What is Rezdiffra?

Rezdiffra is used to treat nonalcoholic steatohepatitis (NASH) in adults who have moderate to advanced liver scarring (fibrosis), but do not have decompensated liver cirrhosis. It is used alongside diet and exercise and is an oral tablet taken 1 time a day.

• NASH is also known as nonalcoholic fatty liver disease or metabolic dysfunction-associated steatohepatitis [MASH].

Rezdiffra (resmetirom) gained FDA approval on March 14, 2024, under the accelerated approval scheme, which means continued approval may be based on the results of further clinical trials. It was the first drug to be approved for advanced liver disease. There is no generic.

How does Rezdiffra work?

Resmetirom’s mechanism of action involves binding to thyroid hormone receptor-beta (THR-beta), predominantly found in liver tissue. Activation of this receptor facilitates the reduction of liver fat accumulation.

NASH develops when excessive fat deposits in the liver, leading to inflammation, fibrotic changes, and potentially cirrhosis if left untreated. By selectively targeting THR-beta receptors, resmetirom lowers triglyceride levels within liver cells, thereby potentially reducing liver damage progression.

Resmetirom is a THR-beta agonist. 

How effective is Rezdiffra?

A large clinical trial of 966 adults with NASH taking Rezdiffra reported:

• 26-30% of patients showed improvement in NASH symptoms without worse scarring, compared to only 10% taking placebo
• 24-26% of patients had reduced liver scarring without other liver problems getting worse
• A lowering of bad cholesterol (LDL) by about 14-16%, while the placebo group saw almost no change.

This clinical trial tested two doses (80mg and 100mg) over 52 weeks, with the higher dose generally showing slightly better results.

Warnings

May cause liver toxicity. Your healthcare provider will monitor you for increases in your liver enzyme levels and the development of liver-related side effects. Should not be used in people with moderate-to-severe liver disease (Child-Pugh Class B or C).

Gallbladder-related side effects, such as cholelithiasis and cholecystitis have been associated with Rezdiffra. Your healthcare provider will monitor you for these and may conduct further diagnostic tests if appropriate.

It is not known if Rezdiffra is safe and effective in children under the age of 18.

Before taking

Before you take Rezdiffra, tell your healthcare provider about all of your medical conditions, including if you:

• have any liver problems other than NASH
• have gallbladder problems or have been told you have gallbladder problems, including gallstones
• are taking other medications such as gemfibrozil to lower your cholesterol or cyclosporine to suppress your immune system, because some of these may not be recommended
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed.

Pregnancy

It is not known if Rezdiffra will harm your unborn baby. Talk to your healthcare provider about the risk to the baby from Rezdiffra if you become pregnant. Report pregnancies to Madrigal Pharmaceuticals, Adverse Event reporting line .

Breastfeeding

It is not known if Rezdiffra passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you are taking it.

How is Rezdiffra administered?

Take Rezdiffra exactly as your healthcare provider tells you to take it.

Your dose is based on your body weight. Your healthcare provider will calculate this for you and it may depend on what other medications you take. The recommended dosage of Rezdiffra is:

• Body weight less than 100kg: 80mg once daily
• Body weight of 100kg or more: 100mg once daily.

Take your dose of Rezdiffra one time a day, by mouth.

• Choose the time of day when you are most likely to remember to take your dose.
• You can take it with or without food.

What are the side effects of Rezdiffra?

Rezdiffra may cause serious side effects, including:

• Liver injury (hepatotoxicity). Stop taking Rezdiffra and call your healthcare provider right away if you develop:
  • tiredness
  • fever
  • pain or tenderness in the upper middle or upper right area of your stomach (abdomen)
  • nausea
  • rash
  • vomiting
  • your skin or the white part of your eyes turns yellow (jaundice)
• Gallbladder problems. Problems such as gallstones, inflammation of the gallbladder, or inflammation of the pancreas from gallstones can occur because of NASH or Rezdiffra. Call your healthcare provider right away if you develop nausea, vomiting, fever, or pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back and the pain may happen with or without vomiting.

The most common side effects of Rezdiffra affecting at least 5% of patients include:

• Diarrhea
• Itching
• Vomiting
• Constipation
• Nausea
• Stomach (abdominal) pain
• Dizziness.

These are not all the possible side effects of Rezdiffra. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.

Does Rezdiffra cause weight loss?

Rezdiffra is not typically associated with weight loss because it primarily works to reduce fat buildup in the liver, not throughout the body. However, some patients may experience minor weight loss as a side effect due to gastrointestinal symptoms like diarrhea, nausea, or vomiting, which can temporarily decrease appetite.

What other drugs will affect Rezdiffra?

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take medicines such as:

• Strong CYP2C8 inhibitors, such as gemfibrozil (concomitant use not recommended)
• Moderate CYP2C8 inhibitors, such as clopidogrel (reduce dosage)
• OATP1B1 and OATP1B3 inhibitors, such as cyclosporine (concomitant use not recommended)
• Statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin (limit the statin dosage)
• CYP2C8 substrates, such as loperamide, montelukast, or paclitaxel (may increase the risk of side effects).

What is Wainua?

Wainua (eplontersen) is used to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN or ATTRv-PN), which is a rare, progressive disease that can be fatal if not treated. Amyloidosis is a disease caused by a buildup of abnormal proteins called amyloid.  Eplontersen works by decreasing the amount of TTR protein that is made, which slows disease progression and improves neuropathy and the patient’s quality of life. 

Wainua drug class of medications called LICA (ligand-conjugated antisense oligonucleotide). Wainua mechanism of action is by causing the breakdown of mutant and wild-type TTR mRNA by binding to the TTR mRNA, which lowers serum TTR protein and TTR protein deposits in tissues.

Wainua is given as a monthly self-administered subcutaneous injection using an autoinjector.

Wainua FDA approval was granted on December 21, 2023, to AstraZeneca to treat the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Wainua FDA approval came after positive results from the phase III clinical trial NEURO-TTRansform (NCT04136184).

What is ATTR amyloidosis?

ATTR amyloidosis is caused by a protein in the body called transthyretin (TTR) that changes from its normal shape and then forms fibrous clumps. These clumps of misshapen protein are then deposited into various organs and nerves, which can stop the organs and nerves from working properly.

ATTR amyloidosis polyneuropathy (ATTR-PN) is the build-up of amyloid protein in nerves and can cause symptoms such as a loss of sensation, tingling, numbness, or pain in the hands and feet.

ATTR cardiomyopathy (ATTR-CM) is when clumps of amyloid build up in the heart tissue, which affects the heart’s ability to work properly, leading to symptoms similar to heart failure and an enlarged heart.

Wainua side effects

Wainua side effects are vomiting (9%), protein in your urine (8%), injection site reactions (7%), blurred vision (6%), cataracts (6%), and decreased vitamin A serum levels (15%) . Low vitamin A level is a serious, but common side effect of treatment with this medicine. Your healthcare provider should tell you to take vitamin A supplements while using eplontersen. Do not take more than the amount of vitamin A your healthcare provider has recommended. Call your healthcare provider if you develop eye problems such as difficulty seeing at night, or in low-lit areas (night blindness), or dry eyes. If you develop eye problems while receiving treatment with this medicine, your healthcare provider should send you to see an eye doctor.

Atrioventricular (AV) heart block is a serious side effect that occurred in 2% of patients in clinical trials.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Before taking this medicine

Pregnancy

Tell your healthcare provider if you are pregnant, plan to become pregnant, or think you may be pregnant, as it is not known if Wainua can harm your unborn baby. Changes in vitamin A levels and vitamin A supplementation related to the use of Wainua may harm your unborn baby. 

Breastfeeding

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if Wainua can pass into your breast milk or harm your baby. Talk with your healthcare provider about the best way to feed your baby while you are using this medicine. 

How should I use Wainua?

Read the detailed Instructions for Use that come with your single-dose autoinjector. Your healthcare provider will show you or your caregiver how, where and when to inject it.

If you or your caregiver have any questions, ask your healthcare provider.

Instructions for use

Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow it to warm to room temperature. Do not use other warming methods. 

Inspect the autoinjector visually for particulate matter and discoloration prior to administration. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. 

Wainua is injected under your skin (subcutaneously) in your stomach area (abdomen), or the front of your upper legs (thighs) by you or a caregiver. A caregiver may also give you an injection in the outer area of your upper arm. 

Wainua should be injected 1 time on the same day of each month

If you miss a dose, take the missed dose as soon as possible. Then inject Wainua 1 month from the date of your last dose to get back on a monthly dosing schedule. If you have questions about your schedule, ask your healthcare provider. 

Dosing information

Recommended Wainua dose: 45 mg administered by subcutaneous injection once a month.

Wainua is available as a 45 mg/0.8 mL single-dose autoinjector.

How effective is Wainua?

In the global, open-label, randomized Phase 3 NEURO-TTRansform trial for Wainua in patients with ATTR amyloidosis polyneuropathy (ATTRv-PN) there was an 81.2% reduction in serum transthyretin (TTR) concentration when compared to the baseline, showing that eplontersen reduced TTR protein production. 

The study showed eplontersen had a statistically significant effect on the modified Neuropathy Impairment Score +7 (mNIS+7), which is a measure of neuropathic disease progression when compared to the placebo group.

Treatment also significantly improved patient-reported quality of life compared to the external placebo group (p<0.0001) as measured by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN).

Eplontersen is also being studied in the treatment of ATTR cardiomyopathy (ATTR-CM).

Interactions

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. 

Tell your healthcare provider if you take: 

• Vitamin A or beta-carotene supplements.

Ask your healthcare provider or pharmacist if you are not sure if you take any of these medicines. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. Not all possible interactions are listed here.

Wainua Package Insert

Review the Wainua Package Insert for more detailed information about this medicine. The Wainua PI contains more detail information on Indications and Usage, Dosage and Administration, Clinical Pharmacology, Clinical Studies, Drug Interaction and more. Discuss any medical questions you have with your doctor or other health care provider. This is not all the information you need to know about this medicine for safe and effective use, and it does not take the place of talking to your doctor about your treatment.

The Package Insert is sometimes called Wainua Prescribing Information (PI) or Wainua FDA label.

Ingredients

Active ingredient: eplontersen sodium. 

Inactive ingredients: dibasic sodium phosphate, anhydrous; monobasic sodium phosphate, dihydrate; sodium chloride; water for injection, and may include hydrochloric acid and sodium hydroxide for pH adjustment. 

Storage

• Store in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton. 
• It can also be kept at room temperature that is no higher than 86°F (30°C) in the original carton for up to 6 weeks. 
• Do not let the medicine reach temperatures above 86°F (30°C).
• If you do not use an autoinjector kept at room temperature within 6 weeks, throw it away.
• Do not freeze.
• Do not expose this medicine to heat or light.

Company

Wainua AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 AstraZeneca.

Ionis Pharmaceuticals, Inc.