A Multicenter, Randomized, Double-Blind Trial of EverolimusVersusAzathioprine and Placebo to Maintain Steroid-Induced Remission in Patients With Moderate-to-Severe Active Crohn's Disease

Abstract

The safety and tolerability of everolimus (6 mg/day) in patients with active CD were comparable to azathioprine. At this dose, everolimus is not more efficacious in achieving a steroid-free remission in active CD than the comparators.

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…116 However, everolimus treatment failed to produce a significant difference in a randomized, controlled clinical trial for Crohn disease that was prematurely terminated after only 96 patients were evaluated (36 of whom received everolimus), likely due to the influence of disease-related factors on pharmacokinetics and pharmacodynamics or on the dosage regimens applied. 117 Nevertheless, the successful use of sirolimus in a so far underpowered clinical setting suggests that the efficacy of MTOR-based pharmaceutical strategies should be evaluated in randomized clinical trials among patients with Crohn disease refractory to conventional treatment, i.e., immunomodulators and biologics. It might be important to investigate such potential autophagytargeting agents based on the fact that ATG16L1 plays considerable roles in the regulation of IL1B production and NODmediated inflammatory responses.…”

Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Similarities, Differences and a Lot of Things We Do Not Know Yet

“…For example based on the recently described pathway of IL-23/ Th17 in IBD, ustekinumab (Janssen-Cilag), a human antiinterleukin-12/-23 monoclonal antibody, which was previously applied in psoriasis, has been successfully tested in moderate to severe CD [188]. Nevertheless, a randomized clinical trial in active CD patients with everolimus (Novartis), an inducer of autophagy, was terminated in the enrollment phase due to the lack of efficacy [189]. This underlines the role of carefully designed studies in the future, where patients are genetically selected and only patients with defective autophagy are enrolled [187].…”

Down the line from genome-wide association studies in inflammatory bowel disease: the resulting clinical benefits and the outlook for the future

“…The genetic risk variants in these loci seem to lead to less effective autophagy and consequently lead to less efficient disposal of invasive microbes. Everolimus (Novartis) and Sirolimus (Pfizer) are both mammalian target of rapamycin (mTOR) inhibitors and up-regulate the autophagy pathway [85,86]. Both drugs are registered for immune suppression after solid organ transplantation.…”

“…Because of their known immunosuppressant effects and their specific effect on the autophagy pathway the drugs were tested in CD. Although case-reports of the treatment of CD with Sirolimus seemed promising, a randomized case-control study with Everolimus was terminated early because the drug showed no efficacy [85,86]. One could speculate that in the future such trials should be repeated but then including only cases with impaired autophagy e.g., carrying the ATG16L1, NOD2 or IRGM risk variants.…”