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Use of an Obese Population in Phase I to Evaluate the Pharmacology of Oral CXA-10, a Nitro-fatty Acid Cell Signaling Agent, as a Disease-modifying Therapy in Pulmonary Arterial Hypertension

Elizabeth Tarka

Carla Chieffo

Jeff Botbyl

KT Perry

TM Blok

DK Jorasky

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 06.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1061

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Excessive production of reactive oxygen species (ROS) that can lead to vascular damage may play a significant role in Pulmonary Arterial Hypertension (PAH). This damage induces excessive cellular inflammatory responses, with increased production of cytokines specifically monocyte chemoattractant protein (MCP-1) and interleukin-6 (IL-6), chemokines, adipokines and growth factors as well as an increase in WBC infiltration and activity, fibrosis and cell death. In the right ventricle (RV), there is a transition from an adaptive pressure overloaded RV to a maladaptive response. Causes may be due to insufficient RV contractility, myocardial fibrosis, capillary rarefaction and disturbed metabolism. Many of these pathways are the major targets for CXA-10 activity, and therefore, key to improving both the pulmonary vasculature and cardiac abnormalities of PAH. CXA-10 is an electrophilic nitro-fatty acid that modulates anti-oxidant, anti-inflammatory and anti-fibrotic pathways through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), heat shock proteins (HSPs) and reduction in nuclear factor kappa B (NFκB), toll-like receptor 4 (TLR4) and xanthine oxidoreductase (XOR) activity.

Methods

We studied an obese population as a surrogate for diseases with impairment in metabolic and inflammatory pathways, like PAH, to evaluate the pharmacology of CXA-10 and to identify a dose range prior to the initiation of Phase 2. The following key biomarkers, MCP-1, IL-6, leptin and lipids were measured prior to and following multiple doses of CXA-10. Cohorts of obese (Body Mass Index 27.0 to 39.5kg/m2) male subjects (n=10 to 12) received CXA-10 (25, 150 or 450mg) or placebo orally once daily for 14 days. Subjects were studied under confined controlled conditions, including diet, to minimize variability in biomarker evaluation and Body Mass Index (BMI).

Results

Consistent decreases in serum MCP-1, IL6, leptin, cholesterol, and triglycerides were observed at 150 mg. These reductions were clinically meaningful (equivalent to a 30 lb. weight loss) for leptin and significantly different from placebo for MCP-1 and triglycerides. In the 150 mg dose group, LS mean difference from placebo in MCP-1 and triglyceride concentrations were -228.5 pg/mL (95% CI: -387.2, -69.77 pg/mL, Figure 1) and -59.60 mg/dL (95% CI: 102.3, 16.91 mg/dL, Figure 2) respectively at Day 14. The % reduction in leptin concentrations was 21.5% in the 150 mg dose group compared to an increase of 35% in the placebo dose group on Day 14. Oral CXA-10 was safe and generally tolerated. Dose-limiting tolerability of diarrhea and nausea was observed at the 450 mg dose which was reduced with food.

Conclusions

Utilizing an obese population enabled target validation of CXA-10 for key biomarkers such as MCP-1 and IL-6 that track with disease progression in PAH and establishment of a dose range for a Phase 2 study to investigate this potential disease-modifying therapy.