The FDA’s Division of Neurology Products has cleared Reata to begin conducting two new Phase 2 clinical programs to test its lead therapy in patients with Friedreich’s Ataxia (FA) and Mitochondrial Myopathies. Reata Pharmaceuticals, Inc. has been developing a new class of drugs called Antioxidant Inflammation Modulators (AIMs) with applicability in several therapeutic areas, including pulmonary arterial hypertension, oncology, dermatology, and ophthalmology. AIMs act as anti-inflammatory, cytoprotective, and energy metabolism influencers, and their pharmacology is now documented in more than 250 scientific papers.
FA and Mitochondrial Myopathies (MM) are rare diseases associated with reduced levels of energy production, fatigue and impaired exercise capacity. There are no approved therapies to treat patients for these diseases. Now, thanks to an increasing body of scientific data, RTA 408 is emerging as a potential therapy for effectively treating FA and MM patients.
FA is caused by an inherited disorder in the encoding gene of frataxin, which regulates iron levels in the mitochondria. When frataxin is defective, the protein itself becomes defective as well and iron levels in mitochondria become deregulated. In FA, there is iron overload in mitochondria affecting metabolism, causing oxidative stress and ultimately damaging mitochondrial DNA. Central and peripheral nervous systems progressively degenerate in FA patients, causing impaired gait and coordination, muscle loss, and fatigue caused by energy deprivation.
Mitochondrial Myophaties are diseases associated with mutations in mitochondrial DNA. Because these cellular organelles are responsible for the majority of cellular energy production, when they become defective, respiratory chain deficits occur. Patients often share similar phenotypic characteristics like fatigue, skeletal muscle weakness, and more symptoms regarding other organ systems (a result of the loss of energy production).
Dr. Colin Meyer (Reata’s Chief Medical Officer) stated in a recent press release: “Our collaborators and we have shown in preclinical studies that genetic or pharmacologic Nrf2 activation positively regulates mitochondrial function and energy production. We hope to translate this effect into improved physical functioning and reduced fatigue in patients with Friedreich’s ataxia and mitochondrial myopathies. These rare, debilitating diseases currently have no approved therapies.”
Nrf2 regulates multiple genes involved in cellular energy production in mitochondria, and RTA 408 works by inducing the Nrf2 pathway. Nrf2 regulates genes directly and indirectly involved in the cellular energy production, and this induction will affect both processes. Directly, it will increase the mitochondrial efficient use of fatty acids and glucose (they work as cellular fuel), mitochondrial biogenesis (forming new mitochondria), and basal oxygen consumption. Indirectly, once Nrf2 is activated, because of its anti oxidative properties, it balances reducing equivalents, which allows the maintenance of mitochondrial homeostasis and efficiency. Besides its positive effects on metabolic efficiency, it has been shown in preclinical studies that by activating Nrf2 muscle repair, recovery is potentiated and oxidative stress markers and muscle injury are bothy reduced.
Reata explained that “the two initial Phase 2 trials will both be multi-center, double-blind, randomized, dose-ranging, placebo-controlled studies. The primary efficacy endpoint in both studies will be peak work as assessed during exercise testing.” Both studies will explore changes in physical activity, fatigue and mitochondrial functioning associated biomarkers.
Reata Pharmaceuticals, Inc. is a privately held drug development company in Irving, Texas. The company is actively engaged in translating its innovative research surrounding antioxidant inflammation modulators (AIMs) into therapies for rare and difficult-to-treat diseases with unmet medical needs. Reata’s development of its novel class of AIM-based drugs feature potent transcription-regulating activity that activates Nrf2, and in turn promotes anti-oxidative, detoxitive, and anti-inflammatory genes, while also inhibiting NF-κB, which regulates a wide range of pro-inflammatory proteins. The pharmacology of the AIMs mimics that of endogenous prostaglandin metabolites that are responsible for the orchestrated resolution of inflammation. The anti-inflammatory, cytoprotective, and energy metabolism effects of AIM pharmacology have been documented in more than 250 scientific papers and are potentially relevant to a wide range of diseases.
The company is currently conducting phase 2 clinical trials for pulmonary arterial hypertension and radiation dermatitis, which will soon be joined by the newly-launched trials for treating Friedreich’s Ataxia and Mitochondrial Myopathies.