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Crohn's disease

RHB-104 is a proprietary and potentially groundbreaking antibiotic combination therapy in oral capsule formulation, with potent intracellular, antimycobacterial and anti-inflammatory properties.

Crohn’s disease is an inflammatory disease of the gastrointestinal system with significant unmet needs. The inflammation caused by Crohn's disease can lead to abdominal pain, severe diarrhea, rectal bleeding, weight loss, malnutrition, fever and other symptoms, the range and severity of which vary. Current therapies target symptomatic relief, are widely considered to be of limited efficacy in the long term, and are associated with numerous side effects.

The development of RHB-104 is based on increasing evidence supporting the hypothesis that Crohn’s disease is caused by the Mycobacterium avium subspecies paratuberculosis (MAP) infection in susceptible patients rather than being an autoimmune disease.

RedHill is currently conducting a Phase III clinical study in the U.S., Canada, Europe, Israel, Australia and New Zealand. The study is designed to evaluate the safety and efficacy of fixed-dose RHB-104 in patients with moderately to severely active Crohn's disease (the MAP US study).

A first DSMB safety-focused meeting recommended unanimously that the study continue as planned (Dec. 2016). A second independent DSMB meeting will be held in late July 2017; A second pre-planned DSMB meeting reviewed safety and efficacy data of the Phase III MAP US study from the first 222 subjects who have completed week 26 assessments in the MAP US study, to which RedHill remains blinded. The independent DSMB provided RedHill with a unanimous positive recommendation to continue the study as planned. The primary endpoint for the study is remission at week 26 of treatment.

The MAP US study is registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies.

Several clinical trials were conducted with earlier formulations of RHB-104, including an Australian Phase III study conducted by Pfizer. RedHill has conducted several supportive studies with the current formulation of RHB-104 and a long-term population pharmacokinetic (Pop-PK) study is ongoing as part of the Phase III MAP US study. The formulation of RHB-104 is covered by several issued and pending patents.

As part of its development efforts for RHB-104, RedHill is developing, in collaboration with Quest Diagnostics, a diagnostic test to aid in detecting the presence of MAP (Mycobacterium avium paratuberculosis) in whole blood. In January 2015 RedHill and Quest Diagnostics concluded a pre-submission meeting with the FDA regarding the development path of a commercial companion diagnostic test for the detection of MAP in Crohn’s disease patients. Ongoing work on RedHill’s companion MAP diagnostic test has led to the successful identification of MAP DNA in blood samples from Crohn’s disease patients; Further development work on the MAP companion diagnostic is in progress

*Selected publications:

  1. R.J. Is Crohn’s disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne’s disease. THE LANCET Infectious Diseases 2003, Vol 3, PP 507-514.
  2. A. M.; Kapur. V. The evidence for Mycobacterium paratuberculosis in Crohn’s disease. Current Opinion in Gastroenterology. 2008, Vol 24, PP 17–21.
  3. Borody T.J.; Leis. S.; Warren. E.F.; Surace. R. Treatment of severe Crohn’s disease using antimycobacterial triple therapy–approaching a cure? Digestive and Liver Disease 2002, Vol 34, 1, PP 29-38.
  4. Taylor, J. H. Treatment with drugs active against Mycobacterium avium subspecies paratuberculosis can heal Crohn’s disease: more evidence for a neglected Public Health tragedy. Digestive and Liver Disease. 2002, Vol 34, PP 9-12.
  5. T.J.; Bilkey. S.; Wettstein. A. R.; Leis. S.; Pang. G.; Tye. S.; Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars Digestive and Liver Disease. 2007, Vol 39, 5, PP 438-44.
  6. W.; Ghobrial. G.; Chehtane. M.; Naser. S. A. Successful Treatment of a Crohn’s Disease Patient Infected with Bacteremic Mycobacterium Paratuberculosis. American Journal of Gastroenterol. 2007, Vol 102, PP 689-691.
  7. C.D.; Wagner. J.; Boniface. K.; Vaughan. J.; Michalski. W. P.; Catto-Smith. A. J.; Cameron. Don .J.S.; Bishop. R. F.Mycobacterium aviumsubspecies paratuberculosis in children with early-onset Crohn’s disease. Inflammatory Bowel Diseases. 2009, Vol 15, 11, PP 1643-1655.
  8. K.; Kaevska. M. Mycobacteria in water, soil, plants and air: a review. Veterinarni Medicina. 2012, Vol 57, 12, PP 623-679
  9. Agrawal G, Borody TJ & Chamberlin W. ’Global warming’ to Mycobacterium avium subspecies paratuberculosis. Future Microbiol. (2014) 9(7), 829–832.
  10. Naser SA et al. Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients. World J Gastroenterol 2014 June 21; 20(23): 7403-7415.
  11. Mendoza JL et al. High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn’s disease. World J Gastroenterol 2010 September 28; 16(36): 4558-4563.
  12. Chiodini RJ et al. Crohn’s disease and the mycobacterioses: A quarter century later. Causation or simple association? Critical Reviews in Microbiology, 2012; 38(1): 52–93.
  13. McNees AL et al. Mycobacterium paratuberculosis as a cause of Crohn’s disease Expert Rev. Gastroenterol. Hepatol. 9(12), (2015).
  14. Alcedo KP, Thanigachalam S, Naser SA. RHB-104 triple antibiotics combination in culture is bactericidal and should be effective for treatment of Crohn’s disease associated with Mycobacterium paratuberculosis, Gut Pathogens, 2016, 8:32.
  15. Qasem A, Naser AE, Naser SA. The alternate effects of anti-TNFα therapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease, EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2017 https://doi.org/10.1080/14787210.2017.1328276
  16. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease. The Lancet Vol 364 September 18, 2004.
  17. Lee A, Griffiths TA, Parab RS, King RK, Dubinsky MC, Urbanski SJ, Wrobel I, Rioux KP. Association of Mycobacterium avium subspecies paratuberculosis With Crohn Disease in Pediatric Patients, JPGN _ Volume 52, Number 2, February 2011