Rare Diseases

Executive Summary

    • A variety of disease processes decrease ATP production, increase oxidative stress, and deplete reducing equivalents. This can lead to a number of pathologies, including chronic muscle weakness, compromised nerve function, fatigue, chronic inflammation, and diminished quality of life.
    • Mitochondria generate energy through production of ATP, during which potentially harmful reactive oxygen species (ROS) are produced as a by-product. The generation of ATP and detoxification of ROS depend on the availability of key molecules called reducing equivalents. The management of these reducing equivalents is a constant and critical balancing act within the mitochondria.
    • In preclinical studies, activation of Nrf2 increases production of reducing equivalents, improves beta-oxidation of fatty acids, improves uptake of glucose, and increases the number of mitochondria in a cell via induction of a central regulator of mitochondrial biogenesis.
    • Reata is planning a Phase 2/3 study of bardoxolone methyl in Alport Syndrome, a rare hereditary chronic kidney disease. If successful, Reata will seek FDA approval for bardoxolone methyl to become the first available therapeutic product for this indication.
    • Reata is conducting Phase 2 studies of omaveloxolone in two rare genetic disorders associated with an inherited mitochondrial dysfunction, Friedreich’s ataxia (MOXIe) and mitochondrial myopathies (MOTOR). If successful, Reata will seek FDA approval for omaveloxolone to become the first available therapeutic product for either indication.

Mitochondrial Dysfunction

Mitochondria are the power plants of the cell and generate energy through the production of ATP. Mitochondrial ATP production occurs as electrons are passed along a series of molecular complexes in the inner mitochondrial membrane known as the electron transport chain1. During the transfer of electrons along the electron transport complexes, single electrons may escape and result in the formation of ROS. It is estimated that as much as 1% of all oxygen consumed is involved in the formation of ROS with the vast majority generated in mitochondria. To counteract the abundance of ROS generation in the mitochondria, the mitochondria also possess multiple antioxidant defense systems. These antioxidant defense systems facilitate the production of a family of proteins and related antioxidant molecules, which are utilized by the electron transport chain as reducing equivalents either to produce ATP or to detoxify ROS2.

The management of these reducing equivalents is a constant and critical balancing act within the mitochondria. Mitochondrial reducing equivalents can either be consumed to produce energy via ATP or consumed to defend against oxidative stress. Disease processes that increase oxidative stress serve to deplete mitochondrial reducing equivalents and therefore, reduce ATP production.

In preclinical studies, activation of Nrf2 increases production of antioxidant proteins and related molecules that act as reducing equivalents and augment the ability of the cell to defend against oxidative stress. This increases the availability of mitochondrial reducing equivalents for ATP production. These effects improve the efficiency of mitochondrial respiration, oxygen consumption, and overall energy output3.

Additionally, in preclinical studies, Nrf2 activation resulted in improved beta-oxidation of fatty acids (the process by which fatty acids are broken down in the mitochondria prior to entering the energy production process) and improved uptake of glucose, thereby improving mitochondrial respiration, oxygen consumption, and energy production. AIMs have been shown to increase oxygen consumption, reduce insulin resistance, and improve glucose clearance in animal models of diet-induced obesity and diabetes3.

In addition to its positive effects on cellular metabolism, in preclinical studies Nrf2 activation has been shown to promote muscle repair and recovery and reduce markers of chronic inflammation, oxidative stress, and muscle wasting and fibrosis4.

Development Program

Reata is planning a Phase 2/3 trial of bardoxolone methyl in Alport Syndrome, a rare hereditary chronic kidney disease. Like other CKDs, Alport Syndrome is characterized by mitochondrial dysfunction, oxidative stress, and inflammation. Bardoxolone methyl has been evaluated in seven studies of patients with CKD, and has a clinical history of increasing eGFR and improving renal function.

Reata has initiated Phase 2 studies in two rare disorders related to mitochondrial dysfunction and muscle wasting, Friedreich’s ataxia (MOXIe) and mitochondrial myopathies (MOTOR). Patients with these diseases have very limited therapeutic options. Preclinical studies are also underway to evaluate the effects of AIMs in other neurological and neuromuscular disorders involving mitochondrial dysfunction and impaired bioenergetics.

Alport Syndrome is a rare and serious hereditary chronic kidney disease. Patients with Alport syndrome are normally diagnosed with the disease in childhood to early adulthood. The progressive decline of the kidney’s ability to filter blood in Alport syndrome inexorably leads to renal failure and end-stage renal disease (ESRD). In males with the most prevalent subtype of Alport syndrome, approximately 50% require dialysis or kidney transplant by the age of 255. Alport syndrome affects approximately 12,000 children and adults in the United States. LEARN MORE »
Friedreich’s ataxia (FA) is an inherited, debilitating, and degenerative neuromuscular disorder that is typically diagnosed during adolescence and can lead to early death. Patients with FA experience progressive loss of coordination, muscle weakness, and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance. FA patients may also experience visual impairment, hearing loss, diabetes, and cardiomyopathy6,7,8. Approximately 15,000 people in the United States and Europe have FA9. Further, data demonstrate that Nrf2 signaling is significantly impaired in both FA patients and in preclinical models of frataxin deficiency, resulting in impairment of antioxidant defense mechanisms10. LEARN MORE »
Mitochondrial myopathies (MM) are a multi-systemic group of myopathies associated with mitochondrial dysfunction that are caused by over 200 different genetic mutations11. Patients present a complex array of symptoms that can vary widely in terms of their severity, although the main symptoms that generally result from mitochondrial dysfunction include muscle weakness, exercise intolerance, and fatigue. The prognosis for patients with MM varies widely depending on the degree of involvement of various organ systems in the disease, with disease progression leading to significant physical impairment and even to death in some individuals12. Approximately 20,000 to 40,000 people in the United States are believed to have some form of mitochondrial myopathy13. LEARN MORE »


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