Initial Data Report from “LARIAT”: A Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy

Oudiz, Ronald J.; Meyer, Colin; Chin, Melanie; Feldman, Jeremy; Goldsberry, Angie; Connell, John; McCullough, P. R.; O’Grady, Megan; Tapson, Victor F.; Torres, Fernando; Waxman, Aaron B.; Rj, White

doi:10.1378/chest.2345856

Cited by 20 publications

(16 citation statements)

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“…Moreover, in a subsequent Phase II trial for pulmonary arterial hypertension, doses of bardoxolone methyl as high as 10 mg/day improved exercise performance compared to placebo without evidence of fluid retention. 21 Therefore, it is possible that the MTD of triterpenoid analogs may exceed the dose required to demonstrate biologic activity.…”

Section: Discussionmentioning

confidence: 99%

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Creelan¹,

Gabrilovich²,

Gray³

et al. 2017

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BackgroundOmaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity.MethodsOmaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression.ResultsOmaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year.ConclusionsOmaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

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Section: Discussionmentioning

confidence: 99%

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Creelan¹,

Gabrilovich²,

Gray³

et al. 2017

OTT

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“…Bardoxolone methyl is a synthetic triterpenoid, and it has been shown to inhibit proliferation of PASMCs and exhibit anti-inflammatory effects via activation of Keap1/Nrf2 and downregulation of transcription factor NF-B (132). While no published preclinical studies of bardoxolone methyl could be found at present, a 16-wk treatment with bardoxolone methyl on one or more background therapies was reported to improve 6MWD in an initial analysis of 24 PAH patients enrolled in an ongoing phase 2 LARIAT trial (NCT02036970) (99). Furthermore, a current phase 3 CATA-LYST trial (NCT02657356) is recruiting PAH patients associated with connective tissue disease to evaluate the effect of bardoxolone methyl.…”

Section: Bardoxolone Methylmentioning

confidence: 99%

Emerging therapeutics in pulmonary hypertension

Hensley

Levine

Lai

2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a progressive and often fatal illness presenting with nonspecific symptoms of dyspnea, lower extremity edema, and exercise intolerance. Pathologically, endothelial dysfunction leads to abnormal intimal and smooth muscle proliferation along with reduced apoptosis, resulting in increased pulmonary vascular resistance and elevated pulmonary pressures. PH is subdivided into five World Health Organization groups based on the disease pathology and specific cause. While there are Food and Drug Administration-approved medications for the treatment of pulmonary arterial hypertension (PAH; Group 1 PH), as well as for chronic thromboembolic PH (Group 4 PH), the morbidity and mortality remain high. Moreover, there are no approved therapies for other forms of PH (Groups 2, 3, and 5) at present. New research has identified molecular targets that mediate vasodilation, anti-inflammatory, and antifibrotic changes within the pulmonary vasculature. Given that PAH is the most commonly studied form of PH worldwide and because recent studies have led to better mechanistic understanding of this devastating disease, in this review we attempt to provide an updated overview of new therapeutic approaches under investigation for the treatment of PH, with a particular focus on PAH, as well as to offer guidelines for future investigations.

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“…Fourth, clinical studies have demonstrated that combining immunosuppressive and vasodilator therapies can improve pulmonary arterial pressure, prognosis and functional class in patients with PAH associated with some forms of CTD [15,16]. As a result of these observations, the efficacy and safety of several immunomodulatory therapies are currently being assessed in clinical trials (summarised in table 1) [17][18][19][20][21][22][23][24][25][26][27][28][29][30].…”

Section: Potential Pah Therapies Currently In Developmentmentioning

confidence: 99%

“…Therefore, drugs that may target mitochondrial dysfunction, such as bardoxolone methyl (an Nrf2 activator and inhibitor of the NF-κB pathway) and GS-4997 (an inhibitor of apoptosis signal regulating kinase 1), are being investigated as potential PAH therapies (summarised in table 1). Promising results were obtained for bardoxolone methyl in a phase II study in PAH patients on background therapy [21] and consequently a large phase III trial is now planned in a population of patients with PAH-CTD [22]. GS-4997 is also currently under investigation in an ongoing phase II trial in PAH patients [23].…”

Section: Potential Pah Therapies Currently In Developmentmentioning

confidence: 99%

Future perspectives in pulmonary arterial hypertension

et al. 2016

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While there have been advances in the field of pulmonary arterial hypertension (PAH), disease management remains suboptimal for many patients. The development of novel treatments and strategies can provide opportunities to target other mechanisms that play a role in the complex pathobiology of PAH outside of the three main pathophysiological pathways. In this review, we highlight some of the potential PAH therapies or techniques that are being, or have been, investigated in phase II clinical trials. This review also discusses potential points for consideration in the development of novel therapies that target putative disease mediators or modifiers.

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Initial Data Report from “LARIAT”: A Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy

Cited by 20 publications

References 0 publications

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Emerging therapeutics in pulmonary hypertension

Future perspectives in pulmonary arterial hypertension

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