Rezdiffra: A Milestone in NASH Treatment🎉

Imagine a predator that is silent and that is skulking among millions of people, slowly consuming their livers and planting the seeds of devastation that they are unaware of.

This sneaky enemy is none other than Nonalcoholic Steatohepatitis (NASH), a terrifying liver disease that is cloaked in danger and mystery.

But worry not; a new era has arrived with the arrival of Rezdiffra (resmetirom), the eagerly anticipated NASH warrior who has received the much-needed US FDA approval.

Understanding NASH

The accumulation of fat in the liver leads to inflammation and damage to the liver, which is known as nonalcoholic steatohepatitis (NASH). 

It belongs to a category of illnesses known as nonalcoholic fatty liver disease (NAFLD).

NASH may worsen and result in hepatic scarring, ultimately leading to cirrhosis.

NASH is comparable to the type of liver disease brought on by high, prolonged drinking. However, NASH happens to those who do not abuse alcohol.

Hepatic inflammation and damage are hallmarks of NASH, a progressive kind of NAFLD that frequently results in fibrosis, cirrhosis, and hepatocellular cancer.

Effective pharmacological therapies for nonalcoholic steatohepatitis (NASH) are lacking, despite the disease's increasing frequency and serious implications.

About Resmetirom

Rezdiffra(resmetirom), a medication approved by the FDA to treat noncirrhotic NASH with moderate to advanced liver fibrosis, is a major breakthrough for Madrigal Pharmaceuticals in the field of hepatology.

Rezdiffra is an oral THR-β agonist that is taken once day with the goal of addressing the main underlying causes of non-alcoholic steatohepatitis.

It is available in three dosage forms of 60 mg, 80 mg, and 100 mg.

The prescribing information for Rezdiffra does not specify that a liver biopsy is necessary for diagnosis.

Rezdiffra is a prescription medication used in conjunction with diet and exercise to treat persons with moderate-to-advanced liver scarring (fibrosis) associated with nonalcoholic steatohepatitis (NASH), but not liver cirrhosis.

The effectiveness and safety of Rezdiffra in pediatric patients (those under the age of 18) are unknown.

Rezdiffra dosage recommendations are based on actual body weight. The suggested dosage for patients under 100 kg (220 lbs.) is 80 mg taken orally once a day.

The suggested dosage for patients weighing more than 100 kg (220 lbs.) is 100 mg taken once daily by oral.

Mechanism of Action

Resmetirom is an innovative oral small-molecule agonist that selectively binds to the β subunit of the thyroid hormone receptor.

Resmetirom, acting as a partial agonist of thyroid hormone receptor-beta (THR-β), demonstrates significant efficacy, achieving 83.8% of the maximal response compared to triiodothyronine (T3) with an EC50 of 0.21 µM for THR-β activation.

Conversely, in thyroid hormone receptor-alpha (THR-α) agonism, its efficacy relative to T3 is 48.6% with an EC50 of 3.74 µM.

Given the prevalence of THR-β in the liver, resmetirom's stimulation of this receptor leads to a reduction in intrahepatic triglycerides, while THR-α activation predominantly influences thyroid hormone actions in extrahepatic tissues like the heart and bone.

Resmetirom addresses important pathogenic pathways underlying the advancement of NASH by activating these receptors, which also decreases hepatic inflammation, increases lipid clearance, and prevents the formation of fibrosis.

Clinical Efficacy

The FDA approval was based on strong clinical evidence from the MAESTRO-NAFLD-1 Phase 3 trial, which demonstrated the drug's safety and effectiveness in these patients.

This trial involved adults diagnosed with biopsy-confirmed NASH and fibrosis stages ranging from F1B to F3 (F0 represents no fibrosis, while F4 indicates cirrhosis).

The effectiveness of both 80 mg and 100 mg once-daily doses surpassed placebo for primary endpoints, achieving NASH resolution without worsening fibrosis and fibrosis improvement by at least one stage without NASH deterioration.

Notably, positive impacts on LDL cholesterol were observed, while maintaining stable body weight and glucose homeostasis.

These findings hold promise for patients with F1 to F3 fibrosis, where cardiovascular events reign as the primary cause of mortality.

Resmetirom exerts a profound reduction in intra-hepatic lipids by primarily enhancing mitochondrial β-oxidation and enhancing the functionality of hepatocyte mitochondria in patients with NASH.

Compared to other nuclear hormone receptors like farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) agonists, resmetirom demonstrates heightened efficacy in reducing hepatic fat.

By hypothesized mechanisms, it diminishes VLDL production and secretion from the liver, consequently lowering plasma LDL cholesterol and triglyceride levels.

Safety Profile

Rezdiffra's common adverse effects are vomiting, dizziness, constipation, diarrhea, nausea, itching, and abdominal pain.

Serious side effects that Rezdiffra may produce are as follows:

• soreness or pain in the upper right or central region of your stomach

• jaundice, or yellowing of the skin or whites of the eyes

• gallbladder inflammation / pancreatitis from gallstones

• Hepatotoxicity, or liver damage

• motion sickness

• gallstones

• vomiting

• fatigue

• fever

• rash

According to a clinical trial resmetirom was associated with nausea and diarrhea shortly after treatment initiation, with 50% of patients in both the 80 mg and 100 mg groups experiencing these symptoms within 4 weeks, compared to approximately 30% in the placebo group.

The incidence of serious adverse events was similar among all groups.

Ultimately, 7.7% of patients in the resmetirom 100 mg group discontinued treatment due to adverse events, contrasting with 2.8% in the 80 mg group and 3.4% in the placebo group.

Notably, resmetirom led to significant increases in total estradiol, testosterone (excluding free testosterone), and sex hormone-binding globulin.

In addition to the aforementioned side effects, it is imperative to acknowledge that resmetirom has been demonstrated to be a safe and efficacious pharmaceutical agent.

Following comprehensive individual patient assessment, it may be judiciously prescribed in accordance with established clinical guidelines and medical discretion.

Co-administration with strong or moderate CYP2C8 inhibitors like gemfibrozil may raise resmetirom maximum plasma concentration (Cmax) levels, increasing the risk of adverse reactions associated with resmetirom. Low dose of both the drug should be used used with each other.

For deeper insights into this topic, delve into the intriguing details provided in the drug label of REZDIFFRA.

Conclusion:

Resmetirom's FDA clearance is a significant development in the field of hepatology, providing patients with moderate to severe liver fibrosis and noncirrhotic NASH with new hope.

Resmetirom is a potentially effective therapy option for this significant liver condition due to its unique mechanism of action, proven efficacy, and good safety profile.

Further investigation and clinical experience will clarify the long-term advantages and ideal dosage of resmetirom in the treatment of nonalcoholic steatohepatitis (NASH).