Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, immune-mediated condition characterized by ongoing inflammation of the large bowel. Symptomatic flares of UC are the result of mucosal inflammation, and patients experience diarrhea, usually with passage of blood, abdominal cramping, and tenesmus. Treatment is directed at reducing inflammation, initially through the use of anti-inflammatory agents such as 5-aminosalicylates1 or corticosteroids administered orally or topically per rectum or immune-suppressing medications such as oral thiopurine agents and systemically delivered biologic agents such as anti-TNF antibodies,2 and more recently the anti-α4β7 integrin antibody, vedolizumab.3 Despite the availability of these therapies, treatment may be ineffective for many patients, and particularly systemically delivered immune-suppressing agents are associated with serious infections and other adverse effects. Additional therapies with novel mechanisms and improved safety profiles are needed. Sirtuins (also called silent information regulator 2 [Sir2] proteins) are a class of proteins with important biological functions in organisms ranging from prokaryotes to eukaryotes.4 They are NAD+-dependent deacetylases, with numerous well-defined substrates, that may play a role in a number of different diseases.5–7 The mammalian sirtuins include a family of 7 recognized members, designated as SIRT1 through SIRT7,4 and are implicated in various physiological roles in metabolism and inflammation.8,9 SIRT1 is best known for its role as a mediator in extending longevity through calorie restriction (CR),10–12 but varieties of other beneficial metabolic and anti-inflammatory effects have been demonstrated.13–17 Resveratrol, a component of red wine, is an SIRT1 activator, and has been shown to have metabolic and anti-inflammatory benefits, as well as an anticancer effect, and in addition may inhibit ischemic injury.18–28 However, resveratrol is not a highly potent nor selective SIRT1 activator and, therefore, a variety of more potent SIRT1 activators have been developed to explore their potential therapeutic effect in diseases of aging and inflammation.29 To explore the effects of SIRT1 activation in UC, we assessed the safety, tolerability, colonic tissue exposure, and anti-inflammatory effects of 2 different doses of SRT2104, a SIRT1 activator, in subjects with mild to moderate UC.