Ardelyx (United States)

OPTIMIZE was a randomized, open-label study evaluating different tenapanor initiation methods. OPTIMIZE evaluated tenapanor alone and in combination with phosphate binders (PBs) to achieve target serum phosphate (P) ≤5.5 mg/dL. Patients with inadequately controlled P receiving maintenance dialysis from 42 US locations who were taking PBs with baseline P >5.5 mg/dL and ≤10.0 mg/dL, or were PB-naive with baseline P >4.5 mg/dL and ≤10.0 mg/dL, were included in OPTIMIZE. Participants taking PBs at baseline were randomized to switch from PBs to tenapanor (Straight Switch; n = 151) or reduce PB dosage by ≥50% and add tenapanor (Binder Reduction; n = 152); PB-naive patients started tenapanor alone (Binder-Naive; n = 30). Participants received tenapanor 30 mg twice a day for 10 weeks (part A), followed by an elective, 16-week open-label extension (part B). Outcomes included changes from baseline in P, intact fibroblast growth factor 23 (iFGF23), parathyroid hormone (PTH), serum calcium, and medication burden; patient-reported outcomes; and safety. By part A endpoint, 34.4% (Straight Switch), 38.2% (Binder Reduction), and 63.3% (Binder-Naive) of patients achieved P ≤5.5 mg/dL. Mean P reduction and median pill burden reduction from baseline to part A endpoint were 0.91± 1.7 mg/dL and 4 pills/day for the Straight Switch and 0.99± 1.8 mg/dL and 1 pill/day for the Binder Reduction group. The mean P reduction for Binder-Naive patients was 0.87± 1.5 mg/dL. Among Straight Switch and Binder Reduction patients who completed patient experience questionnaires, 205 of 243 (84.4%) reported an improved phosphate-management routine. Diarrhea was the most common adverse event (133 of 333 [39.9%]). Tenapanor as monotherapy or in combination with PBs effectively lowered P toward the target range in patients who were PB naïve or who were not at goal despite PB use. Ardelyx, Inc. NCT04549597.

Introduction: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the intestinal sodium/hydrogen exchanger isoform 3 (NHE3), approved for the treatment of IBS-C in adults. Most recently ROME IV diagnostic criteria recognize that rather than being distinct entities functional constipation (FC) and IBS-C represent a continuum of symptoms. Wong, et al (AJG 2010) demonstrated that 89.5 % of patients meeting ROME III criteria for IBS-C also met the criteria for FC. Recognizing this overlap we performed a post hoc analysis, evaluating the efficacy of tenapanor for FC by utilizing the primary endpoint for chronic idiopathic constipation (CIC) in patients with IBS-C from the T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) phase 3 studies. Am J Gastroenterol 2010; 105:2228–2234 Wong RK et al. Methods: Adult patients with IBS-C (ROME III) with < 3 weekly complete spontaneous bowel movements (CSBM), ≤5 weekly spontaneous bowel movements (SBM) and weekly worst abdominal pain score ≥3 (0-10 numerical rating scale) during a 2-week screening period were randomized to tenapanor 50 mg or placebo twice a day. Data from the first 12 weeks of both trials was used to calculate the durable responder rate, which is the regulatory endpoint for CIC. A durable responder is a patient with a weekly increase of ≥1 CSBM from baseline and ≥3 CSBM per week for 9 of 12 weeks and 3 of the last 4 weeks of study. Results: In the T3MPO-1 ITT population (tenapanor, n=307; placebo, n=299; mean age 45 years; 81% female), the responder rate vs placebo in durable responder rate was 11.28% (adjusted relative risk 3.35; p < 0.001). In the T3MPO-2 ITT population (tenapanor, n=293; placebo, n=300; mean age 45 years; 82% female), the responder rate vs placebo in durable responder rate was 15.49% (adjusted relative risk 3.75; p < 0.001). Tenapanor was generally well tolerated. Diarrhea was the most common adverse event; severe diarrhea was reported in 2.5% of tenapanor-treated patients. Conclusion: Based on results from this post hoc analysis of the T3MPO-1 and T3MPO-2 Phase 3 studies for IBS-C in adults, tenapanor, with its novel mechanism of action, shows promise as a potential therapeutic option for CIC. Further clinical trials are needed to evaluate tenapanor for the CIC population to confirm these results.

Introduction: Tenapanor is a minimally absorbed, small-molecule inhibitor of intestinal sodium/hydrogen exchanger 3 (NHE3), approved for the treatment of irritable bowel syndrome with constipation (IBS-C). Preclinical studies demonstrated that tenapanor reduced intestinal permeability, inhibited TRPV1 signaling, and was associated with reduced visceral hypersensitivity and abdominal pain. Here we investigate the effects of tenapanor on multi-item abdominal score using data from T3MPO-2 (NCT02686138), a long-term phase 3 study of tenapanor. Methods: Patients with IBS-C with < 3 weekly complete spontaneous bowel movements and weekly abdominal pain score ≥3 (0-10 scale) during a 2-week screening period were randomized to tenapanor 50 mg or placebo twice a day in a 26-week randomized treatment period (RTP). Patients rated 5 abdominal symptoms on an 11-point scale (0=no symptom to 10=worst possible symptom) using an eDiary. The abdominal score 3 (AS3) is the mean of weekly scores for abdominal pain, discomfort, and bloating. The abdominal score 5 (AS5) is the mean of weekly scores for abdominal pain, discomfort, bloating, fullness, and cramping. The overall change from baseline (CFB) in the 26-week RTP and week 26 CFB in AS3 and AS5 were compared between arms using mixed-effects models with repeated measures. The cumulative distribution of CFB in AS3 or AS5 at week 26 was compared along with the Wilcoxon rank sum test. The 13/26-week AS3 or AS5 response, defined as achieving a reduction of ≥2 points in AS3 or AS5 for ≥13 weeks of the 26-week RTP, was compared using the Pearson’s chi-square test. Results: T3MPO-2 randomized 620 patients. In the intent-to-treat analysis set (tenapanor, n=293; placebo, n=300), the tenapanor arm had greater mean reduction in AS3 than placebo over the 26-week RTP (Figure a; −2.74 vs −2.15, P=0.0001) and in week 26 (−3.27 vs −2.60, P=0.0007). At week 26, cumulative distribution of CFB significantly favored tenapanor over placebo (P=0.0094). The tenapanor arm also had a higher 13/26-week AS3 response rate than placebo (46.4% vs 35.7%, P=0.0078). For AS5, mean CFB (Figure b;P=0.0001), distribution of CFB at week 26 (P=0.0121), and 13/26-week response rate (P=0.0015) were similarly improved with tenapanor. Conclusion: Few treatments for IBS-C improve abdominal pain, discomfort, or bloating. This post hoc analysis demonstrates that tenapanor significantly improves IBS-C–associated abdominal symptoms with an early onset of action that is sustained throughout the treatment period.Figure 1.: Treatment with tenapanor resulted in a greater and sustained reduction from baseline in combined abdominal symptom scores over the 26-week treatment period vs placebo. Error bars represent standard error. AS3, abdominal score 3; AS5, abdominal score 5; bid, twice a day; BL, baseline; CFB, change from baseline; LS, least squares.

Introduction: Tenapanor, a minimally systemic, small molecule inhibitor of the Na+/H+ exchanger isoform 3 (NHE3), is an investigational drug being evaluated for the treatment of IBS-C, and hyperphosphatemia in dialysis patients. In a recent Phase 2b study, tenapanor 50 mg BID produced a statistically significant increase in responder rates (6 of 12 weeks and 9 of 12 weeks) for CSBM, abdominal pain and overall responder rate, and abdominal symptoms as compared to placebo; this data has been previously presented. Global endpoints play an important role in evaluating IBS symptoms in clinical trials and have been used for many years. In this study, weevaluate the effect of tenapanor on Global Endpoints, including IBS severity, constipation severity, adequate relief, degree of relief, and treatment satisfaction. Methods: In this randomized, double-blind, placebo-controlled trial (NCT01923428), patients with IBS-C, using the Rome III criteria, with an average of < 3 complete spontaneous bowel movements (CSBM)/week, < 5 SBM/week, and abdominal pain ≥3 (0-10 Likert scale) during a 2 week baseline period received oral, twice daily tenapanor 5, 20 or 50 mg or placebo for 12 weeks. Results: There were 356 patients in the ITT population; mean age = 45.7, 87% female with baseline CSBMs = 0.2/week, SBMs = 2/week, Bristol Stool Form Scale (BSFS) score = 1.8, and abdominal pain score (0-10) = 6.1. While the lower doses were not significantly different from placebo in all measures, 50 mg tenapanor twice daily demonstrated statistically significant improvement in IBS severity, constipation severity, adequate relief, degree of relief, and treatment satisfaction (Table). Conclusion: In patients with IBS-C, 50 mg of tenapanor BID produced statistically and clinically significant improvements in responder analyses and important global endpoints, consistent with the expectations of major regulatory agencies.Table 1: The Effect of Tenapanor on Global Endpoints in Phase 2b IBS-C Clinical Trial

Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis. This phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain ≥3.0% of postdialysis weight and ≥2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week. Sixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, -0.26% (95% confidence interval, -0.57% to 0.06%) and placebo, -0.23% (95% confidence interval, -0.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [±SD]: tenapanor, 36.6 [±21.8] mmol/d; placebo, 2.8 [±2.7] mmol/d; P<0.001) and higher stool weight (tenapanor, 172.5 [±68.1] g/d; placebo, 86.3 [±30.0] g/d; P<0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment. Tenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.

This chapter contains sections titled: Introduction Mechanism of Action Antibacterial Spectrum Resistance Pseudomembranous Colitis Next-Generation Lincosamides Conclusions

Non-systemic drugs act within the intestinal lumen without reaching the systemic circulation. The first generation included polymeric resins that sequester phosphate ions, potassium ions, or bile acids for the treatment of electrolyte imbalances or hypercholesteremia. The field has evolved towards non-absorbable small molecules or peptides targeting luminal enzymes or transporters for the treatment of mineral metabolism disorders, diabetes, gastrointestinal (GI) disorders, and enteric infections. From a drug design and development perspective, non-systemic agents offer novel opportunities to address unmet medical needs while minimizing toxicity risks, but also present new challenges, including developing a better understanding and control of non-transcellular leakage pathways into the systemic circulation. The pharmacokinetic-pharmacodynamic relationship of drugs acting in the GI tract can be complex due to the variability of intestinal transit, interaction with chyme, and the complex environment of the surface epithelia. We review the main classes of non-absorbable agents at various stages of development, and their therapeutic potential and limitations. The rapid progress in the identification of intestinal receptors and transporters, their functional characterization and role in metabolic and inflammatory disorders, will undoubtedly renew interest in the development of novel, safe, non-systemic therapeutics.