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Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with
Bruce E Sands1, Shashidhar Joshi, Jonathan Haddad
1*Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; †Quantitiative Sciences, GlaxoSmithKline, Bangalore, India; ‡Quantitative Sciences, Clinical Statistics, GlaxoSmithKline, Research Triangle Park, North Carolina; §Computational Biology, GlaxoSmithKline, Research Triangle Park, North Carolina; ‖Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts; and ¶Academic Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania.
Background:
Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC).
Methods:
Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin.
Results:
Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures.
Conclusions:
SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.
Insights
SRT2104, a SIRT1 activator, showed no significant clinical benefit for ulcerative colitis (UC) patients. Further research into SRT2104 for UC treatment is not recommended based on these findings.
Area of Science:
- Biochemistry
- Gastroenterology
- Pharmacology
Background:
- Sirtuins are proteins involved in metabolism and inflammation.
- SIRT1 activation is a potential, yet unexplored, therapeutic avenue for ulcerative colitis (UC).
Purpose of the Study:
- To evaluate the efficacy and safety of SRT2104, a selective SIRT1 activator, in patients with mild to moderate UC.
- To assess colonic drug exposure and clinical outcomes in UC patients treated with SRT2104.
Main Methods:
- Double-blind, randomized study of mild to moderate UC patients receiving 50 mg or 500 mg of SRT2104 daily for 8 weeks.
- Assessed colonic exposure, safety, endoscopic scoring, Mayo score, Simple Clinical Colitis Activity Index, and fecal calprotectin levels.
Main Results:
- Only 3 of 26 evaluable subjects achieved endoscopic remission; 4 patients achieved clinical remission.
- Fecal calprotectin levels decreased but remained significantly elevated.
- Treatment emergent adverse events occurred in 61% of subjects; dose-dependent drug exposure was observed with high colonic bioavailability.
Conclusions:
- SRT2104 did not demonstrate significant clinical activity in patients with mild to moderate UC.
- The study suggests that further investigation of SRT2104 for UC treatment is not warranted.
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