Braden Kuo, MD, MSc1, Wilmin Bartolini, PhD2, Kenneth Tripp, MS3, Ramesh Boinpally, PhD4, Niels Borgstein, MD2
1Massachusetts General Hospital, Boston, MA; 2Ironwood Pharmaceuticals, Inc., Cambridge, MA; 3Formerly of Ironwood Pharmaceuticals, Inc., Cambridge, MA; 4Allergan plc, Madison, NJ
Introduction: MD-7246 is a delayed-release formulation of linaclotide (LIN), releasing drug in the distal ileum, under development for treating visceral pain with limited pro-secretory effects. LIN, a GC-C agonist, is approved as an immediate-release (IR) formulation, releasing in the stomach, for treating irritable bowel syndrome with constipation and chronic idiopathic constipation. This study assessed the safety, tolerability, and pharmacokinetics of MD-7246 and explored select pharmacodynamic (PD) parameters.
Methods: This double-blind, placebo-controlled study randomized healthy adult volunteers to placebo or 1 of 3 daily doses of MD-7246 for 7 days. Safety and tolerability were assessed at each dose prior to dose escalation. PD assessments for spontaneous bowel movement [SBM]/week and stool consistency (Bristol stool form scale [BSFS]) were recorded in a diary.
Results: Placebo, low, mid, or high doses of MD-7246 were received by 6 subjects each. Neither LIN nor its active metabolite were detected in plasma after 7 days of oral administration and no intact tablets were discovered in any subject’s stool. The median and interquartile range (IQR) for change from baseline (CFB) in SBM and BSFS were similar and overlapping for placebo and all 3 MD-7246 dose groups (median (IQR) CFB: SBM: -2.6 (-4.6, 2.9), -1.9 (-4.4, -1.4), -1.3 (-2.0, 0.0), and 0.0 (‑7.7, 0.9); BSFS: 0.4 (-0.2, 1.0), 0.2 (-1.0, 0.9), 0.2 (-0.4, 1.0) and 0.4 (-0.3, 1.8) in placebo and low, mid, and high MD-7246 doses, respectively). MD-7246 was well tolerated and there were no adverse events of diarrhea reported in any subject (placebo or MD-7246). For comparison, the PD effects of LIN (290 µg) IR formulation was evaluated in a previous food effect study in healthy volunteers (n = 18). SBM frequency and BSFS showed an increase from baseline (median (IQR) CFB: SBM: 3.5 (3.0, 8.0) and 1.0 (0.0, 4.0); BSFS: 2.3 (2.1, 2.8) and 1.6 (1.3, 2.4) in fed and fasted state, respectively) with a greater mean CFB in the fed state vs. the fasted (p < 0.01). Diarrhea was reported in those who received IR LIN 290 µg.
Discussion: MD-7246, a delayed-release formulation of LIN, was safe and well tolerated for 7 days at all 3 doses. MD-7246 appears to have distinct clinical properties from the approved LIN 290 µg IR formulation and showed no effect on SBM frequency or stool consistency. In comparison, SBM frequency increased and stool consistency shifted to looser stools in healthy volunteers following LIN 290 µg IR QD for 7 days.
Citation: Braden Kuo, MD, MSc; Wilmin Bartolini, PhD; Kenneth Tripp, MS; Ramesh Boinpally, PhD; Niels Borgstein, MD. P1259 - MD-7246, A DELAYED-RELEASE FORMULATION OF LINACLOTIDE TARGETING VISCERAL PAIN ASSOCIATED WITH IBS-D, DOES NOT IMPACT BOWEL FREQUENCY OR STOOL CONSISTENCY IN HEALTHY VOLUNTEERS: RESULTS FROM PHASE I TRIAL. Program No. P1259. ACG 2019 Annual Scientific Meeting Abstracts. San Antonio, Texas: American College of Gastroenterology.