Experimental Therapy Targets Inflammation in Pulmonary Arterial Hypertension

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Bardoxolone methyl

Bardoxolone methylReata Pharmaceuticals, Inc. is a privately held company located in Irving, Texas aiming to translate innovative research into breakthrough medicines for difficult-to-treat diseases that have significant unmet needs. Their approach specifically involves developing a novel class of drugs with potent transcriptional activity, called antioxidant inflammation modulators (AIMs), which can control the body’s production of hundreds of antioxidative and cytoprotective molecules and is associated with protection against a broad range of diseases involving inflammation and oxidative stress.  When both of these conditions occur in the vascular endothelium, a layer of cells that lines the entire vascular system, impaired endothelial production of nitric oxide induces vasoconstriction and disrupts the structural integrity of the endothelium, increasing the probability of cardiovascular disease such as Pulmonary Arterial Hypertension (PAH), a life-threatening disease that Reata is aggressively targeting using their novel treatment approach.

PAH is a disease in which endothelial dysfunction, vasoconstriction in small pulmonary arteries, dysregulated proliferation of vascular cells, and dysregulated inflammatory signaling leads to pulmonary arterial obstruction increasing pulmonary vascular resistance and resulting in right ventricular failure.  Even though it does not involve metastasis or disruption of tissue boundaries, this disease shares some features with cancer, such as activation of NF- κB and STAT3 transcription factors, hyperproliferation, resistance to apoptosis of certain cells and glycolytic metabolism of these proliferating cells.

In the United States alone, there are an estimated 15 to 20 thousand people affected by PAH, with a mortality rate of 60 to 80% just within five years of diagnosis.

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Even though there are available treatments for PAH that can improve patients’ syndromes through vasoconstriction relief, these do not directly suppress inflammation or proliferation pathways involved in the disease, allowing it to progress.  Thus, a serious clinical need for a new therapy is eminent, prompting an extensive body of non-clinical research by leading academic scientists and Reata scientists to develop cutting edge investigation for production of novel drugs.

Targeting Inflammation in PAH: A New Approach

In many different studies published in peer-reviewed journals, bardoxolone methyl — the molecule at the center of Reata’s experimental PAH therapy —  and other AIMs were shown to have antioxidative and anti-inflammatory properties, including beneficial effects on endothelial dysfunction, as well as potent anti-proliferative and anti-fibrotic effects. Additionally, internal Reata research has demonstrated that AIMs inhibit endothelin-1 signaling, partly by reducing its expression, and are also inhibitors of NF-κB and STAT3 signaling.

AIM activation of Nrf2, a transcription factor acting as the primary cellular defense against the cytotoxic effects of oxidative stress, was also shown to have positive effects on energy metabolism, possibly being beneficial for PAH patients.

Thus, bardoxolone methyl has the potential to address several aspects of PAH pathology that are not addressed by current therapies. With this potential in mind, Reata has launched the LARIAT study, a 16-week placebo-controlled, randomized double-blind and multicenter Phase 2 clinical trial aiming to assess the safety and efficacy of bardoxolone methyl relative to placebo in patients with pulmonary arterial hypertension.

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In addition to PAH, AIMs have possible applications in many other cardiovascular diseases, including vasculitis, vascular complications of diabetes, and venous ulcers, emphasizing the unexplored potential of this kind of therapy.