How Do Nrf2 Activators Work?

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators are medications used in the treatment of Friedreich’s ataxia, an inherited, genetic, neurodegenerative disorder that affects some parts of the nervous system. Friedreich’s ataxia impairs movement, balance and speech and can cause unsteady gait, slurred speech, and eventually, spinal and foot deformities, and cardiac muscle disease.

The exact mechanism of the therapeutic effects of Nrf2 activators in Friedreich’s ataxia is not fully known, but they are believed to work by reducing inflammation and oxidative stress caused by free radicals. Free radicals, also known as reactive oxygen species (ROS), result from cellular metabolic processes and are normally neutralized by natural antioxidants in the body. Excessive ROS can cause oxidative stress that damages tissues.

Nrf2 activators activate Nrf2, a transcription factor that is involved in the cellular response to oxidative stress. Nrf2 stimulates pathways that resolve inflammation by reducing oxidative stress, inhibiting pro-inflammatory signaling and restoring the function of mitochondria, the organelles in the cells that produce energy. Nrf2 signaling pathway and mitochondrial function are usually impaired in Friedreich’s ataxia.

Currently, the first and only Nrf2 activator approved by the FDA in February 2023, is omaveloxolone for the treatment of Friedreich’s ataxia. Omaveloxolone is expected to be commercially available in the second quarter of 2023. Bardoxolone, a second Nrf2 activator, is undergoing clinical trials for the treatment of chronic kidney disease caused by Alport syndrome, a genetic disease.

Nrf2 activators are oral capsules used in the treatment of:

• FDA-approved:
  • Friedreich’s ataxia in patients 16 years and older
• Pending FDA approval:
  • Chronic kidney disease caused by Alport syndrome in patients 12 years and older

Side effects of Nrf2 activators may include the following:

• Elevated liver enzymes ALT and AST
• Headache
• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Reduced appetite
• Fatigue
• Musculoskeletal pain
• Mouth and throat (oropharyngeal) pain
• Muscle spasms
• Back pain
• Influenza
• Rash

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of Nrf2 activators include:

• bardoxolone (pending FDA approval)
• omaveloxolone
• Skyclarys