Nuclear factor erythroid 2-related factor 2 (NRF2) agonists are medicines that dampen inflammation in your central nervous system and slow MS disease progression. They treat relapsing MS by “turning on” the production of proteins that rid your body of harmful free radicals. This helps protect cells of your brain and spinal cord from damage.

How Do NRF2 Agonists Work?

Although doctors know NRF2 agonists reduce inflammation, they don’t know the exact process that makes this happen. NRF2 is a protein called a transcription factor, which helps turn specific genes "on" or "off" by binding to DNA. When NRF2 is activated, it binds to specific parts of DNA that boost an anti-inflammatory response.

Oxidative stress is a process that damages cells. Fumarates have antioxidant properties that help shield cells from this damage.

Which NRF2 Agonists Are Used to Treat Relapsing MS?

Three NRF2 agonists treat the relapsing forms of MS:

  • Dimethyl fumarate (Tecfidera)
  • Diroximel fumarate (Vumerity)
  • Monomethyl fumarate (Bafiertam)

All NRF2 agonist medications are in a drug class called fumarates. Doctors consider these drugs “first-line” oral treatments for MS, which means they turn to them first when choosing medication. 

Researchers made dimethyl fumarate specifically for treating MS. Doctors in Germany have used a chemically related compound called Fumaderm (dimethyl fumarate and fumaric acid esters) at higher doses for decades to treat psoriasis flare-ups.

Monomethyl fumarate (Bafiertam) is a bioequivalent to dimethyl fumarate (Tecfidera), which means it has the same active ingredients and desired outcome. It’s the newest NRF2 the FDA has approved. It has the same effect as dimethyl fumarate (Tecfidera) at a lower dose and with fewer side effects.

NRF2 Agonist infographic

When Are NRF2 Agonists Prescribed for Relapsing MS?

NRF2 agonists treat all relapsing forms of MS including:

  • Relapsing-remitting MS (RRMS), the most common form of MS.
  • Clinically isolated syndrome (CIS), a rare neurological episode that can be a sign of MS.
  • Secondary progressive MS (SPMS), a stage of MS that can happen after RRMS that is marked by a steady decline in motor function.

Doctors recommend treatment with a disease-modifying therapy (DMT) like NRF2 agonists when:

  • You’re diagnosed with a form of relapsing MS
  • You have your first episode of neurological symptoms and other causes have been ruled out
  • You’ve been diagnosed with SPMS but continue to have relapses or signs of inflammation on MRI scans

How Do You Take NRF2 Agonists?

All three NRF2 agonists are capsules you take by mouth twice a day. You shouldn’t crush, chew, or open the capsules to sprinkle the contents on food. You can take the capsules either with or without food. 

When your doctor prescribes your NRF2 agonist, you’ll start with an initial dose for seven days. On the eighth day, you’ll increase your dose to the maintenance dose. If your body doesn’t seem to tolerate the maintenance dose right away, you can temporarily reduce the dosage back to the starting dose for four weeks and then try again.

How Effective Are NRF2 Agonists?

When researchers study NRF2 agonists, they use certain markers to see how well they’re working to treat MS over time. One is the annualized relapse rate (ARR), or number of relapses you have in a year. Another is the number of new lesions or growth of existing lesions. They also look at your brain volume before and during treatment.

Research shows that NRF2 agonists can “significantly” reduce ARR and the number of lesions doctors see on MRI. 

Are NRF2 Agonists Safe?

NRF2 agonists are primarily safe and effective, but like all medications, they have the potential to cause side effects. Rarely, these can be serious.

Some people may have a serious allergic reaction to NRF2 agonists. If you notice your throat or tongue swelling or you have trouble breathing after you take it, tell your doctor right away. 

Another rare but serious side effect is progressive multifocal leukoencephalopathy (PML). A very few people who have taken dimethyl fumarate have gotten this potentially fatal brain infection. 

Other serious side effects that are less common include:

  • Liver damage
  • Increased white blood cell count
  • Shingles

What Are the Common Side Effects of NRF2 Agonists?

Common side effects of NRF2 agonists include:

  • Flushing (redness and warmth in your cheeks and upper body)
  • Itching

Both dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity) are prodrugs, which mean they’re inactive until you metabolize them. After they go through your GI tract, they’re activated to start working. This can cause GI issues for some people such as:

  • Feeling sick
  • Diarrhea
  • Abdominal pain
  • Vomiting
  • Indigestion

Monomethyl fumarate (Bafiertam) is not a prodrug. Since it doesn’t need to be activated in the GI tract, it’s easier on the stomach for many people.

Who Should Not Take NRF2 Agonists?

If you have an allergic reaction such as welts, hives, swelling of the face, lips, mouth, or tongue, or difficulty breathing after taking any NRF2 agonists, stop taking them until you can see a doctor. 

Talk to your doctor if you’re pregnant, breastfeeding, or planning to get pregnant. Small amounts do pass into breast milk, although studies show this amount appears to be safe for babies.   

How Much Do NRF2 Agonists Cost?

The amount you’ll pay out of pocket for an NRF2 agonist depends on many things including your insurance coverage and your pharmacy. 

Dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity) have the same cost profile.

If you’re on Medicare, your copay for an NFR2 agonists could range from $0 to $270. The average retail price is $6,207.12, but it’s unlikely you’ll ever have to pay all of that amount. 

Monomethyl fumarate (Bafiertam) is the most expensive of the three. You can get it out of pocket from $6,813.15 to $16,641.45. Medicare does not cover monomethyl fumarate (Bafiertam). 

You can find coupons online through GoodRx and assistance from programs like NeedyMeds to help you afford your treatments.

The manufacturers of some drugs offer financial assistance programs:

Dimethyl fumarate (Tecfidera)
Diroximel fumarate (Vumerity)

To help manage the financial side of your treatments, connect with an MS Navigator, financial planner, or health insurance provider.

Clinical Trials of NRF2 Agonists for Relapsing MS

Clinical trials are a vital part of developing new treatments for disease or finding new ways to use existing treatments. There are many reasons you might take part in a clinical trial. You may be hoping to be part of an MS breakthrough. You may want to help others. Or you may want closer attention from health care professionals as you manage your disease. 

You have to qualify for a clinical trial in order to be part of one. Researchers look for people with specific diseases or history of treatment, for example. Your doctor can help you find a trial that might fit you. You can also search on ClinicalTrials.gov for MS-specific clinical trials.

What to Know if You’re a Caregiver

Your loved one is weighing the pros and cons of a big decision: how to treat their MS. You can be a sounding board and an extra set of ears at doctor visits as they gather information. 

Since NRF2 agonists are oral medications you take at home, it may also be helpful for you to talk through ways they can stick to their dosing schedule. Pill organizers can be a visual cue for remembering to take medications. Alarms set on smartphones can also serve as reminders.

Is an NRF2 Agonist Right for Me?

When it comes to which DMT is best for your MS, you and your doctor will work together to make the choice. Factor in these points as you think it through:  

The way you take it

All three NRF2 agonists are capsules you take by mouth. If you’re worried about remembering to take your dose or you prefer a less frequent treatment than a daily med, an NRF2 agonist may not be for you.

Other medical conditions

NRF2 agonists aren’t a good fit for everyone, such as if you have an allergic reaction to them or you’re pregnant or plan to be soon. Liver damage isn’t common, but it can happen with NRF2 agonists, so you may choose another treatment if you deal with liver issues. 

Side effects

Although side effects of NRF2 agonists tend to be mild, the GI issues they cause can be severe. Flushing is a common issue, too. 

Previous treatments

If you already tried an oral DMT and it hasn’t worked, it may be time to talk to your doctor about injections or infusions.

Cost

Treatment prices can be high, especially for the newest NRF2 agonist, monomethyl fumarate (Bafiertam), which doesn’t have any manufacturer financial assistance program.

Show Sources

SOURCES:

Antioxidants: “Neurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways.”

Practical Neurology: “MS Minute: Oral Therapies for MS.”

National MS Society: “Oral Therapies,” “Secondary Progressive Multiple Sclerosis (SPMS).”

Drugs.com: “FDA Approves Bafiertam.”

Mayo Clinic: “Multiple Sclerosis.”

Cedars Sinai: “Clinically Isolated Syndrome.”

Medscape: “Multiple Sclerosis Guidelines,” “Dimethyl fumarate (Rx).”

FDA: “Tecfidera.”

Multiple Sclerosis Journal: “Diroximel fumarate in patients with relapsing–remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.”

DailyMed: “DIMETHYL FUMARATE capsule, delayed release.”

Bafiertam patient information.

Advances in Therapy: “Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study.”

Therapeutic Advances in Neurological Disorders: “Dimethyl fumarate transfer into human milk.”

GoodRx: “Tecfidera.”

National Institutes of Health: “Clinical Trials and You.”

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