BMI is 34 kg/m2 and liver fat content is 10% (confirmed by MRI-derived proton density fat fraction [MRI-PDFF]) despite 6 months of structured diet and exercise.

You consider encouraging her to enroll on a clinical trial targeting MASLD in patients with an elevated BMI. Which of the following investigational agents would fit best with this goal?