A Phase 1/2 Study of Flavocoxid, an Oral NF-κB Inhibitor, in Duchenne Muscular Dystrophy

Abstract

Flavocoxid is a blended extract containing baicalin and catechin with potent antioxidant and anti-inflammatory properties due to the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, nuclear factor-κB (NF-κB), tumor necrosis factor (TNF)-alpha, and the mitogen-activated protein kinases (MAPKs) pathways. This phase 1/2 study was designed to assess the safety and tolerability of flavocoxid in patients with Duchenne muscular dystrophy (DMD). Thirty-four patients were recruited: 17 were treated with flavocoxid at an oral dose of 250 or 500 mg, according to body weight, for one year; 17 did not receive flavocoxid and served as controls. The treatment was well tolerated and nobody dropped out. Flavocoxid induced a significant reduction in serum interleukin (IL)-1 beta and TNF-alpha only in the group of DMD boys on add-on therapy (flavocoxid added to steroids for at least six months). The decrease in IL-1 beta was higher in younger boys. The serum H₂O₂ concentrations significantly decreased in patients treated with flavocoxid alone with a secondary reduction of serum glutathione peroxidase (GPx) levels, especially in younger boys. The exploratory outcome measures failed to show significant effects but there was a trend showing that the younger boys who received treatment were faster at performing the Gowers' maneuver, while the older boys who received treatment were faster at doing the 10-m walk test (10MWT). Therefore, a double-blind, placebo-controlled study for at least two/three years is warranted to verify flavocoxid as a steroid substitute or as add-on therapy to steroids.

Keywords: Duchenne muscular dystrophy; NF-κB inhibitor; anti-inflammatory agent; antioxidant; flavocoxid; phase 1/2 study.

Figure 1

Study profile. All patients completed the study. BW, body weight.

Figure 2

Levels of serum creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) measured in patients at baseline (T0) and after 6 and 12 months (T6 and T12, respectively) of treatment with flavocoxid, and in untreated controls at T0 and T12. Data expressed as mean ± SD. There were no significant differences within groups versus T0.

Figure 3

Levels of serum interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, H₂O₂, and glutathione peroxidase (GPx) measured in DMD patients (n = 17) at baseline (T0) and after 6 (T6) and 12 (T12) months of treatment with flavocoxid. Data are expressed as mean ± SD.

Figure 4

Levels of serum IL-1-beta, TNF-alpha, H₂O₂, and GPx measured in patients at baseline (T0) and after 6 (T6) and 12 (T12) months of treatment with flavocoxid. Eight boys were steroids-naïve and were treated with flavocoxid alone; nine boys were already treated with steroids and started flavocoxid as an add-on therapy. Data are expressed as mean ± SD.

Figure 5

Levels of serum IL-1-beta, TNF-alpha, H₂O₂, and GPx measured in patients at baseline (T0) and after 6 (T6) and 12 (T12) months of treatment with flavocoxid. Eleven boys started treatment when aged less than seven years; six boys started flavocoxid when aged greater than seven years. Data are expressed as mean ± SD.