Omaveloxolone - Uses, Side Effects, and Pharmacology

Overview

Omaveloxolone treats Friedreich's ataxia, a rare genetic neurological disorder. Friedreich's ataxia is characterized by progressive loss of coordination and muscle weakness due to a mutation in the frataxin gene. Omaveloxolone works by activating the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway, which helps the body defend against oxidative stress and inflammation. Various studies have assessed its safety and efficacy for Friedreich's ataxia treatment.

Drug Group

Omaveloxolone belongs to a class of drugs known as Nrf2 activators. Nrf2 activators are designed to stimulate the Nrf2 pathway, a cellular signaling pathway involved in the body's defense against oxidative stress and inflammation. This drug class is being explored for various medical conditions where oxidative stress and inflammation play a significant role in disease progression.

Available Doses and Dosage Forms

The recommended dose for Omaveloxolone is 150 mg (milligrams) orally on an empty stomach once daily. It should be taken with a whole glass of water. It is important to take Omaveloxolone on an empty stomach, as directed. This typically means taking it at least one hour before or two hours after a meal. Follow the healthcare provider's advice regarding the timing of the dose.

For Patients

What Is Friedreich’s Ataxia?

Friedreich's ataxia (FA) is a rare and inherited neurological disorder characterized by progressive loss of coordination and muscle function due to a genetic mutation in the frataxin gene. This leads to reduced production of the frataxin protein and mitochondrial dysfunction. This results in an unsteady gait (abnormal walking style), muscle weakness, and sensory impairment, typically beginning in childhood or adolescence and progressing over time. FA can also affect the heart, leading to cardiac complications, and there is currently no cure for the condition. However, treatment and management strategies aim to alleviate symptoms and improve quality of life.

How Does Omaveloxolone Work?

Omaveloxolone activates a special defense system inside the cells called the Nrf2 pathway. This defense system helps the body deal with stress and inflammation, which can be harmful. Normally, it is kept in check by a protein called Keap1 (Kelch-like ECH-associated protein 1), which stops it from doing its job. Omaveloxolone steps in and frees Nrf2 from Keap1's control. Once Nrf2 is free, it goes to the cell's command center (the nucleus) and tells the body to make more antioxidants and anti-inflammatory agents. These are like shields that protect the cells from damage caused by stress and inflammation. So, Omaveloxolone helps the body defend itself better against these harmful effects. This can be important in conditions like Friedreich's ataxia, where the body needs extra protection.

What Is the Dosage of Omaveloxolone?

The recommended dosage of Omaveloxolone for treating Friedreich ataxia is 150 mg orally once daily. It is taken in three capsules of 50 mg each. The capsules should be swallowed whole with water, and they can be taken with or without food.

How Effective Is Omaveloxolone?

A study by Karen L. Madsen et al. showed that Omaveloxolone 160 mg was well tolerated and did not affect the main outcome measure. Still, it enhances exploratory endpoints by reducing heart rate and lactate generation (increased energy and oxygen supply-demand during extensive exercise) during submaximal activity, consistent with increased mitochondrial function and submaximal exercise tolerance. Omaveloxolone may thus benefit people with mitochondrial myopathy, which motivates additional research into the drug's effects in this patient population.

What Are the Things to Inform the Doctor Before Taking the Drug?

Here are some key things to inform the doctor about before taking Omaveloxolone:

• Provide a complete medical history, including any underlying health conditions, past medical treatments, surgeries, and a list of all medications and supplements people are currently taking. This includes over-the-counter drugs, vitamins, and herbal products.

• Inform the doctor of any known allergies or adverse reactions people have had to medications or substances in the past.

• Discuss with the healthcare provider if people are pregnant, planning to become pregnant, or breastfeeding. Using Omaveloxolone during pregnancy and breastfeeding should be carefully considered, and the doctor will assess the potential risks and benefits.

• If people have liver or kidney problems, make sure the doctor is aware, as this may impact the dosing and use of omaveloxolone.

• Mention any other medications people are taking, especially drugs that may interact with Omaveloxolone. This includes prescription medications, over-the-counter drugs, and supplements. The doctor will assess potential drug interactions.

• Discuss alcohol consumption and recreational drug use with the doctor, as these factors can affect the medication or impact its effectiveness.

• If people have previously experienced significant side effects or adverse reactions to medications, report them to the doctor.

• Inform the healthcare provider of the current health status, including any recent changes in symptoms or overall health.

• Share any other medical conditions or issues relevant to the treatment with Omaveloxolone, even if they do not seem directly related to the treated condition.

• Discuss the dietary habits, including any special diets or dietary restrictions, exercise routine, and lifestyle factors that may affect the treatment.

What Are the Side Effects of Omaveloxolone?

Common Side Effects:

• Raised liver enzyme levels of aspartate transaminase (AST) and alanine transaminase, aka alanine aminotransferase (ALT).

• Headache.

• Nausea.

• Vomiting.

• Continent pain.

• Diarrhea.

• Diminished appetite.

• Fatigue.

• Skeletal muscle ache.

• Pain in the mouth and throat (oropharynx).

• Spasms of muscles.

• Backache.

• Influenza.

• Rash.

• LDL (low-density lipid) cholesterol levels are rising.

• Lower HDL (high-density lipid) cholesterol levels

• An increase in the protein brain-type natriuretic peptide (BNP)

Serious Side Effects:

• Shortness of breath, fluttering in the chest, rapid or hammering heartbeats, and abrupt dizziness are all serious cardiac symptoms.

• Extreme weakness, vomiting, disorientation, slurred speech, feeling unstable, severe headache, and lack of coordination;

• Severe nervous system reaction accompanied by very rigid muscles, a high fever, sweating, bewilderment, a rapid or irregular pulse, trembling, and a sense of death.

• Vision blurriness, tunnel vision, eye discomfort or swelling, or the perception of haloes surrounding lights are examples of serious eye symptoms.

Dietary Considerations:

Missed Dose:

If people miss a dose of Omaveloxolone, take it as soon as people remember it on the same day. If it is close to the time for the next scheduled dose, skip the missed dose and resume the regular dosing schedule the next day. Do not take a double dose to make up for a missed one. If unsure what to do, consult the healthcare provider or pharmacist.

Overdose:

If people suspect an overdose of Omaveloxolone or experience severe side effects, seek immediate medical attention or contact a poison control center. Overdosage symptoms can vary. including severe dizziness, confusion, or other unusual symptoms. It is essential not to exceed the prescribed dose to avoid the risk of overdosing.

Storage:

Store Omaveloxolone as directed by the manufacturer's instructions and the healthcare provider. Typically, medications should be stored in a cool, dry place away from excessive heat, moisture, and direct sunlight. Keep Omaveloxolone out of the reach of children and pets. Do not use the medication if it has reached its expiration date, and if people have any unused medication, consult the healthcare provider or pharmacist on proper disposal methods. Always follow the storage instructions provided with the specific prescription, as they may include specific temperature and storage conditions. Feel free to ask the healthcare provider or pharmacist for guidance if people have any questions or concerns about storage or other medication.

For Doctors

Indication:

One of the primary indications is Friedreich's ataxia, a rare genetic neurological disorder characterized by progressive loss of coordination and muscle weakness.

Dose:

The recommended dosage of Omaveloxolone for treating Friedreich ataxia is 150 mg orally once daily. It is taken in three capsules of 50 mg each.

Dosing Considerations:

• If people are also taking drugs like Erythromycin or Ketoconazole, they are metabolized by the liver enzyme CYP3A4. In this situation, the doctor could advise taking Omaveloxolone at a lesser dosage, such as 100 mg once a day.

• Suppose people experience liver issues in this situation. In that case, the doctor may advise taking Omaveloxolone at a reduced dosage, such as 100 mg once daily, or they may advise against using the drug.

• If people are nursing a baby or pregnant,. It is not advised to take Omaveloxolone while nursing or when pregnant.

What Are the Pharmacological Aspects of Omaveloxolone?

Pharmacodynamics:

Pharmacodynamics refers to how a drug affects the body and its mechanism of action at the cellular and molecular levels. Omaveloxolone is known to activate the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway.

Here Is How Its Pharmacodynamics Work?

• Nrf2 Activation: Omaveloxolone binds to a protein called Keap1 (Kelch-like ECH-associated protein 1) in the cell. Keap1 normally keeps Nrf2 inactive. When Omaveloxolone binds to Keap1, it allows Nrf2 to become active.

• Nuclear Translocation: Active Nrf2 can then move into the cell nucleus. In the nucleus, it binds to the antioxidant response element (ARE) in the DNA (deoxyribonucleic acid).

• Gene Expression: This binding to ARE prompts the cell to produce more antioxidant and anti-inflammatory proteins. These proteins help the cell defend itself against oxidative stress and inflammation.

Mechanism:

The mechanism of action of Omaveloxolone is primarily centered around its ability to activate the Nrf2 pathway. Doing so enhances the body's defense mechanisms against oxidative stress and inflammation. The drug works at the molecular level to regulate gene expression in cellular protection and repair.

Pharmacokinetics:

The pharmacokinetics of Omaveloxolone refer to how the body absorbs, distributes, metabolizes, and eliminates the drug.

• Absorption: After oral administration, omaveloxolone is rapidly absorbed from the gastrointestinal tract. The maximum plasma concentration (Cmax) is reached within two to three hours after dosing.

• Distribution: Omaveloxolone is distributed to most tissues in the body, with the highest concentrations found in the liver, kidney, and lung.

• Metabolism: Omaveloxolone is primarily metabolized by the liver enzyme CYP3A4. The main metabolites are inactive.

• Elimination: Omaveloxolone is eliminated from the body through the feces (about 92 percent) and urine (about 0.1 percent). The half-life is about 12 hours.

Toxicity:

The toxicity of omeveloxolone is still being studied. However, the available data suggests that it is a relatively safe drug. The most serious side effect is increased liver enzymes, which usually resolves with discontinuation of the drug. Other side effects, such as nausea, vomiting, and diarrhea, are usually mild and can be managed with medication.

Clinical Studies:

MOXIe study by David R. Lynch et al. suggested the security and efficiency of Omaveloxolone. This medication activates the Nrf2 pathway to improve mitochondrial function, lessen oxidative stress, and lessen inflammation in FA models. The study involved people with Friedreich's ataxia (FA), a genetic and progressive neurological disorder lacking an approved treatment. One hundred and three participants between the ages of 16 and 40 participated in this double-blind, randomized experiment across different sites.

Two groups of patients were formed, one of which received omaveloxolone and the other a placebo. The main objective was to monitor changes in a neurological rating scale after 48 weeks. Results showed that, as compared to the placebo group, Omaveloxolone significantly improved neurological function.

Omaveloxolone was generally well tolerated, with usual side symptoms such as headaches, nausea, and fatigue. However, some individuals did suffer brief elevations in liver enzyme levels when taking the drug. This implies that omaveloxolone may be effective in treating FA.

David R. Lynch et al. This study aimed to evaluate the value of the Friedreich ataxia Clinical Outcome Measures Study (FACOMS), a long-term study of the progression of Friedreich ataxia (FA), as a tool for examining the results of clinical trials. They compared patients from FACOMS with those who participated in the open-label MOXIe extension research, which used omaveloxolone to achieve this.

Propensity matching is a statistical method that the researchers used to match MOXIe extension patients with FACOMS patients according to various criteria, including sex, age, illness severity ratings, and more. Then, they looked at how the disease severity ratings of the patients in the MOXIe extension group and the matching FACOMS group changed over three years (as determined by the modified Friedreich Ataxia Rating scale, or mFARS).

The findings demonstrated that omaveloxolone-treated MOXIe extension patients consistently outperformed the matched, untreated FACOMS cohort over three years. The research showed that, compared to those who received omaveloxolone treatment in the MOXIe extension phase, the FACOMS patients generally dropped their mFARS scores more. This raises the possibility that propensity-matched analysis may be useful in determining how well omaveloxolone slows the course of Friedreich ataxia and highlights the possible advantages of such research. This study also highlights the important function of natural history studies, such as FACOMS, in assessing the efficacy of therapies in clinical trials.

What Are the Contraindications of Omaveloxolone?

• Omaveloxolone is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

• Omaveloxolone is not recommended in patients with active liver disease, such as hepatitis or cirrhosis.

• Omaveloxolone is not recommended in patients with a history of blood clots.

• Omaveloxolone is not recommended for use during pregnancy or breastfeeding.

• Omaveloxolone should not be used with strong CYP3A4 inducers like Rifampicin or Carbamazepine.

• Omaveloxolone should be used cautiously with moderate CYP3A4 inducers, such as Phenobarbital or Phenytoin.

Warnings and Precautions:

• Omaveloxolone can cause an increase in liver enzymes, which is a marker of liver damage. This usually occurs in the first few months of treatment and is mild. However, in rare cases, it can lead to more serious liver problems. The doctor will monitor liver function regularly while people are taking Omaveloxolone.

• Omaveloxolone can cause nausea, vomiting, and diarrhea. These side effects are usually mild and can be managed by taking the drug with food or by taking an anti-nausea medication.

• Omaveloxolone can cause headaches and dizziness. These side effects are less common but can be bothersome. They usually go away on their own.

• Omaveloxolone can cause muscle pain. This side effect is also less common. It is usually mild and goes away on its own.

• Omaveloxolone can cause an allergic reaction. This is a rare but serious, side effect. Symptoms of an allergic reaction can include hives, swelling, and difficulty breathing. If people experience these symptoms, stop taking omaveloxolone and seek medical attention immediately.

• Omaveloxolone can increase the risk of blood clots. This rare side effect can occur in people with a history of blood clots. If people have a history of blood clots, talk to the doctor before taking omaveloxolone.

• Omaveloxolone is not recommended for use during pregnancy or breastfeeding. If pregnant or breastfeeding, talk to the doctor before taking omaveloxolone.

• Omaveloxolone can interact with other medications, so tell the doctor about all the medications people are taking.

What Are the Drug Interactions of Omaveloxolone?

Some of the medications that can interact with Omaveloxolone include:

• Strong CYP3A4 Inducers: Strong CYP3A4 inducers can increase the metabolism of Omaveloxolone, leading to lower levels of Omaveloxolone in the blood. This can reduce the effectiveness of omaveloxolone. Examples of strong CYP3A4 inducers include Rifampicin, Carbamazepine, and Phenytoin.

• Moderate CYP3A4 Inducers: Moderate CYP3A4 inducers can also increase the metabolism of Omaveloxolone, but to a lesser extent than strong CYP3A4 inducers. Examples of moderate CYP3A4 inducers include Phenobarbital and Omeprazole.

• CYP3A4 Inhibitors: CYP3A4 inhibitors can decrease the metabolism of Omaveloxolone, leading to higher levels of Omaveloxolone in the blood. This can increase the risk of side effects from Omaveloxolone. Examples of CYP3A4 inhibitors include Ketoconazole, Erythromycin, and Diltiazem.

• Hormonal Contraceptives: Omaveloxolone can decrease the effectiveness of hormonal contraceptives, such as birth control pills, patches, and rings. This is because Omaveloxolone can induce the metabolism of these medications, leading to lower levels of the hormones in the blood. If people take hormonal contraceptives, talk to the doctor about using an alternative form of birth control while taking omaveloxolone.

Specific Considerations:

• Monitoring: The doctor will monitor the liver function regularly while people are taking Omaveloxolone. This is because Omaveloxolone can cause an increase in liver enzymes.

• Dose Adjustment: The doctor may need to adjust the dose of Omaveloxolone if people take other medications that interact with it.

• Pregnancy and Breastfeeding: Omaveloxolone is not recommended during pregnancy or breastfeeding.

• Other Medications: Be sure to tell the doctor about all the medications people take, including prescription and over-the-counter medications, vitamins, and supplements.

• Side Effects: Omaveloxolone can cause side effects such as increased liver enzymes, nausea, vomiting, diarrhea, headache, fatigue, dizziness, muscle pain, allergic reactions, and blood clots.