Traditionally, the primary goal of inflammatory bowel disease (IBD) treatment was for patients to achieve “clinical remission”, defined by the absence of signs and symptoms of active disease.[i] More recently, focus has shifted to the induction of “mucosal healing”, a state defined not only by the absence of clinical symptoms, but also the absence of ulcers and inflammatory lesions during colonoscopy.[ii]–[iii][iv] This paradigm shift has been endorsed by the FDA, which issued a draft guidance in August 2016 indicating that the assessment of mucosal healing should be a primary endpoint in clinical trials of new ulcerative colitis (UC) therapies.[v]
While the alleviation of symptoms improves UC patient quality of life in the short term, mucosal healing is associated with a number of long-term clinical benefits and improved overall outcomes. Various studies have shown that mucosal healing is associated with fewer and less frequent disease flares, fewer hospitalizations, reduced need for surgery, reduced colon cancer risk, and improved quality of life.[ii] Thus, it is clear that mucosal healing should be a priority of UC medical management.
Current UC therapies are able to induce mucosal healing with varying rates of success. A recent meta-analysis of about 4000 patients estimates that mesalamine is associated with mucosal healing in 37% of patients receiving oral therapy and 50% of patients receiving rectal therapy.[vi] Corticosteroids appear to be similarly effective, with two key studies estimating a mucosal healing rate of 30-35%.[vii],[viii] Slightly better efficacy has been reported for more aggressive agents, with the immunomodulator azathioprine associated with a 55% mucosal healing rate in steroid-dependent UC patients.[viii] Mucosal healing rates for the approved biologic therapies (infliximab, adalimumab, golimumab, and vedolizumab) are estimated to be 25-60%.[ii] Importantly, many of the studies described above defined mucosal healing using an endoscopic scoring system that allowed for some inflammation and friability, which indicate low-grade active disease. Thus, published rates may overestimate the true efficacy of approved agents for inducing mucosal healing.
Novel therapies capable of achieving higher mucosal healing rates may provide significant clinical benefit for UC patients. Most approved therapies are anti-inflammatory, and enable mucosal healing by suppressing inflammation in the colon and allowing the body’s natural wound healing processes to take over.[ix] Thetis’ lead candidate, TP-317, delivers Resolvin E1 (RvE1), a substance that is produced naturally by the body to regulate inflammation and healing.[x] In animal models of IBD, RvE1 administration has been shown to protect the colonic mucosa and preserve tissue integrity.[xi] Furthermore, RvE1 has been reported to accelerate colonic wound healing in multiple experimental systems by activating natural repair processes.[xii] Thetis is currently investigating whether TP-317 has similar wound-healing properties, and whether these properties might lead to enhanced mucosal healing in the clinic.
[i] Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365(18):1713-25.
[ii] Vaughn BP, Shah S, Cheifetz AS. The role of mucosal healing in the treatment of patients with inflammatory bowel disease. Curr Treat Options Gastroenterol. 2014;12(1):103-17.
[iii] Papi C, Fascì-spurio F, Rogai F, Settesoldi A, Margagnoni G, Annese V. Mucosal healing in inflammatory bowel disease: treatment efficacy and predictive factors. Dig Liver Dis. 2013;45(12):978-85.
[iv] Cintolo M, Costantino G, Pallio S, Fries W. Mucosal healing in inflammatory bowel disease: Maintain or de-escalate therapy. World J Gastrointest Pathophysiol. 2016;7(1):1-16.
[v] Food and Drug Administration Center for Drugs Evaluation Research (2016). Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry (FDA, Maryland).
[vi] Römkens TE, Kampschreur MT, Drenth JP, Van oijen MG, De jong DJ. High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials. Inflamm Bowel Dis. 2012;18(11):2190-8.
[vii] Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2(4947):1041-8.
[viii] Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi porro G. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;55(1):47-53.
[ix] Garud S, Peppercorn MA. Ulcerative colitis: current treatment strategies and future prospects. Therap Adv Gastroenterol. 2009;2(2):99-108.
[x] Serhan CN. Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol Aspects Med. 2017;58:1-11.
[xi] Campbell EL, Macmanus CF, Kominsky DJ, et al. Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification. Proc Natl Acad Sci USA. 2010;107(32):14298-303.
[xii] Quiros M, Nishio H, Leoni G, et al. The Specialized Pro-resolving Lipid Mediator Resolvin E1 Promotes Intestinal Mucosal Wound Repair. FASEB. 2016;30(1)