643 RHB-104, a Fixed-Dose, Oral Antibiotic Combination Against Mycobacterium Avium Paratuberculosis (MAP) Infection, Is Effective in Moderately to Severely Active Crohn's Disease

Abstract

INTRODUCTION: MAP US was a global multicenter randomized trial comparing the efficacy and safety of RHB-104, a fixed-dose oral combination of clarithromycin, rifabutin and clofazimine against MAP infection, in moderately to severely active Crohn's disease (CD). We report evaluations of efficacy, symptom improvement and exposure-response by individual RHB-104 components. METHODS: Patients with active CD (CDAI ≥220 and ≤450) and failure with conventional therapies were randomized 1:1 to RHB-104 or placebo for up to 52 Wks. Concomitant corticosteroids, immunosuppressives (IS) and anti-TNF agents were permitted. The primary endpoint was clinical remission (CDAI <150) at Wk 26. Secondary endpoints included clinical response at Wk 26 (CDAI decrease ≥100 points), early remission at Wk 16 and remission at Wk 52. A population pharmacokinetic (PK) and exposure-response analysis was performed based on PK assessments and remission at Wk 26; a subset of patients underwent colonoscopy at baseline and Wk 26. RESULTS: 331 subjects were randomized at 92 sites. The proportion achieving remission at Wk 26 (36.7% vs 23%, P = .007), remission at Wk 16 (42.2% vs 29.1%, P = .015) and response at Wk 26 (44% vs 30.9%, P = .017) were significantly greater with RHB-104 vs placebo. The superiority of RHB-104 was more pronounced in patients receiving RHB-104 with concomitant anti-TNF or IS treatment. Despite the small numbers (n = 35), a greater proportion of RHB-104 patients achieved endoscopic response by SES-CD 50 (28.6% vs 4.8%, P = .11). Differences in fecal calprotectin (FCP) increased over time (Figure 1); improvements in PRO-2 symptoms appeared by Wk 4 and reached significance by Wk 16 (Figure 2). A significantly greater proportion of patients receiving RHB-104 achieved clinical remission with at least a 50% reduction from baseline in either FCP or CRP concentration at Wk 16 (25.9% vs 9.7%, P = .0002), Wk 26 (21.1% vs 9.1%, P = .0003) and Wk 52 (16.9% vs 7.9%, P = .02). Exposure-response modeling demonstrated the combination of the individual components of RHB-104 contributed to the higher rate of remission compared to placebo and that the probability of achieving remission was most sensitive to clofazimine. CONCLUSION: RHB-104 demonstrated meaningful improvement in efficacy and biomarkers of active inflammation, with exposure-response for each drug component, early onset of response and benefit in patients with and without concomitant anti-TNF or IS therapy.