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

• Published in: The American journal of gastroenterology Vol. 114; no. 1; pp. S376 - S377
• Main Authors: Graham, David Y., Naser, Saleh A., Offman, Elliot, Kassir, Nastya, Hardi, Robert, Welton, Thomas, Rydzewska, Grazyna, Stepien, Beata, Arlukowicz, Tomasz, Wos, Anna, Fehrmann, Clara, Anderson, Patricia, Bibliowicz, Aida, McLean, Patrick, Fathi, Reza, Harris, M. Scott, Kalfus, Ira N.
• Format: Journal Article
• Language: English
• Published: 01.10.2019
• ISSN: 0002-9270; 1572-0241
• DOI: 10.14309/01.ajg.0000592108.53051.68

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.