Northwestern University Feinberg School of Medicine ARLINGTON HTS, IL
Award: Presidential Poster Award
Darren M. Brenner, MD1, Anthony Lembo, MD2, Yang Yang, PhD3, David Rosenbaum, PhD3 1Northwestern University Feinberg School of Medicine, Chicago, IL; 2Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH; 3Ardelyx, Inc., Waltham, MA
Introduction: Tenapanor (TEN) is a first-in-class, minimally systemic inhibitor of intestinal sodium-hydrogen exchanger isoform 3 (NHE3) approved by the FDA for adults with irritable bowel syndrome with constipation (IBS-C). In human intestinal cell cultures, TEN increased transepithelial electrical resistance and decreased paracellular permeability. In an in vivo rat model of IBS-like colonic hypersensitivity, TEN normalized colonic sensory neuronal excitability and signaling through inhibition of the transient receptor potential cation channel subfamily V member 1 (TRPV1). We conducted a post hoc analysis of pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies to examine the effects of TEN on abdominal pain and other abdominal symptoms independent of changes in bowel function in IBS-C.
Methods: Study methods have been described previously for all studies. Patients (pts) were randomized to TEN 50 mg or placebo (PBO) bid for 12 or 26 weeks. Phone diaries were used to collect daily data on abdominal symptoms (including pain, bloating, and discomfort; each on a 0- to 10-point scale). The abdominal score (AS) was derived as the mean of average weekly abdominal pain, bloating, and discomfort scores. Pts with 0 complete spontaneous bowel movements (CSBMs) in a given week pooled from all three studies were used in analyses for that week.
Results: The pooled population included 1372 intent-to-treat pts (688 PBO, 684 TEN). Pt demographics were generally similar across the studies. At week 12, 531 pts (TEN=231; PBO=302) reported 0 CSBMs. TEN pts with 0 CSBMs had a significantly greater decrease from baseline than PBO pts with 0 CSBMs in average weekly abdominal pain score (least squares [LS] mean change: -1.82 vs -1.25; p=0.0010) and AS score (LS mean change: -1.65 vs -1.15; p=0.0021), respectively. Similarly, compared with PBO pts with 0 CSBMs, a significantly greater proportion of TEN pts with 0 CSBMs had a ≥2 point reduction in average weekly abdominal pain score (40.7% vs 31.1%; p< 0.0001) and AS score (36.4% vs 29.1%; p< 0.0001), respectively. The most common adverse event seen across TEN studies was diarrhea.
Discussion: TEN improves abdominal symptoms regardless of improvement in CSBMs in adult pts with IBS-C, which may be a result of TEN’s novel mechanism of action that has been shown to improve both intestinal permeability and visceral hypersensitivity in nonclinical studies.
Disclosures:
Darren Brenner: AbbVie Inc. – Advisor or Review Panel Member, Consultant, Speakers Bureau. Alnylam – Advisor or Review Panel Member, Consultant, Speakers Bureau. Ardelyx – Advisor or Review Panel Member, Consultant, Speakers Bureau. Bayer – Advisor or Review Panel Member, Consultant, Speakers Bureau. Entrinsic Bioscience – Advisor or Review Panel Member, Consultant, Speakers Bureau. Gemelli Biotech – Advisor or Review Panel Member, Consultant, Speakers Bureau. International Foundation for Gastrointestinal Disorders (IFFGD) – Advisory Committee/Board Member. Ironwood Pharmaceuticals, Inc. – Advisor or Review Panel Member, Consultant, Speakers Bureau. Mahana – Advisor or Review Panel Member, Consultant, Speakers Bureau. Owlstone – Advisor or Review Panel Member, Consultant, Speakers Bureau. Redhill – Advisor or Review Panel Member, Consultant, Speakers Bureau. Salix – Advisor or Review Panel Member, Consultant, Speakers Bureau. Takeda – Advisor or Review Panel Member, Consultant, Speakers Bureau. Vibrant – Advisor or Review Panel Member, Consultant, Speakers Bureau.
Anthony Lembo: AEON Biopharma Inc. – Consultant. Alkermes – Consultant. Allakos – Consultant. Allurion – Stock Options. Anji Pharmaceuticals – Consultant. Arena Pharmaceuticals – Consultant. BioAmerica – Consultant. Bristol Myers Squibb – Stock Options. Gemelli Biotech – Consultant. Ironwood Pharmaceuticals – Consultant. Johnson & Johnson – Stock Options. Maunea Kea – Consultant. Neurogastrx, Inc. – Consultant. OrphoMed, Inc. – Consultant. Pfizer – Consultant. QOL Medical – Consultant. Shire, a Takeda company – Consultant. Takeda Pharmaceuticals – Consultant. Vibrant Pharma, Inc. – Consultant.
Yang Yang: Ardelyx, Inc. – Employee, Stock Options.
David Rosenbaum: Ardelyx, Inc. – Employee, Stock Options.
Darren M. Brenner, MD1, Anthony Lembo, MD2, Yang Yang, PhD3, David Rosenbaum, PhD3. P1597 - Tenapanor Can Improve Abdominal Symptoms Independent of Changes in Bowel Movement Frequency in Adult Patients with IBS-C, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.
