IBSRELA Medical FAQ

IBSRELA is a first-in-class therapy that received approval in the US for the treatment of adults with irritable bowel syndrome with constipation (IBS-C) in 2019.

IBSRELA is commercially available in the US as of April 4, 2022, for the treatment of IBS-C.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1] Ardelyx, Inc. 2022. Ardelyx Announces US Launch of IBSRELA®, a New First-in-Class Treatment for IBS-C in Adults. Ardelyx, Inc. [online] Available at: https://ir.ardelyx.com/news-releases...nces-us-launchibsrelar-new-first-class-treatment

IBSRELA is available in Canada by Knight Therapeutics, Inc.

Ardelyx has established a commercialization agreement with Fosun Pharma in China for IBSRELA and is currently in development (not yet available).

Ardelyx, Inc. 2022. Ardelyx Launching IBSRELA® Second Quarter of 2022 | Ardelyx, Inc. [online] Available at: https://ir.ardelyx.com/news-releases...d-quarter-2022

Ardelyx may provide financial support for qualified communities or healthcare-related charitable organizations for a bona fide philanthropic purpose to promote the public good in line with Ardelyx funding priorities.

You may contact GrantsAndGiving@Ardelyx.com or visit https://ardelyx.com/medicalprofessionals/ [Grants Giving] for more information. Charitable or Educational grant requests may be submitted to https://grantsandgiving.ardelyx.com/

Ardelyx will consider requests related to the mechanism of disease, disease management, clinical outcomes of disease management and tenapanor mechanism of action.

You may contact IST@ardelyx.com or visit https://ardelyx.com/medical-professionals/ [Investigator Sponsored Trials] for more information.

Investigator Sponsored Trial (IST) concept application form can be downloaded from https://ardelyx.com/wp-content/uploa...ubmission-Form25July2022.pdf. The completed application form should be emailed to IST@ardelyx.com

As part of the commitment to the medical and patient community, Ardelyx may provide financial support to independent medical education (IME) for professionals and independent educational programs for patients and caregivers.

You may contact GrantsAndGiving@Ardelyx.com or visit https://ardelyx.com/medicalprofessionals/ [Grants Giving] for more information. Educational grant requests may be submitted to https://grantsandgiving.ardelyx.com/

The recommended dosage of IBSRELA in adults with irritable bowel syndrome with constipation (IBS-C) is 50 mg orally twice daily.

IBSRELA should be taken immediately prior to breakfast or the first meal of the day and immediately prior to dinner.

In clinical trials, IBSRELA was administered immediately prior to the first meal of the day and immediately prior to dinner. Administration of IBSRELA 5 to 10 minutes before a meal increased the 24-hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition.

If a dose is missed, the missed dose should be skipped and the next dose should be taken at the regular time. Do not take 2 doses at the same time.

IBSRELA should be kept in the original bottle in a dry place. Do not subdivide or repackage. Do not remove the desiccant from the bottle as IBSRELA should be protected from moisture.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 2, 12, 17]

How is IBSRELA dosed?

When should IBSRELA be administered?

What should patients do if a dose is missed?

The recommended dosage of IBSRELA is 50 mg orally twice daily.

Take IBSRELA immediately prior to breakfast or the first meal of the day and immediately prior to dinner.

If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 2]

IBSRELA tablets contain 50 mg tenapanor and are oval, white to off-white, debossed with the “Ardelyx logo and 50” on one side and “5791” on the other side.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 3]

iBSRELA is a coated tablet and there are no available data on splitting, chewing, crushing tablets, or mixing with food.

• IBSRELA is not a sustained-release formulation.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 16]

The FDA-approved dose of IBSRELA is 50 mg twice daily. Ardelyx cannot recommend dosing or dose titration other than mentioned in the approved prescribing information. Data presented below with other IBSRELA doses are intended to provide a general overview and do not suggest the off-labeled use of IBSRELA in the given patient population.

In a multicenter, Phase 2a, randomized, double-blind- placebo-controlled dose-finding study, IBSRELA 10 mg, 30 mg, and 100 mg once-daily (QD) were compared to placebo (N=185, ITT). The 8-week study included a 2-week treatment-free screening period, a 4-week blinded treatment period, and a 2-week treatment-free follow-up period. The mean age of patients across treatment groups was 46 years and the majority were women (84%) and white (79%).

• QD administration demonstrated some change in weekly complete spontaneous bowel movement (CSBM) frequency in subjects with IBS-C. Mean weekly CSBM frequency increased from baseline to Week 4 (last observation carried forward) in all treatment groups with mean changes of 1.50, 1.54, and 1.57 in the IBSRELA 10 mg, 30 mg, and 100 mg QD dose groups, respectively, vs. 1.01 in the placebo group. Although the mean changes (and LS mean changes) from baseline in the 30 mg and 100 mg IBSRELA groups were greater than in the placebo group, the overall test of the equality of the 3 treatment arms was not statistically significant (p=0.4371); therefore, no further statistical testing of pairwise comparisons is reported.

Different twice-daily (BID) doses were also compared in a separate Phase 2b, double-blind study with patients randomized to 5 mg bid, 20 mg bid, and 50mg bid for 12 weeks.

• Overall, 356 patients were randomized (mean age: 45.7 years; 86.8% women and 76% white) and 304 completed the study. The CSBM responder rate was significantly higher in the IBSRELA 50 mg b.i.d. group than in the placebo group (60.7 vs. 33.7%; p<0.001), as was the composite responder rate (50.0 vs. 23.6%; p<0.001). Responder rates for abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) were significantly higher in the IBSRELA 50 mg b.i.d. group than in the placebo group (all <0.05). Diarrhea was the most frequent adverse event (IBSRELA b.i.d.: 20 mg, 12.4%; 50 mg, 11.2%). Based on these dose-finding studies, 50 mg BID was selected for the phase 3 study.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report - RDX5791-201) William D Chey WD, Lembo AJ, Phillips JA, Rosenbaum DP. Efficacy and safety of tenapanor in patients with constipation-predominant irritable bowel syndrome: a 12-week, double-blind, placebo-controlled, randomized phase 2b trial. Presented: Digestive Disease Week, May 16-19, 2015. Washington DC. [Link] Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial. Am J Gastroenterol. 2017;112(5):763-774. [PubMed

What is the effect of food on IBSRELA administration?

How was IBSRELA administered in the clinical trials?

A Phase 1, open-label, 3-way crossover study with healthy volunteers, evaluated the effect of food on the pharmacodynamics of IBSRELA. Eighteen volunteers completed a randomized sequence of three 4-day treatments with IBSRELA 15 mg twice daily: before food (5-10 minutes before the start of breakfast and dinner), after food (30 minutes after the start of breakfast and dinner), or while fasting 1 hour before breakfast and 3 hours after dinner/1 hour before evening snack). Participants received a diet standardized for sodium content.

• Stool sodium was significantly higher with IBSRELA administration before versus after food (difference, +8.8 mmol/day, p=0.006) or while fasting (+11.8 mmol/day, p=0.0004). Differences in urinary sodium were not significant.

• Therefore, administration of IBSRELA 5 to 10 minutes before a meal increased the 24- hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition.

In clinical trials with IBS-C patients, IBSRELA was administered immediately prior to the first meal of the day and immediately prior to dinner.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.2] Johansson SA, Knutsson M, Leonsson-Zachrisson M, Rosenbaum DP. Effect of food intake on the pharmacodynamics of tenapanor: a phase 1 study. Clin Pharmacol Drug Dev. 2017;6:457. [Link

IBSRELA tablets contain 50 mg of tenapanor (equivalent to 53.2 mg of tenapanor hydrochloride).

The inactive ingredients in the tablet are colloidal silicon dioxide, hypromellose, lowsubstituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid powder, titanium dioxide, and triacetin.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 11]

Ingredients found in IBSRELA are not derived from corn, based on information from each of the starting materials manufacturers used to make IBSRELA.

Ardelyx, Inc. Data on File. Waltham, MA

IBSRELA tablets are declared free of gluten based on information from each of the starting materials manufacturers used to make IBSRELA.

Ardelyx, Inc. Data on File. Waltham, MA.

IBSRELA is a sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for the treatment of irritable bowel syndrome with constipation (IBS- C) in adults.

IBSRELA is a locally acting inhibitor of NHE3, an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. In vitro and animal studies indicate its major metabolite, M1, is not active against NHE3.

• Ardelyx in vitro studies indicated that IBSRELA has an effect in the human small intestine (duodenum and ileum) and in the human colon where NHE3 is expressed.

By inhibiting NHE3 on the apical surface of the enterocytes, IBSRELA reduces the absorption of sodium from the small intestine and colon, resulting in an increase in water content into the intestinal lumen, which accelerates intestinal transit and results in softer stool consistency.

IBSRELA has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In a rat model of colonic hypersensitivity, IBSRELA reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 1, 12.1] King AJ, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456):eaam6474. [PubMed] Wang J. et al. Tenapanor attenuates increased macromolecule permeability in human colon monolayer cultures induced by inflammatory cytokines and human fecal supernatants. Poster presented at: Digestive Disease Week, June 2–5, 2018, Washington, DC, USA. [Link

In patients with irritable bowel syndrome (IBS), increased intestinal permeability has been observed and can lead to immune responses and increased concentration of mast cells in proximity of nerve fibers throughout the gut epithelium, resulting in abdominal pain. By impacting the tight junction structure of the paracellular pathway through sodium/hydrogen exchanger 3 (NHE3) inhibition, IBSRELA restores the gut barrier function through attenuating increased intestinal permeability as shown in animal models.

An in vitro study also showed that IBSRELA attenuated the increase in permeability of human colonic epithelial monolayers to macromolecules caused by cytokines or human fecal supernatants. The beneficial effect of tenapanor on abdominal pain in patients with IBS-C may be a result of its ability to reduce colonic permeability to luminal macromolecules, which may reduce hyperexcitability of sensory neurons.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.1] Camilleri M, et al. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303(7):G775-G785. [PubMed] King AJ, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456):eaam6474. [PubMed] Wang J. et al. Tenapanor attenuates increased macromolecule permeability in human colon monolayer cultures induced by inflammatory cytokines and human fecal supernatants. [Sa1600] Poster presented at: Digestive Disease Week, June 2–5, 2018, Washington, DC, USA. [Link]

How does IBSRELA specifically impact visceral hypersensitivity?

Is pain reduction only due to the improvement in constipation or is it an independent mechanism?

IBSRELA has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In a rat model of colonic hypersensitivity, IBSRELA reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.

Based on animal data, IBSRELA reduces visceral hypersensitivity to colorectal distension and normalizes colonic sensory neuronal excitability, likely through inhibition of transient receptor potential vanilloid subfamily, member 1 (TRPV1) cation channel, a central receptor involved in the nociceptive pathway.

TRPV1, commonly referred to as the capsaicin receptor highly expressed in sensory neurons is recognized as a molecular integrator of inflammatory mediators and plays a central role in the transduction of pain.

In an established rat model of irritable bowel syndrome (IBS)-like colonic hypersensitivity, treatment with IBSRELA resulted in significantly reduced visceral motor responses to colorectal distension, normalized colonic sensory neuronal excitability, and TRPV1 currents.

A post hoc analysis of pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies, examined the effects on abdominal pain and abdominal score 3 (AS3), independent of changes in bowel functions over the first 12 weeks of the study.

 • The pooled population included 1372 intent-to-treat patients (688 placebo, 684 tenapanor). Phone diaries were used to collect daily data on abdominal symptoms (including pain, bloating, and discomfort).

The data showed that IBSRELA improved abdominal symptoms regardless of improvement in complete spontaneous bowel movements (CSBMs) in adult patients with IBS-C and that improvement in abdominal symptoms without improvement in CSBMs may be a result of IBSRELA’s mechanism of action that has been shown to reduce both intestinal permeability and visceral hypersensitivity in nonclinical studies.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.1] LI Q et al. Tenapanor reduces IBS pain through inhibition of TRPV1-dependent neuronal hyperexcitability in vivo. [P2027] Poster presented at: World Congress of Gastroenterology at The American College of Gastroenterology Annual Scientific Meeting; October 13-18, 2017, Orlando, FL, USA. [Link] Szallasi A et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept [published correction appears in Nat Rev Drug Discov. 2007 Jun;6(6):442]. Nat Rev Drug Discov. 2007;6(5):357-372. [PubMed]

Brenner D, Lembo A, Yang Y, Rosenbaum DP. Tenapanor Can Improve Abdominal Symptoms Independent of Changes in Bowel Movement Frequency in Adult Patients With IBS-C. [P1597] Poster presented at: ACG 2023 Annual Scientific Meeting. October 20-25, 2023. Vancouver, BC, Canada: American College of Gastroenterology. [Link

Is there a difference of the effect of IBSRELA on the small versus large bowel?

Where in the intestines does IBSRELA work?

In vitro studies indicated that tenapanor has an effect in the human small intestine (duodenum and ileum) and in the human colon where the sodium/hydrogen exchanger 3 (NHE3) is expressed.

• NHE3 is expressed on the apical surface of the small intestine and proximal colon. NHE3 mRNA expression was the lowest in the distal colon of normal/healthy rats.

• In a different rat study, immunofluorescence staining of NHE3 in the colon indicated that the proximal colon (first ~50%) expresses NHE3 protein whereas the distal colon is nearly devoid of NHE3.

• In biopsy samples from healthy humans, NHE3 expression was also significantly lower in the distal colon as shown by mRNA levels in the sigmoid colon and rectum.

Altogether, these data suggest that there is a gradient of NHE3 expression in the gastrointestinal tract and the highest expression is in the small intestine and proximal colon.

King AJ, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456):eaam6474. [PubMed] Wang J. et al. Tenapanor attenuates increased macromolecule permeability in human colon monolayer cultures induced by inflammatory cytokines and human fecal supernatants. [Sa1600] Poster presented at: Digestive Disease Week, June 2–5, 2018, Washington, DC, USA. [Link] Talbot C, Lytle C. Segregation of Na/H exchanger-3 and Cl/HCO3 exchanger SLC26A3 (DRA) in rodent cecum and colon. Am J Physiol Gastrointest Liver Physiol. 2010;299(2):G358-G367. [PubMed] Farkas K, Yeruva S, Rakonczay Z Jr, et al. New therapeutic targets in ulcerative colitis: the importance of ion transporters in the human colon. Inflamm Bowel Dis. 2011;17(4):884-898. [PubMed]

Is IBSRELA pH sensitive?

What pH range does IBSRELA work across?

The solubility of IBSRELA is pH dependent. Preliminary data show that the pharmacodynamic effect, measured as fecal sodium of IBSRELA is similar whether dosed under conditions of low or high gastric pH.

IBSRELA® (tenapanor) Investigator Brochure. Waltham, MA: Ardelyx, Inc. [Section 5.2]

IBSRELA is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1]

IBSRELA is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

IBSRELA is not indicated for the treatment of chronic idiopathic constipation (CIC).

A recent literature search (February 2024) retrieved no information regarding the use of IBSRELA for CIC.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1] Patel S, Doerfler B, Boutros K, et al. Review of treatment options for irritable bowel syndrome with constipation and chronic idiopathic constipation. Int J Gen Med. 2021;14:1457. [Link

Is IBSRELA indicated for gastroparesis?

Is there any data on the use of IBSRELA in patients with gastroparesis?

IBSRELA is not indicated for use in patients with gastroparesis. IBSRELA is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

There is no clinical data on the use of IBSRELA in patients with gastroparesis. However, the effect of IBSRELA has been evaluated on gastric motility/emptying in normal rats.

• In an animal study conducted on rats, 3 different doses of IBSRELA (100 mg/kg, 300 mg/kg, and 1000 mg/kg) were administrated followed by a dose of 10% activated charcoal in three different study groups (each group, n=10). The charcoal (dosed as a suspension) is a non-absorbed marker commonly used to visually assess transit. After 30 minutes of dosing, the animals were euthanized, their gastrointestinal tracts were removed, and the distance traveled by the charcoal down the intestine was measured. • The study reported a motility ratio (mean ± standard error of mean) of 0.65 ± 0.02 in the vehicle group (no IBSRELA given), 0.65 ± 0.02 in the IBSRELA 100 mg/kg group, 0.67 ± 0.02 in the IBSRELA 300 mg/kg group, and 0.66 ± 0.02 in the IBSRELA 1000 mg/kg group.

• The observed motility ratio suggests that IBSRELA at all three dose levels did not cause any statistically significant or biologically relevant changes in gastric motility/emptying in normal rats.

Ardelyx, Inc. Data on File. Waltham, MA. (Internal email communication)

IBSRELA (tenapanor) is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

IBSRELA is not indicated for the treatment of hyperphosphatemia in patients with chronic kidney disease (CKD).

Ardelyx also markets another tenapanor product, XPHOZAH, which is indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy. 

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1]

XPHOZAH® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 1]

There are no comparative clinical trials between IBSRELA and other irritable bowel syndrome with constipation (IBS-C) treatment agents.

IBSRELA is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. By inhibiting NHE3 on the apical surface of the enterocytes, IBSRELA reduces the absorption of sodium from the small intestine and colon, resulting in an increase in water content into the intestinal lumen, which accelerates intestinal transit and results in softer stool consistency.

Other IBS-C agents work by activating the chloride channel or are agonists of serotonin type-4 (5-HT4) receptor or Guanylate cyclase-C.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12]

During IBSRELA (tenapanor) Phase 3 clinical trials, where patient demographics and baseline characteristics were balanced between the IBSRELA and placebo groups, improvements in the mean number of weekly complete spontaneous bowel movements (CSBMs) and abdominal pain were observed by week 1.

Within the first week of tenapanor treatment, approximately 40% of patients had a CSBM response (an increase of ≥1 in average weekly CSBM frequency), and approximately 20% of patients achieved a response to abdominal symptoms of pain, bloating, or discomfort (≥30% reduction in average weekly abdominal symptom score).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 14] Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Foge R, Edelstein S, Zhai S, et al. Tenapanor Has Early Onset of Action in Treating Symptoms of Irritable Bowel Syndrome with Constipation (T3MPO-1 and T3MPO-2).Presented at DDW Digestive Disease Week, In Person and Virtual. May 21-24, 2022, San Diego, CA.

There are no comparative clinical trials between IBSRELA (tenapanor) and linaclotide.

During IBSRELA clinical trials, improvements in the mean number of weekly complete spontaneous bowel movements (CSBMs) and abdominal pain were observed by week 1.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 14] Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

IBSRELA is metabolized primarily by CYP3A4/5 and low levels of its major metabolite, M1, is detected in plasma.

The maximum concentration (Cmax) of M1 is approximately 13 ng/mL after a single dose of IBSRELA 50 mg and 15 ng/mL at steady-state following repeated dosing of IBSRELA 50 mg twice daily in healthy subjects

IBSRELA is indicated as monotherapy for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults. Ardelyx cannot recommend the use of IBSRELA outside of the approved prescribing label.

Ardelyx does not have information on the concomitant use of other IBS-C therapies with IBSRELA as the use of the following IBS-C treatments (linaclotide, tegaserod, lubiprostone) was prohibited in the IBSRELA pivotal Phase 3 trials (T3MPO-1 and T3MPO-2) and the longterm open-label safety trial (T3MPO-3). Plecanatide was not commercially available during the IBSRELA studies.

IBSRELA® (tenapanor) Tablets [package insert]. Waltham, MA: Ardelyx, Inc. [Page 1] Ardelyx, Inc. Data on File. Waltham, MA.(Clinical Study Reports - Studies Ten-01- 301,- 302,- 303) TRULANCE® (plecanatide) Tablets [package insert]. Bridgewater, NJ: Salix Pharmaceuticals, Inc. [Page 1, date

Ardelyx does not have specific treatment/management recommendations for switching adult patients to or from IBSRELA with another irritable bowel syndrome with constipation (IBS-C) therapy (i.e., linaclotide, plecanatide, lubiprostone, tegaserod). Healthcare providers should use their clinical judgment when determining the optimal treatment approach for their patients.

The efficacy of IBSRELA for the treatment of IBS-C in adult patients was established in two double-blind, placebo-controlled, randomized, multicenter Phase 3 studies (T3MPO-1 and T3MPO-2).

o In these Phase 3 pivotal studies, the use of medications that were known to affect stool consistency (e.g., IBS-C therapies [linaclotide, tegaserod, lubiprostone], antidiarrheals, laxatives) were excluded/prohibited. Patients were required to discontinue the use of all prohibited medications at Visit 1 (Screening/Day -14) for the duration of the study.

o Please note: plecanatide was not commercially available during the IBSRELA pivotal studies.

IBSRELA® (tenapanor) Tablets [package insert]. Waltham, MA: Ardelyx, Inc. {Clinical Trials] Chey WD et al. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome with Constipation: A 12- Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. [PubMed] Chey WD et al. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome with Constipation: A 26- Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [PubMed] Ardelyx, Inc. Data on File. Waltham, MA. (CSRs 301, 302,) TRULANCE® (plecanatide) Tablets [package insert]. Bridgewater, NJ: Bausch Health US, LLC. [Page 1, date]

IBSRELA is minimally absorbed following repeated twice-daily oral administration.

Plasma concentrations of IBSRELA were below the limit of quantitation (95%) from healthy subjects following single and repeated oral administration of IBSRELA 50 mg twice daily.

Therefore, standard pharmacokinetic parameters such as the area under the curve (AUC), maximum concentration (Cmax), and half-life (t1/2) could not be determined.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.3

Following administration of a single 15 mg radiolabeled 14C-IBSRELA dose to healthy subjects, approximately 70% of the radioactivity was excreted in feces within 120 hours postdose and 79% within 240 hours post-dose, mostly as the parent drug accounting for 65% of the dose within 144 hours post-dose.

Approximately 9% of the administered dose was recovered in urine, primarily as metabolites. M1, the major metabolite, is excreted in urine unchanged accounting for 1.5% of the dose within 144 hours post-dose.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.3]

Adult patients in the two pivotal phase 3, randomized, double-blind, placebo-controlled, multicenter trials (T3MPO-1 and T3MPO-2) diagnosed with IBS-C based on the Rome III criteria were randomized 1:1 to receive either IBSRELA 50 mg or placebo twice daily.

In both trials, secondary efficacy endpoints included durable combined, abdominal pain, and CSBM responder rates vs placebo.

In T3MPO-1, the durable overall abdominal pain responder rate are defined as weekly responder for the first 9/12 weeks and 3 of the last 4 weeks; decrease of ≥30% of worst abdominal pain from baseline) vs placebo. A durable overall responder rate (weekly responder for the first 9/12 weeks and 3 of the last 4 weeks for both CSBM and abdominal pain, described below) vs placebo. And a durable overall CSBM responder rate (weekly responder for the first 9/12 weeks and 3 of the last 4 weeks; ≥ 1 CSBM from baseline and ≥3 CSBM) vs placebo.

• In T3MPO-1, the durable combined responder rate was significantly higher with IBSRELA treatment than with placebo (p<0.001)

• Treatment with IBSRELA, compared with placebo, also resulted in significantly higher durable abdominal pain responder (p=0.006) and durable CSBM responder rates (p<0.001).

In T3MPO-2, the durable abdominal pain response is defined as a decrease in average weekly worst abdominal pain of ≥30.0% from baseline for ≥9 of the first 12 treatment weeks, including ≥3 of the final 4 weeks of the first 12 weeks of the treatment period. A durable CSBM response is defined as an increase of ≥1 CSBM/week from baseline and ≥3 CSBM/week for ≥9 of the first 12 treatment weeks, including ≥3 of the final 4 weeks of the first 12 weeks of the treatment period.

• In T3MPO-2, the durable combined responder rate was significantly higher with IBSRELA treatment than with placebo (18.1% vs 5.0%, p<0.001). Treatment with IBSRELA, compared with placebo, also resulted in significantly higher durable abdominal pain responder (34.8% vs. 26.7%; p=0.028) and durable CSBM responder rates (21.2% vs. 5.7%; p<0.001).

In both trials, improvements from baseline in average weekly CSBMs and abdominal pain were observed by Week 1, with improvement maintained through the end of treatment.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 14] Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. [Link] Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

IBSRELA exerts its effect on the NHE3 protein (not transcription) and no evidence of tachyphylaxis could be found.

The safety and efficacy of IBSRELA was evaluated in 2 pivotal Phase 3 trials, and in both of the trials, IBSRELA-treated patients achieved a “durable overall response” (defined as a patient who met criteria for 9/12 week response, where additionally, 3 of the last 4 weeks had to be responder weeks) and no incidences of tachyphylaxis was reported.

IBSRELA® (tenapanor) Tablets [package insert]. Waltham, MA: Ardelyx, Inc. [Link] Ardelyx, Inc. NDA/BLA Multidisciplinary Review and Evaluation of IBSRELA® (tenapanor) Tablets. 2019 [Link]

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [PubMed]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [PubMed]

There was no guidance on sodium intake in the IBSRELA clinical studies. Patients on low sodium diets have not been specifically studied in IBSRELA clinical trials.

IBSRELA blocks a portion of the absorption of dietary sodium by inhibiting the NHE3 isoform located along the luminal surface of the small and large intestines thereby increasing stool water content.

The resulting decrease in net sodium absorption would not be expected to have adverse clinical consequences, even in patients on low sodium diets, unless they experience severe and persistent diarrhea. This is mainly due to the limited amount of sodium excreted in the stool as a result of treatment but also based on the ability of the healthy kidneys to adjust to a wide variation in dietary sodium intake (absorption).

Indeed, in healthy volunteers administered IBRSELA the increased stool Na was paralleled by a decrease in urine sodium demonstrating the maintenance of sodium balance. Furthermore, in IBSRELA clinical trials with patients with IBS-C clinically significant volume depletion (dehydration) was not observed nor were there any observations of abnormal electrolytes. As per the USPI, diarrhea was the main side effect seen in clinical studies and 6.5% of patients discontinued IBSRELA due to diarrhea.

IBSRELA carries a boxed warning for the risk of serious dehydration in pediatric patients. IBSRELA is contraindicated in patients less than 6 years of age; in nonclinical studies in young juvenile rats, the administration of IBSRELA caused deaths presumed to be due to dehydration. Avoid the use of IBSRELA in patients 6 years to less than 12 years of age. The safety and effectiveness of IBSRELA have not been established in patients less than 18 years of age.

Severe diarrhea is defined by a BSFS (Bristol Stool Form Scale) score of ≥6 and stool frequency ≥7/day for 2 consecutive days.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303

The pharmacodynamics of IBSRELA are as follows:

Cardiac Electrophysiology

At 3 times the mean maximum exposure of M1 at the recommended dosage, there were no clinically relevant effects on the QTc interval.

Food Effect

Administration of IBSRELA 5 to 10 minutes before a meal increased the 24-hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition.

In clinical trials, IBSRELA was administered immediately prior to the first meal of the day and immediately prior to dinner.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.2]

The IBSRELA Phase 3 clinical studies include 2 pivotal (T3mpo-1 and T3MPO-2) studies and 1 long-term safety (T3MPO-3) study. In these IBSRELA studies, GLP-1 (glucagon-like peptide-1) agonists could be used concomitantly.

Approximately 3% of patients in the IBSRELA studies received concomitant GLP-1 agonists, with slightly more randomized to the IBSRELA group.

Ardelyx does not have further information regarding the use of GLP-1 agonists and IBSRELA in these clinical studies.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Ardelyx, Inc. Data on File. Waltham, MA. (CSR 301, 302, 303)

The efficacy and safety of IBSRELA for the treatment of irritable bowel syndrome with constipation (IBS-C) in adult patients were established in two Phase 3 pivotal studies (T3MPO-2 and T3MPO-1) and 1 long-term open-label safety study (T3MPO-3).

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link] A Long-Term Safety Study of Tenapanor for the Treatment of IBS-C (T3MPO-3). [NCT02727751] clinicaltrials.gov; 2020. [Link]

What was the study design for T3MPO-1?

What was the study design for T3MPO-2? What was the study design for T3MPO-3?

The efficacy and safety of IBSRELA for treating IBS-C were based on data derived from two pivotal Phase 3 randomized, double-blind, placebo-controlled, multicenter clinical trials (T3MPO-1 and T3MPO-2).

T3MPO-1 consisted of a 2-week screening period, a 12-week treatment period with patients randomized to IBSRELA 50 mg or placebo twice daily (N=629), and a 4-week randomized withdrawal (RW) period (n=533). Efficacy endpoints were derived from the ITT analysis set which included 307 IBSRELA-treated patients and 299 placebo patients (n=606) for the treatment period; 4-week RW for placebo/IBSRELA (n=263), IBSRELA/placebo (n=129) and IBSRELA/IBSRELA (n=121).

T3MPO-2 consisted of a 2-week screening period and a 26-week treatment period with patients randomized to IBSRELA 50 mg or placebo twice daily (N=620).1,2 Efficacy endpoints were derived from the intention-to-treat (ITT) analysis set which included 293 IBSRELAtreated patients and 300 placebo patients (n=593).

T3MPO-3 was a multicentered, Phase 3, long-term, open-label safety study with patients who had completed either T3MPO-2 (26 weeks) or T3MPO-1 (16 weeks). Enrolled patients received IBSRELA 50 mg twice daily in 5 cohort treatment arms (n=312 ITT population; n=262 overall completion).

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

A 12-Week Study With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the Treatment of IBS-C (T3MPO-1). [NCT02621892] clinicaltrials.gov; 2020. [Link]

A 26-Week Study to Evaluate the Efficacy and Safety of Tenapanor in IBS-C (T3MPO-2). [NCT02686138] clinicaltrials.gov; 2020. [Link]

A Long-Term Safety Study of Tenapanor for the Treatment of IBS-C (T3MPO-3). [NCT02727751] clinicaltrials.gov; 2020. [Link]

In T3MPO-1 and T3MPO-2: A subject was eligible for inclusion in the study if all of the following criteria were met:

1. 18 to 75 years old.

2. Females must have been of non-childbearing potential; either post-menopausal for at least 12 months as confirmed by follicle-stimulating hormone test (if <60 years old), or surgically sterile (e.g., tubal ligation, hysterectomy, bilateral oophorectomy with appropriate documentation). If of child-bearing potential, they must have had negative pregnancy tests at Visits 1 and 2 and confirmed the use of one of the following appropriate means of contraception:

• Oral birth control pills administered for at least one monthly cycle prior to study drug administration.

• Contraceptive patch is worn for at least one monthly cycle prior to study drug administration.

• Progesterone implants.

• Intrauterine devices.

• Abstinence from intercourse for 2 weeks prior to the study drug administration, throughout the treatment phase (and the 4-week RW phase for T3MPO-1).

• Double barrier method.

• Sterilization of one or both partner(s).

3. Males must have agreed to use an appropriate method of barrier contraception (e.g., latex condom with a spermicidal agent) or have documented surgical sterilization.

4. Subject was ambulatory.

5. Subject met the definition of IBS-C using Rome III criteria for the diagnosis of IBS.

6. Colonoscopy requirements:

• Subjects, aged 50 years or older, must have had a colonoscopy within 10 years of enrollment (American Gastroenterological Association guidelines).

• Subjects of any age with unexplained warning symptoms (e.g., lower GI bleeding, iron-deficiency anemia, clinically significant weight loss, systemic signs of infection or colitis) must have had a colonoscopy, with non-significant findings, after the onset or worsening of the warning symptoms.

7. Ability to communicate well with the Investigator and to comply with the requirements of the entire study, including an understanding of how to use the IVRS diary.

8. Written informed consent and a willingness to participate in the study as it is described.

9. Daily access to a touch-tone telephone.

T3MPO-3 inclusion criteria were as follows:

1. Subjects completed all 16 weeks of T3MPO-1 or all 26 weeks of T3MPO-2

2. Subject demonstrated adequate compliance with the study procedures during either the T3MPO-1 or T3MPO-2 studies.

3. Females must be of non-childbearing potential; If of child-bearing potential, must have a negative pregnancy test and confirm the use of one of the appropriate means of contraception.

4. Males must agree to use appropriate methods of barrier contraception or have documented surgical sterilization.

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01-301, -302, -303) A Long-Term Safety Study of Tenapanor for the Treatment of IBS-C (T3MPO-3). [NCT02727751] clinicaltrials.gov; 20

T3MPO-1 and T3MPO-2: A subject was not eligible for inclusion in the study if any of the following criteria were met:

1. Functional diarrhea as defined by Rome III criteria.

2. IBS with diarrhea (IBS-D), mixed IBS, or unsubtyped IBS as defined by Rome III criteria.

3. Diagnosis or treatment of any clinically symptomatic biochemical or structural abnormality of the GI tract within 6 months prior to screening, or active disease within 6 months prior to screening. Including but not limited to cancer, IBD, diverticulitis, duodenal ulcer, erosive esophagitis, gastric ulcer, pancreatitis (within 12 months of screening), cholelithiasis, amyloidosis, ileus, non-controlled gastroesophageal reflux disease (GERD), GI obstruction, or carcinoid syndrome.

4. Use of medications that were known to affect stool consistency. Note: subjects on a stable, continuous regimen of fiber, bulk laxatives, stool softeners, or probiotics during the 30 days before the Screening Visit were allowed to continue, provided they maintained a stable dosage throughout the study.

5. Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, GI, hematologic, neurologic, psychiatric, or any disease that may have interfered with the subject successfully completing the study.

6. The subject has a history or current evidence of laxative abuse (in the clinical judgment of the Investigator).

7. Hepatic dysfunction (alanine aminotransferase/serum glutamic-puruvic transaminase [ALT/SGPT] or aspartate aminotransferase/serum glutamic-puruvic transaminase [AST/SGOT] >2.5 times the upper limit of normal) or renal impairment (serum creatinine >2mg/dL).

8. Any evidence of or treatment of malignancy (other than a localized basal cell, squamous cell skin cancer, or cancer in situ that has been resected) within the previous year.

9. Any surgery on the stomach, small intestine, or colon, excluding appendectomy, and cholecystectomy.

10. If, in the opinion of the Investigator the subject was unable or unwilling to fulfill the requirements of the protocol or has a condition, which would render the results uninterpretable.

11. A major psychiatric disorder (Diagnostic and Statistical Manual III Revisited or Diagnostic and Statistical Manual IV) including major depression or other psychoses that has required hospitalization in the last 3 years. History of attempted suicide or uncontrolled bipolar disorder.

12. Alcohol or substance abuse in the last year.

13. Subject had been randomized into any Phase 1 or 2 study in which IBSRELA was a treatment.

14. Subject was involved in the conduct and/or administration of this trial as an Investigator, sub-Investigator, trial coordinator, or other staff member, or the subject was a first-degree family member, significant other, or relative residing with one of the above persons involved in the study.

15. Participation in other clinical trials within 1 month prior to Day –14 (beginning of screening period).

16. Pregnant or lactating women

17. Subject had a potential central nervous system cause of constipation (e.g., Parkinson’s disease, spinal cord injury, or multiple sclerosis).

T3MPO-3 Exclusion Criteria:

1. Subject has been withdrawn or discontinued prematurely from either T3MPO-1 or T3MPO-2

2. The subject reports using any prohibited medication and is not willing to abide by the restrictions for intake.

3. Pregnant or lactating women.

4. If, in the opinion of the Investigator, the subject was unable or unwilling to fulfill the requirements of the protocol or had a condition that would render the results uninterpretable.

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Protocol Ten-01-301; Clinical Study Reports - Studies Ten01-302, -303)

In T3MPO-1, of 1,599 patients who were screened, 629 (39.3%) were randomized. The treatment period was completed by 261 of the 319 patients (81.8%) who were randomized to receive IBSRELA and 272 of the 310 patients (87.7%) who received a placebo. A total of 610 patients were included in the safety analysis set, of whom 309 received IBSRELA and 301 received placebo. Four patients in the safety analysis set were ineligible for inclusion in the ITT analysis set, leaving 307 and 299 subjects in the IBSRELA and placebo groups, respectively.

In T3MPO-2, of 1,461 patients who were screened, 620 (42.4%) were randomly assigned to treatment with IBSRELA or placebo for 26 weeks. In total, 593 patients were included in the ITT and safety analysis sets, of whom 293 received IBSRELA and 300 received placebo.

In T3MPO-3, a total of 312 subjects were enrolled into the study: 37 into Cohort 1, 52 into Cohort 2, 88 into Cohort 3, 63 into Cohort 4, and 72 into Cohort 5. Definitions for each cohort are presented in Table 9–3. Overall, 262 (84%) subjects completed the study; 31 (83.8%) in Cohort 1, 39 (75.0%) in Cohort 2, 72 (81.8%) in Cohort 3, 60 (95.2%) in Cohort 4, and 60 (83.3%) in Cohort 5. Overall, 50 (16%) subjects withdrew prior to completing the study with the most common reasons for withdrawal being withdrawal of consent (21 [67%] subjects), and adverse events, and lost to follow-up (both 13 [0.3%] subjects). No subjects were excluded from the Safety Analysis Set. A total of 130 subjects were treated for 52 weeks; 31 subjects were in Cohort 1, 39 subjects were in Cohort 2, and 60 subjects were in Cohort 4. An additional 72 subjects in Cohort 3 completed the 39-week treatment period. A total of 262 subjects completed the 26-week treatment period: 31 subjects in Cohort 1, 39 subjects in Cohort 2, 72 subjects in Cohort 3, 60 subjects in Cohort 4, and 60 subjects in Cohort 5.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

The intent-to-treat (ITT) analysis population included 620 patients in T3MPO-2 and 606 patients in T3MPO-1 with a mean age of 46 years (range 18 to 75 years), 80% females, 64% White, and 31% Black/African American.

In both trials, treatment groups were well balanced regarding patient demographics and baseline IBS-related characteristics.

In T3MPO-3, overall, the mean (SD) age of subjects was 49.5 (13.15) years and most subjects (255 [81.7%]) were female. The majority of subjects (219 [70.2%] subjects) were White followed by Black or African American (88 [28.2%] subjects). Demographic and baseline characteristics were generally similar between cohorts.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 14] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link

In T3MPO-1, after a 2-week screening period, eligible patients were randomly assigned to receive IBSRELA 50 mg BID or placebo BID for 12 weeks. Patients were instructed to take 1 tablet immediately before breakfast or the first meal of the day and another tablet immediately before dinner. Patients who completed the 12-week treatment period entered a 4-week randomized withdrawal (RW) period. In the RW period, patients who had received 12 weeks of placebo were assigned to receive IBSRELA for 4 weeks and patients who had received 12 weeks of IBSRELA were rerandomized to either receive placebo or continue with IBSRELA for 4 weeks.

In T3MPO-2, after a 2-week screening period, eligible patients were randomly assigned to receive 1 of 2 treatments for 26-weeks: IBSRELA 50 mg BID or placebo BID immediately prior to breakfast or the first meal of the day and immediately prior to dinner.

In T3MPO-3, patients who had completed either T3MPO-2 (26 weeks) or T3MPO-1 (16 weeks). Enrolled patients received IBSRELA 50 mg twice daily in 5 cohort treatment arms. Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

Concomitant medications (e.g., omeprazole, lisinopril, ibuprofen) including rescue medications (e.g., bisacodyl) were permitted during the IBSRELA clinical trials. Patients on a stable, continuous regimen of fiber, bulk laxatives, stool softeners, or probiotics during the 30 days before the Screening Visit were allowed to continue, provided they maintained a stable dosage throughout the study.

For a full list of concomitant medications in the IBSRELA clinical trials please see Drug Interactions SRD.

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

In both pivotal trials (T3MPO-1 and T3MPO-2, the primary endpoint was the proportion of responders, where a responder was defined as a patient achieving both the stool frequency and abdominal pain intensity responder criteria in the same week for at least 6 of the first 12 weeks of treatment. The stool frequency (CSBM) and abdominal pain responder criteria assessed each week were defined as:

• CSBM responder: a patient who experienced an increase of at least 1 CSBM in weekly average from baseline.

• Abdominal pain responder: a patient who experienced at least a 30% reduction in the weekly average of abdominal pain score compared with baseline.

In T3MPO-1, a significantly greater proportion of patients treated with IBSRELA met the primary endpoint than patients treated with placebo (27.0% IBSRELA vs 18.7% placebo, p=0.020).

In T3MPO-2, a significantly greater proportion of patients treated with IBSRELA were 6/12- week combined responders than those treated with placebo (36.5% IBSRELA vs 23.7% placebo; p<0.001).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [page 11 table 2] Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

In T3MPO-1, key secondary endpoints:

• A significantly greater proportion of patients receiving IBSRELA were 6/12-week abdominal pain responders compared with patients receiving placebo (44.0% vs 33.1%, p=0.008), however, statistical significance was not reached for the difference in the 6/12 CSBM response rate (33.9% vs 29.4%, p=0.270)

• A significantly greater proportion of patients receiving IBSRELA were 9/12-week combined (13.7% vs 3.3%, p<0.001), abdominal pain (30.3% vs 19.4%, p=0.003), and CSBM responders (16.9% vs 5.0%, p<0.001) compared with those receiving placebo.

In T3MPO-2, key secondary endpoints:

• A significantly greater proportion of patients receiving IBSRELA were 6/12-week abdominal pain responders compared with patients receiving placebo (49.8% vs 38.3%, p=0.004), and with the 6/12 complete spontaneous bowel movement (CSBM) response rate (47.4% vs 33.3%, p<0.001).

• A significantly greater proportion of patients receiving IBSRELA were 9/12-week combined (18.4% vs 5.3%, p<0.001), abdominal pain (35.8% vs 26.7%, p=0.015), and CSBM responders (22.2% vs 6.0%, p<0.001) compared with those receiving placebo.

• A significantly greater proportion of patients receiving IBSRELA were 13/26-week combined (35.5% vs 24.3%, p=0.003), abdominal pain (50.2% vs 40.0%, p=0.013), and CSBM responders (41.3% vs 31.0%, p=0.010) compared with those receiving placebo.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Do you have data on abdominal symptoms (discomfort, bloating, cramping, and fullness) in patients treated with IBSRELA?

Are there any data on patient-related outcomes from the IBSRELA clinical studies?

Patients treated with IBSRELA in both the pivotal Phase 3 trials reported significant improvement in abdominal symptoms (discomfort, bloating, cramping, and fullness) compared to patients in the placebo group.

T3MPO-1

Abdominal symptom responder rates (12-week treatment period, ITT analysis set):

• A significantly greater proportion of patients receiving IBSRELA were 6/12-week abdominal discomfort responders compared with patients receiving placebo (42.7% vs 31.4%, p=0.006), abdominal bloating responders (37.8% vs 28.1%, p=0.014), abdominal cramping responders (45.6% vs 35.5, p=0.015) and abdominal fullness responders (38.4% vs 28.1%, p=0.007).

o Six- of 12-week responder rates for abdominal symptoms were defined as the proportion of patients with a decrease of ≥30.0% from baseline in the average weekly severity score for ≥6 of 12 treatment weeks.

• A significantly greater proportion of patients receiving IBSRELA were 9/12-week abdominal discomfort responders compared with patients receiving placebo (29.0% vs 17.1%, p<0.001), abdominal bloating responders (27.0% vs 16.1%, p=0.001), abdominal cramping responders (30.6% vs 23.1, p=0.044) and abdominal fullness responders (27.4% vs 14.4%, p<0.001).

Nine- of 12-week responder rates for abdominal symptoms were defined as the proportion of patients with a decrease of ≥30.0% from baseline in the average weekly severity score for ≥9 of 12 treatment weeks.

T3MPO-2

A significantly greater proportion of patients receiving tenapanor experienced improvements in abdominal symptoms (discomfort, bloating, cramping, and fullness) for ≥6 and ≥9 of the first 12 weeks, and ≥13 of 26 weeks of the treatment period than those receiving placebo. Similarly, patients receiving tenapanor had a significantly greater improvement in global IBS treatment measures than those receiving placebo.

• Patients receiving IBSRELA were at week 26, abdominal discomfort responders compared with patients receiving placebo (51.9% vs 40.4%, p=0.002), abdominal bloating responders (48.4% vs 35.9%, p=0.001), abdominal cramping responders (55.5% vs 42.3%, p<0.001) and abdominal fullness responders (47.2% vs 37.4%, p=0.014).

Post-hoc analysis

A recent post hoc analysis of pooled data from the phase 2b and 3 studies assessed the relationship between improvement in bloating and overall CSBM response with IBSRELA treatment. A phone diary was used to collect data on daily abdominal bloating on an 11-point scale. The pooled population of the phase 2b and phase 3 studies included 684 intent-to-treat patients who received IBSRELA.

• Patients with IBS-C treated with tenapanor demonstrated marked improvement in average weekly bloating score, with a greater improvement in bloating among patients who achieved an overall complete spontaneous bowel movements (CSBM) response versus non-responders (low-CSBM subgroup).

o In the pooled population, both 6 of 12-week CSBM responders showed improvements in abdominal bloating throughout the first 12 weeks of treatment, with mean reductions of 3.53 in weekly abdominal bloating score during week 12. Similarly, in the individual studies, both 6 of 12-week CSBM responders had improvements in abdominal bloating, with mean reductions of 3.62 and 1.54 in the phase 2b study, 3.28 in T3MPO-1, and 3.69 in T3MPO-2 in weekly abdominal bloating score during week 12. In the T3MPO-2 study, both 13 of 26-week CSBM responders had improvements in abdominal bloating with mean reductions of 4.16 in weekly abdominal bloating score during week 26.

o A high correlation was observed between the average weekly scores of abdominal bloating and abdominal pain, at baseline and during week12, signifying a relationship between abdominal pain and bloating.

A post hoc analysis of pooled data from the phase 2b and phase 3 T3MPO-1 and T3MPO-2 studies examined the effects on abdominal pain and abdominal score 3 (AS3), independent of changes in bowel functions over the first 12 weeks of the study. • The pooled population included 1372 intent-to-treat patients (688 placebo, 684 tenapanor). Phone diaries were used to collect daily data on abdominal symptoms (including pain, bloating, and discomfort).

• The data showed that IBSRELA improved abdominal symptoms regardless of improvement in complete solid bowel movements (CSBMs) in adult patients with IBS-C and that improvement in abdominal symptoms without improvement in CSBMs may be a result of IBSRELA’s mechanism of action that has been shown to reduce both intestinal permeability and visceral hypersensitivity in nonclinical studies.

A post hoc analysis of the T3MPO-2 study in adult patients with irritable bowel syndrome with constipation (IBS-C) examined the relationship between patient-reported satisfaction (as measured by adequate relief and degree of relief) and improvement in abdominal symptoms (assessed by the 3-item abdominal symptom score [AS3]). The Phase 3 T3MPO-2 study randomized adult patients to tenapanor 50 mg twice a day or matched placebo for 26 weeks of treatment. A phone diary was used to collect information on daily abdominal symptoms.

• The analysis demonstrated that IBSRELA meaningfully reduced multiple abdominal symptoms in patients with IBS-C, including bloating, discomfort and pain, compared to placebo.

o Patients who have either a decrease of ≥2.53 points or a 28.3% change from baseline (at week 26) in abdominal symptom score are likely to report “any relief” of their IBS-C symptoms.

• The analysis also indicates that patient-reported treatment satisfaction was strongly correlated with the IBS-C abdominal score (AS3, combining mean weekly abdominal pain, bloating and discomfort scores) and could be a useful tool to assess clinically meaningful improvements in adult patients with IBS-C.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Shah E, et al. Improvement in Bloating and Overall Complete Spontaneous Bowel Movement Response With Tenapanor Treatment: A Post Hoc Analysis of the IBS-C Clinical Studies. [P1590] Poster presented at: ACG 2023 Annual Scientific Meeting. October 20-25, 2023. Vancouver, BC, Canada: American College of Gastroenterology.[Link]

Brenner D, Lembo A, Yang Y, Rosenbaum DP. Tenapanor Can Improve Abdominal Symptoms Independent of Changes in Bowel Movement Frequency in Adult Patients With IBS-C. [P1597] Poster presented at: ACG 2023 Annual Scientific Meeting. October 20-25, 2023. Vancouver, BC, Canada: American College of Gastroenterology. [Link]

Lembo A. et al. Analysis of Patient-Reported Treatment Satisfaction and Abdominal Score in Patients With Irritable Bowel Syndrome With Constipation (IBS-C) Treated With Tenapanor. Poster: Tu1618 presented at: Digestive Disease Week (DDW23); May 6–9, 2023, Chicago, IL, USA. [Link]

Were there any qualityof-life improvements?

Were there improvements in specific QoL domains (e.g., dysphoria, health worry, sexual)?

The IBS-QoL is a validated quality-of-life tool used for IBS patients. Subjects were asked to complete the assessment at Visit 2 (prior to treatment or the randomization visit), Visit 6 (at the end of the 12-week treatment period), and Visit 8 (at the end of the 4-week RW period in T3MPO-1) or Visit 9 (at the end of the 26-week treatment period in T3MPO-2).

• The IBS-QoL included thirty-four individual questions which measured 8 subscales found to be relevant to IBS patients: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships, and overall.

T3MPO-1

In the 12-week treatment period, the mean (SD) change from baseline in the overall score at Week 12 was 16.9 (21.2) in the IBSRELA 50 mg BID group and 13.2 (17.4) in the placebo group.

• The LS mean difference (SE; 95% CI LS mean difference) in the overall score for IBSRELA versus placebo was 2.63 (1.546; -0.41, 5.67; p-value=0.089).

In the 4-week randomized withdrawal (RW) period, the mean (SD) change from baseline in the overall score at Week 16 was 4.37 (19.059) in the IBSRELA 50 mg BID/placebo group, 2.28 (15.173) in the IBSRELA 50 mg BID/IBSRELA 50 mg BID group, and 3.03 (13.579) in the placebo/IBSRELA 50 mg BID group.

• The LS mean difference (SE; 95% CI LS mean difference) in the overall score between the IBSRELA 50 mg BID/placebo group and the IBSRELA 50 mg BID/IBSRELA 50 mg BID group was -1.38 (1.902; -5.11, 2.36; p-value=0.470).

• The LS mean difference (SE; 95% CI LS mean difference) in the overall score between the IBSRELA 50 mg BID/placebo group and the placebo/IBSRELA 50 mg BID group was -0.81 (1.596; -3.95, 2.33; p-value=0.612).

T3MPO-2

Overall, the mean (SD) change from baseline in the overall score at Week 26 was 21.0 (22.7) in the IBSRELA 50 mg BID group and 17.1 (22.0) in the placebo group.

• The LS mean difference (SE; 95% CI LS mean difference) in the overall score for IBSRELA versus placebo was 4.17 (1.637; 0.95, 7.39), which was statistically significant (p=0.011).

• The study also reported statistically significant differences between treatment groups in 4 of the 8 IBS-QoL subscales: dysphoria (p = 0.002), body image (p = 0.016), health worry (p = 0.003), and food avoidance (p = 0.007).

• The subscales of interference with activity, social reaction, sexual, and relationships returned a non-significant difference.

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01-301, -302)

The T3MPO-1 responder (6/12) difference is 8.3% (0.083); 1/0.083 = 12 NNT.

For T3MPO-2 it is 1/0.13 = 8 NNT.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

The IBSRELA pivotal trials and long-term safety trial were only conducted in the US.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

A Long-Term Safety Study of Tenapanor for the Treatment of IBS-C (T3MPO-3). [NCT02727751] clinicaltrials.gov; 2020. [Link

There are no comparative clinical trials between IBSRELA and linaclotide.

IBSRELA has a different mechanism of action than linaclotide.

• In the T3MPO-1 study, 27.0% of subjects in the IBSRELA group were overall combined responders vs. 18.7% in the placebo group. The difference (95% CI) in response rates of 8% (2%, 15%) was significant (p=0.02).

• In the T3MPO-2 study, 36.5% of IBSRELA-treated subjects were overall combined responders vs. 23.7% in the placebo group. The difference in response rates of 13% (6%, 20%) was significant (p<0.001).

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link

According to ClinicalTrials.gov, Ardelyx is currently conducting 4 IBSRELA clinical trials:

A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of Tenapanor for the Treatment of Irritable Bowel Syndrome With Constipation (IBS-C) in Pediatric Patients 12 to Less Than 18 Years Old (NCT05643534)

• This study consists of 2-week screening period followed by 12-week randomized treatment period (RTP). At the beginning of the 2-week Screening period, patients who provide written assent will be fully assessed for eligibility into the study and will be asked to self-report daily information about the status of their IBS symptoms via an electronic diary (eDiary) device. Eligible patients will be randomized to receive one of the study medications: IBSRELA 25 mg BID, IBSRELA 50 mg BID, or placebo.

• During the 12-week double-blind RTP, patients will continue recording daily assessments via the eDiary system as instructed and compliance with eDiary entries will be monitored on an ongoing basis. Patients will return for study visits every two or four weeks (Visits 3- 6) and will undergo safety assessments at these visits.

• Primary outcome measure: 6/12-week APS (abdominal pain and SBM (spontaneous bowel movement)) +2 response, defined as achieving the weekly APS +2 response criteria (i.e., achieving both weekly SBM +2 response and weekly abdominal pain response during the same week) for ≥6 out of the 12 weeks of the RTP [Time Frame: 12 weeks].

o The weekly SBM +2 response is defined as having an increase of ≥2 from baseline in the average weekly SBM frequency for a given week.

o The weekly abdominal pain response is defined as having ≥30% reduction from baseline in the average weekly abdominal pain score for a given week.

Open-Label Long-Term Safety Study of Tenapanor for the Treatment of Irritable Bowel Syndrome With Constipation (IBS-C) in Pediatric Patients 6 to Less Than 18 Years Old (NCT05905926)

• Open-label long-term safety study of IBSRELA in pediatric patients with IBS-C. Eligible patients who complete the parent study will have an option to enroll in this study (N=150).

• Patients from the parent study will continue IBSRELA at the same dose assigned in the parent study which can be titrated to either 50 mg BID or 25 mg BID per guidance in protocol after a patient's first week on the assigned dose. Patients will also return for study visits approximately every 6 weeks for safety assessments.

• Primary outcome measure: To evaluate the difference in % adverse events between Placebo and IBSRELA to assess the long-term safety (number of participants with treatment-related adverse events as assessed by MedDRA v26.0 [Time Frame: 40 weeks]).

Open-label Study to Evaluate the Pharmacokinetics of Oral Tenapanor in Breast Milk of Lactating Females (NCT06203444)

• This will be an open-label study to investigate the PK of IBSRELA and AZ13792925 in the breast milk of lactating female subjects.

• Potential subjects will be screened to assess their eligibility to enter the study within 15 days prior to the first dose administration. Subjects will receive IBSRELA from Days 1 to 4 and will be monitored for 24 hours after the last dose of IBSRELA. On Day 4, breast milk to evaluate concentrations of tenapanor and AZ13792925 will be collected pre-dose (Hour 0), 1, 2, 4-, 6-, 8-, and 24-hours post-dose. Subjects will return for a follow-up visit, 5 to 7 days (Day 10±1) after the last dose.

• The primary objective of the study is to determine the maximum observed milk concentration (Cmax) of IBSRELA and its primary metabolite AZ13792925 in the breast milk of lactating female subjects (Concentration of IBSRELA and its major metabolite in breast milk [Time Frame: 26 Days]).

• The secondary objective of the study is to assess the incidence and severity of treatmentemergent adverse events of IBSRELA when administered to lactating female subjects (safety of IBSRELA in lactating females [Time Frame: 26 Days]).

Open-label, Single Center Investigator Sponsored Study Assessing the Effect of Tenapanor on Metagenomic and Metabolomic Markers in Patients With Irritable Bowel Syndrome With Constipation (NCT05995899)

• The aim of this study is to better understand how IBSRELA affects the metagenomics and metabolomics of patients with irritable bowel syndrome with constipation (IBS-C). • This study consists of an 8-week treatment period in which subjects will ingest one capsule of IBSRELA (50 mg per dose), twice daily, and send in stool samples following 4 weeks and 8 weeks of treatment.

• Primary outcome measures:

o Measuring metagenomics of stool samples using whole genome shotgun sequencing (WGS) [Time Frame: Subjects will submit stool samples at 0 weeks, 4 weeks, and 8 weeks following treatment.]

o Measuring metabolomics of stool samples using the DiscoveryHD4TM Platform [Time Frame: Subjects will submit stool samples at 0 weeks, 4 weeks, and 8 weeks following treatment.]

Study to Assess the Safety and Efficacy of Tenapanor for the Treatment of IBS-C. [NCT05643534] clinicaltrials.gov; 2023. [Link]

Tenapanor for the Treatment of Pediatric Patients With Irritable Bowel Syndrome With Constipation (IBS-C). [NCT05905926] clinicaltrials.gov; 2023. [Link]

An Open-label Study to Evaluate the Pharmacokinetics of Oral Tenapanor in Breast Milk of Lactating Females. [NCT06203444] clinicaltrials.gov; 2023. [Link] Effect of Tenapanor on the Metagenomics and Metabolomics of Patients With Irritable Bowel Syndrome With Constipation. [NCT05995899] clinicaltrials.gov; 2023

In T3MPO-1 and T3MPO-2, the use of medications that were known to affect stool consistency was excluded from these studies. Patients on a stable, continuous regimen of fiber, bulk laxatives, stool softeners, or probiotics during the 30 days before the Screening Visit were allowed to continue, provided they maintained a stable dosage throughout the study.

• Bisacodyl as a rescue medication was permitted during the IBSRELA clinical studies.

In T3MPO-3, The following medications were specifically prohibited from use during T3MPO-3 unless specified as a rescue medication and approved by the investigator: All prescription and/or over-the-counter medications used to treat constipation and/or IBS-C (e.g., Linzess, Amitiza, Miralax, Dulcolax, lactulose, bisacodyl). However, bisacodyl was allowed as a rescue medication.

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

Five patients in the tenapanor treatment group in T3MPO-1 trial (12-week treatment period and randomized withdrawal period combined) and 2 patients in the tenapanor treatment group in T3MPO-2 trials were taking spironolactone.

• No notable changes were observed in serum electrolytes over time in T3MPO-1 and T3MPO-2 studies. 

• Ardelyx does not have further information on the concomitant use of spironolactone with IBSRELA. Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302)

IBSRELA is contraindicated in patients less than 6 years of age due to the risk of serious dehydration.

• In young juvenile rats (less than 1 week old; approximate human age equivalent of less than 2 years of age), decreased body weight and deaths occurred, presumed to be due to dehydration, following oral administration of IBSRELA. There are no data available in older juvenile rats (human age equivalent 2 years to less than 12 years).

• Avoid the use of IBSRELA in patients 6 years to less than 12 years of age. Although there are no data in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of IBSRELA in patients 6 years to less than 12 years of age.

The safety and effectiveness of IBSRELA have not been established in pediatric patients less than 18 years of age.

CLINICAL TRIALS: According to ClinicalTrials.gov, Ardelyx is currently conducting 2 IBSRELA clinical trials in the pediatric population.

A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of Tenapanor for the Treatment of Irritable Bowel Syndrome With Constipation (IBS-C) in Pediatric Patients 12 to Less Than 18 Years Old (NCT05643534)

• This study consists of 2-week screening period followed by 12-week randomized treatment period (RTP). At the beginning of the 2-week Screening period, patients who provide written assent will be fully assessed for eligibility into the study and will be asked to self-report daily information about the status of their IBS symptoms via an electronic diary (eDiary) device. Eligible patients will be randomized to receive one of the study medications: IBSRELA 25 mg BID, IBSRELA 50 mg BID, or placebo.

• During the 12-week double-blind RTP, patients will continue recording daily assessments via the eDiary system as instructed and compliance with eDiary entries will be monitored on an ongoing basis. Patients will return for study visit every two or four weeks (Visits 3-6) and will undergo safety assessments at these visits.

• Primary outcome measure: 6/12-week APS (abdominal pain and SBM (spontaneous bowel movement)) +2 response, defined as achieving the weekly APS +2 responscriteria (i.e., achieving both weekly SBM +2 response and weekly abdominal pain response during the same week) for ≥6 out of the 12 weeks of the RTP [Time Frame: 12 weeks].

o The weekly SBM +2 response is defined as having an increase of ≥2 from baseline in the average weekly SBM frequency for a given week.

o The weekly abdominal pain response is defined as having ≥30% reduction from baseline in the average weekly abdominal pain score for a given week.

Open-Label Long-Term Safety Study of Tenapanor for the Treatment of Irritable Bowel Syndrome With Constipation (IBS-C) in Pediatric Patients 6 to Less Than 18 Years Old (NCT05905926)

• Open-label long-term safety study of IBSRELA in pediatric patients with IBS-C. Eligible patients who complete the parent study will have an option to enroll in this study (N=150).

• Patients from the parent study will continue IBSRELA at the same dose assigned in the parent study which can be titrated to either 50 mg BID or 25 mg BID per guidance in protocol after a patient's first week on the assigned dose. Patients will also return for study visits approximately every 6 weeks for safety assessments.

• Primary outcome measure: To evaluate the difference in % adverse events between Placebo and IBSRELA to assess the long-term safety (number of participants with treatment-related adverse events as assessed by MedDRA v26.0 [Time Frame: 40 weeks]).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 4, 5.1] Study to Assess the Safety and Efficacy of Tenapanor for the Treatment of IBS-C. [NCT05643534] clinicaltrials.gov; 2023. [Link]

Tenapanor for the Treatment of Pediatric Patients With Irritable Bowel Syndrome With Constipation (IBS-C). [NCT05905926] clinicaltrials.gov; 2023. [Link

IBSRELA is contraindicated in:

• Patients less than 6 years of age due to the risk of serious dehydration.

• Patients with known or suspected mechanical gastrointestinal obstruction. IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 4]

Yes, IBSRELA has a boxed warning. IBSRELA is contraindicated in patients <6 years of age; in nonclinical studies in young juvenile rats administration of IBSRELA caused deaths presumed to be due to dehydration. Avoid the use of IBSRELA in patients 6 years to <12 years of age. The safety and effectiveness of IBSRELA have not been established in pediatric patients <18 years of age.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Page 2]

Boxed Warning: IBSRELA is contraindicated in patients <6 years of age; in young juvenile rats, IBSRELA caused death presumed to be due to dehydration. Avoid the use of IBSRELA in patients 6 years to <12 years of age. The safety and effectiveness of IBSRELA have not been established in pediatric patients <18 years of age.

The most common adverse reactions (≥2%) are diarrhea, abdominal distension, flatulence, and dizziness.

In the pivotal T3MPO-1 trial, with 309 IBSRELA-treated patients and 301 placebo-treated patients, the most common adverse reactions were diarrhea (15% IBSRELA [n=309] vs 2% placebo [n=301]) and abdominal distension (2% IBSRELA vs 0% placebo).

In the pivotal T3MPO-2 trial, with 293 patients in the IBSRELA-treated group and 300 placebo-treated group, the most common adverse reactions reported in at least 2% of patients in the IBSRELA-treated patients and at an incidence greater than placebo were diarrhea (16% IBSRELA vs 4% placebo), abdominal distension (3% IBSRELA vs <1% placebo), flatulence (3% IBSRELA vs 1% placebo), and dizziness (2% IBSRELA vs <1% placebo).

Severe diarrhea was reported in 2.5% of IBSRELA-treated patients compared to 0.2% of placebo-treated patients during the 26 weeks of T3MPO-2 and the 12 weeks of T3MPO-1. If severe diarrhea occurs, suspend dosing and rehydrate the patient.

Discontinuations due to adverse reactions occurred in 7.6% of IBSRELA-treated patients and 0.8% of placebo-treated patients during the 26 weeks of T3MPO-2 and the 12 weeks of T3MPO-1. The most common adverse reaction leading to discontinuation was diarrhea: 6.5% of IBSRELA-treated patients compared to 0.7% of placebo-treated patients.

• In the long-term open-label safety study, T3MPO-3 (N=312), diarrhea was the most commonly reported adverse event reported by 10.6% of patients overall. Followed by headache (3.5%), flatulence (2.2%), upper respiratory tract infection (2.2%), nasopharyngitis (1.9%), back pain (1.9%), and arthralgia (1.6%). The overall rate of discontinuation due to an adverse event was 3.5% of patients discontinuing due to diarrhea. Severe diarrhea occurred in 2 (0.6%) patients. Severe diarrhea is defined by BSFS (Bristol Stool Form Scale) score of ≥6 and stool frequency ≥7/day for 2 consecutive days.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Page 1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

In T3MPO-1, the incidence of diarrhea was 15% in the IBSRELA group (n=309) and 2% in the placebo group (n=301) and in T3MPO-2, the incidence of diarrhea was 16% in the IBSRELA group (n=293) and 4% in the placebo group (n=300).

In the long-term open-label safety study, T3MPO-3, the incidence of diarrhea was 10.6% overall (N=312), 5.4% in IBSRELA/IBSRELA/IBSRELA-treated patients (n=37), 5.8% in IBSRELA/placebo/IBSRELA-treated patients (n=52), 9.1% in placebo/IBSRELA/IBSRELAtreated patients (n=88), 14.3% in IBSRELA/IBSRELA-treated patients (n=63), 15.3% in placebo/IBSRELA-treated patients (n=72).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6.1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303]

Severe diarrhea was reported in 2.5% of IBSRELA-treated subjects vs. 0.2% of placebotreated subjects during the 26-week T3MPO-2 (N=610) and 12-week T3MPO-1 (N=593).

In the long-term open-label safety study, T3MPO-3 (N=312), severe diarrhea occurred in 0.6% of IBSRELA-treated patients.

• Severe diarrhea is defined by a BSFS score of ≥6 and stool frequency ≥7/day for 2 consecutive days.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

In the pivotal trials, T3MPO-1, and T3MPO-2 (N=1203), the most common adverse event leading to discontinuation was diarrhea in 6.5% of IBSRELA-treated subjects vs. 0.7% of placebo-treated subjects.

In the long-term open-label safety study, T3MPO-3 (N=312), the most common adverse event leading to discontinuation was diarrhea with 3.5% of the overall patients discontinuing due to diarrhea. Diarrhea led to discontinuation in 2.7% of the IBSRELA/IBSRELA/IBSRELA-treated patients (n=37), 0% of the IBSRELA/placebo/IBSRELA-treated patients (n=52), 3.4% of the placebo/IBSRELA/IBSRELA-treated patients (n=88), 0% of the IBSRELA/IBSRELA-treated patients (n=63), and 9.7% of the placebo/IBSRELA-treated patients (n=72).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6.1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

No head-to-head studies have been conducted.

In both IBSRELA pivotal trials, the most commonly reported adverse event was diarrhea. In T3MPO-1, diarrhea occurred in 15% of IBSRELA-treated subjects (n=309) vs 2% of placebotreated subjects (n=301). In T3MPO-2, diarrhea occurred in 16% of IBSRELA-treated subjects (n=293) vs 4% of placebo-treated subjects (n=300).

In the long-term open-label safety study (T3MPO-3; N=312), the most commonly reported adverse event was diarrhea which occurred in 10.6% of overall patients. Diarrhea occurred in 5.4% of the IBSRELA/IBSRELA/IBSRELA-treated patients (n=37), 5.8% of the IBSRELA/placebo/IBSRELA-treated patients (n=52), 9.1% of the placebo/IBSRELA/IBSRELAtreated patients (n=88), 14.3% of the IBSRELA/IBSRELA-treated patients (n=63), and 15.3% of the placebo/IBSRELA-treated patients (n=72). IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6.1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303)

In clinical trials, diarrhea was typically mild to moderate in severity and resolved on treatment interruption or withdrawal in most cases.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Three randomized, Phase 3 trials evaluated the efficacy and/or safety of 50 mg BID IBSRELA in patients with IBS-C. In all the trials, diarrhea was the most commonly reported adverse event (AE).

T3MPO-1

In the T3MPO-1 trial, patients received IBSRELA 50 mg or placebo BID for 12 weeks followed by a 4-week randomized withdrawal (RW) period. During the 12-week treatment period, diarrhea was reported by 45 patients (14.6%) receiving IBSRELA and 5 patients (1.7%) receiving placebo and, during the 4-week RW period, diarrhea was reported by 30 patients (11.4%) in the placebo/IBSRELA group and 2 patients (1.6%) in the IBSRELA/IBSRELA group.

T3MPO-2

In the T3MPO-2 trial, patients received 50 mg IBSRELA or placebo BID for 26 weeks. Diarrhea was reported by 47 patients (16.0%) receiving IBSRELA and 11 patients (3.7%) receiving the placebo during the treatment period.

T3MPO-3

T3MPO-3 was an open-label, Phase 3 trial which evaluated the long-term safety of 50 mg BID IBSRELA in patients with IBS-C for 52-55 weeks in patients who completed either T3MPO-1 and T3MPO-2. Diarrhea was the most common AE during the treatment period at a rate of 10.6% resulting in a discontinuation rate of 3.5%; there were two (2.8%) cases of severe diarrhea in Cohort-5.

Ardelyx, Inc. Data on File. Waltham, MA.(CSRs 301, 302, 303)

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients with Irritable Bowel Syndrome with Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-293. [PubMed]

Chey WD, Lembo AJ, Yang Y, et al. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome with Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO2). Am J Gastroenterol. 2021;116(6):1294-1303. [PubMed

The most common adverse reactions (≥2%) are diarrhea, abdominal distension, flatulence, and dizziness.

In the pivotal T3MPO-1 trial, with 309 IBSRELA treated patients and 301 placebo-treated patients, the most common adverse reactions were diarrhea (15% IBSRELA vs 2% placebo) and abdominal distension (2% IBSRELA vs 0% placebo).

In the pivotal T3MPO-2 trial, with 293 IBSRELA-treated patients and 300 placebo-treated patients, the most common adverse reactions were diarrhea (16% IBSRELA vs 4% placebo), abdominal distension (3% IBSRELA vs <1% placebo), flatulence (3% IBSRELA vs 1% placebo), and dizziness (2% IBSRELA vs <1% placebo).

Severe diarrhea was reported in 2.5% of IBSRELA-treated patients compared to 0.2% of placebo-treated patients in both T3MPO-1 and T3MPO-2 (N=1203). If severe diarrhea occurs, suspend dosing and rehydrate the patient.

In the long-term open-label safety study, T3MPO-3 (N=312), diarrhea was the most commonly reported adverse event reported by 10.6% of patients overall. Followed by headache (3.5%), flatulence (2.2%), upper respiratory tract infection (2.2%), nasopharyngitis (1.9%), back pain (1.9%), and arthralgia (1.6%). The overall rate of discontinuation due to AEs was 3.5% of patients discontinuing due to diarrhea. Severe diarrhea occurred in 2 (0.6%) patients.

• Severe diarrhea is defined by a BSFS (Bristol Stool Form Scale) score of ≥6 and stool frequency ≥7/day for 2 consecutive days.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6.1] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

In the pivotal T3MPO-1 trial, serious adverse events were experienced by 4 patients receiving IBSRELA during the 12-week treatment period and were not judged to be treatment-related by the site investigator. Serious adverse events (SAE) were panic attacks, osteoarthritis, migraine, and major depression. A further 2 SAEs (alcohol withdrawal syndrome and pineal neoplasm) occurred in the post-treatment period and were not judged to be treatment related. In all instances, the patients recovered.

In the pivotal T3MPO-2 trial, four patients in the IBSRELA group experienced SAEs. The SAEs were abdominal pain, diarrhea, nausea, and chronic obstructive pulmonary disease. Only the SAE of diarrhea reported in the IBSRELA group was judged to be “possibly related” to treatment.

In the long-term open-label safety study (T3MPO-3), three patients reported SAEs: leukocytosis and status migrainosus in 1 patient in IBSRELA/IBSRELA-treated patients; endometriosis in 1 patient in IBSRELA/placebo/IBSRELA-treated patients, and 1 patient with abdominal injury with cervical and rib fracture in the placebo/IBSRELA-treated patients. None of these serious adverse events were considered by the investigator to be related to IBSRELA treatment.

Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [Link]

Chey WD, Lembo AJ, Yang Y, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [Link]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Report Ten-01-303

Cardiovascular adverse events (AEs) are not identified as typical AEs associated with the use of IBSRELA.

USPI - Cardiac Electrophysiology: At 3 times the mean maximum exposure of M1 at the recommended dosage, there were no clinically relevant effects on the QTc interval.

The safety of IBSRELA has been assessed in two pivotal Phase 3 studies (T3MPO-1 and T3MPO-2) and 1 long-term open-label study (T3MPO-3) in patients with irritable bowel syndrome with constipation (IBS-C).

• In T3MPO-1, during the 4-week RW period, 1 patient (male, aged 42 years) in the placebo/IBSRELA group had a clinically significant abnormal 12-lead ECG finding of left-precordial ST elevation (consistent with acute ischemia). The adverse event (AE) was nonserious, moderate in nature, and was judged to be possibly treatment-related. The AE resolved within 2 weeks without any dose modification. The patient had abnormal but clinically insignificant sinus bradycardia at screening and did not have a known history of cardiac events or associated risk factors.

• In T3MPO-2, a total of 6 patients (2%) in the placebo group and 2 patients (0.7%) in the IBSRELA group reported hypertension during the 26-week treatment period.

• In T3MPO-3, 1 patient in the placebo/IBSRELA/IBSRELA group (1.1%) reported AE of tachycardia, and 1 patient each in the IBSRELA/placebo/IBSRELA group (1.9%) and placebo/IBSRELA group (1.4%) reported AE of hypertension.

• In all three trials, there were no notable changes from baseline in heart rate, systolic or diastolic blood pressure, ECG parameters (QTc, QTcB interval, QTcF, PR, or QRS interval) during the study, and no evidence of differences between treatment groups. IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.2] Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281- 293. [PubMed]

Chey WD, Lembo AJ, Yang Y, et al. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome with Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol. 2021;116(6):1294-1303. [PubMed]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01-301, -302,-303)

IBSRELA is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium.

Administration of IBSRELA 5 to 10 minutes before a meal increased the 24-hour stool sodium excretion compared to taking IBSRELA in the fed or fasting condition.

IBSRELA did not significantly change the serum sodium concentration in clinical trials. In T3MPO-1, the mean change (SD) in serum sodium, from screening to week 12 was 0.0 mmol/L (2.22) in IBSRELA-treated patients vs -0.5 (2.20) in placebo-treated patients. The mean change (SD) in serum sodium from screening to the end of the 4-week withdrawal period was 0.1 (2.49) mmol/L in IBSRELA/placebo patients, -0.1 (2.25) in IBSRELA/IBSRELA patients, and -0.6 (2.38) in placebo/IBSRELA patients.

In T3MPO-2, the mean change (SD) in serum sodium, from screening to week 26 was -0.2 mmol/L (2.22) in IBSRELA-treated patients vs -0.1 (2.45) in placebo-treated patients.

In the long-term open-label safety study (T3MPO-3), the mean change (SD) in serum sodium from screening to week 26 was 0.0 mmol/L (2.04) in IBSRELA/IBSRELA-treated patients and 0.1 (1.90) in placebo/IBSRELA-treated patients. The mean change (SD) in serum sodium from screening to week 39 was 0.8 mmol/L (2.04) in IBSRELA/IBSRELA/IBSRELA-treated patients, -0.1 (2.40) in IBSRELA/placebo/IBSRELA-treated patients, and -0.4 (3.43) in placebo/IBSRELA/IBSRELA-treated patients.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 12.2]

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303

There was no effect of IBSRELA on potassium in patients with IBS-C as shown in the data from the Phase 3 program detailed below.

In T3MPO-1, the mean change (SD) in serum potassium from screening to week 12 was 0.03 mmol/L (0.434) in IBSRELA-treated patients vs 0.00 (0.434) in placebo-treated patients. The mean change (SD) in serum potassium from screening to week 4 of the withdrawal period was 0.00 mmol/L (0.396) in IBSRELA/placebo-treated patients, -0.01 (0.449) in IBSRELA/IBSRELA-treated patients, and 0.04 (0.414) in placebo/IBSRELA-treated patients.

In T3MPO-2, the mean change (SD) in serum potassium from screening to week 12 was 0.03 mmol/L (0.449) in IBSRELA-treated patients vs 0.05 mmol/L (0.460) in placebo-treated patients.

In the long-term open-label safety study (T3MPO-3), the mean change (SD) in serum potassium from enrollment to week 26 was -0.07 mmol/L (0.436) in IBSRELA/IBSRELAtreated patients, -0.02 (0.398) in placebo/IBSRELA-treated patients. The mean change (SD) in serum potassium from enrollment to week 39 was 0.01 mmol/L (0.451) in SRELA/IBSRELA/IBSRELA-treated patients, -0.15 (0.435) in IBSRELA/placebo/IBSRELAtreated patients, and -0.07 (0.495) in placebo/IBSRELA/IBSRELA-treated patients.

In an IBSRELA trial in subjects with chronic kidney disease (defined by eGFR from 25 to 70 mL/min/1.73m2) and Type 2 diabetes mellitus, three serious adverse reactions of hyperkalemia resulting in hospitalization were reported in 3 patients (2 IBSRELA-treated patients and 1 placebo-treated patient).

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 6] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303)

Hypo- or hyperglycemia is not a known or typical adverse event of IBSRELA.

In the 2 pivotal Phase 3 studies following were the incident rates of hypo- or hyperglycemia:

T3MPO-1

• During the 12-week randomized treatment period, there were no reports of hypo- or hyperglycemia.

• During the 4-week RWP, in safety analysis set (N=515), 1 patient (0.8%) in IBSRELA/placebo group and 1 patient (0.4%) in the placebo/IBSRELA group reported AE of hyperglycemia. There were no reports of hypo- or hyperglycemia in the IBSRELA/IBSRELA treatment group.

T3MPO-2

Only 1 (0.3%) patient in the placebo group reported the adverse event of hyperglycemia, there were no reports of hypo- or hyperglycemia in patients treated with IBSRELA in the safety analysis set (N=593).

Also, there were no reports of hypo- or hyperglycemia in the long-term open label study (T3MPO-3).

Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302,- 303

Drug interactions with IBSRELA are as follows:

OATP2B1 Substrates

Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1. Drugs which are substrates of OATP2B1 may have reduced exposures when concomitantly taken with IBSRELA. Monitor for signs related to loss of efficacy and adjust the dosage of concomitantly administered drug as needed.

• Enalapril is a substrate of OATP2B1. When enalapril was coadministered with IBSRELA (30 mg twice daily for five days, a dosage 0.6 times the recommended dosage), the peak exposure (Cmax) of enalapril and its active metabolite, enalaprilat, decreased by approximately 70% and total systemic exposures (AUC) decreased by approximately 50% to 65% compared to when enalapril was administered alone.

• Monitor blood pressure and increase the dosage of enalapril if needed when IBSRELA is co-administered with enalapril.

Drug Interaction Studies

CYP Metabolism Mediated Drug Interactions:

• Tenapanor and M1 did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 in vitro.

• Tenapanor and M1 did not induce CYP1A2 and CYP2B6 in vitro.

• No significant inhibition or induction of CYP3A4 enzyme using midazolam as a substrate was observed when IBSRELA 50 mg was administered twice a day for 13 days in healthy subjects.

• Following co-administration of a single dose of IBSRELA 50 mg with repeated doses of itraconazole 200 mg, a CYP3A4 inhibitor, the mean AUC and Cmax of M1 was decreased 50% in healthy subjects. The decrease in M1 systemic exposure is not clinically relevant. Plasma concentrations of IBSRELA were mostly below the limit of quantitation (less than 0.5 ng/mL) after co-administration of itraconazole.

• No significant effect on CYP2C9 activity using warfarin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects.

Membrane Transporter-Mediated Drug Interactions:

• Tenapanor inhibited OATP2B1, but is not an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3. M1 did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K.

• M1 is a substrate of P-gp. Tenapanor is not a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is not a substrate of BCRP, OAT1, OAT3, OCT2, MATE1 and MATE2-K. 

• No significant effect on PepT1 activity using cefadroxil as a substrate was observed when IBSRELA 50 mg was administered twice a day for 12 days in healthy subjects.

• No significant effect on P-gp activity using digoxin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects.

• Following administration of a single 20 mg dose of enalapril (OATP2B1 substrate) with tenapanor 30 mg administered twice a day (a dosage 0.6 times the recommended dosage) at steady state in healthy subjects, the mean AUC and Cmax of enalapril was decreased by 64% and 69%, respectively.

• The mean AUC and Cmax of enalaprilat was decreased by 52% and 68%, respectively. IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 7, 12.3]

Based on nonclinical data, an overdose of IBSRELA may result in gastrointestinal adverse effects such as diarrhea as a result of exaggerated pharmacology with a risk for dehydration if diarrhea is severe or prolonged.

Accidental ingestion of IBSRELA in children, especially children less than 6 years of age, may result in severe diarrhea and dehydration. Instruct patients to store IBSRELA securely and out of reach of children.

If severe diarrhea occurs, suspend dosing and rehydrate the patient.

• Severe diarrhea is defined by a BSFS score of ≥6 and stool frequency ≥7/day for 2 consecutive days.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Sections 5.2, 10, 17] Ardelyx, Inc. Data on File. Waltham, MA. (Clinical Study Reports - Studies Ten-01- 301,- 302

Box Warning: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS.

IBSRELA is contraindicated in patients less than 6 years of age; in nonclinical studies in young juvenile rats administration of IBSRELA caused deaths presumed to be due to dehydration. Avoid the use of IBSRELA in patients 6 years to less than 12 years of age. The safety and effectiveness of IBSRELA have not been established in patients less than 18 years of age.

IBSRELA is contraindicated in patients below 6 years of age. The safety and effectiveness of IBSRELA in patients less than 18 years of age have not been established. In young juvenile rats (less than 1 week old; approximate human age equivalent of less than 2 years of age), decreased body weight and deaths occurred, presumed to be due to dehydration, following oral administration of IBSRELA. There are no data available in older juvenile rats (human age equivalent 2 years to less than 12 years). Avoid the use of IBSRELA in patients 6 years to less than 12 years of age. Although there are no data in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of IBSRELA in patients 6 years to less than 12 years of age.

Juvenile Animal Toxicity Data

• In a 21-day oral dose range-finding toxicity study in juvenile rats, IBSRELA was administered to neonatal rats (post-natal day (PND) 5) at doses of 5 and 10 mg/kg/day. IBSRELA was not tolerated in male and female pups and the study was terminated on PND 16 due to mortalities and decreased body weight (24% to 29% reduction in females at the respective dose groups and 33% reduction in males in the 10 mg/kg/day group, compared to control).

• In a second dose range-finding study, IBSRELA doses of 0.1, 0.5, 2.5, or 5 mg/kg/day were administered to neonatal rats from PND 5 through PND 24. Treatment-related mortalities were observed at 0.5, 2.5, and 5 mg/kg/day doses. These premature deaths were observed as early as PND 8, with the majority of deaths occurring between PND 15 and 25. In the 5 mg/kg/day group, mean body weights were 47% lower for males on PND 23 and 35% lower for females on PND 22 when compared to the controls. Slightly lower mean tibial lengths (5% to 11%) were noted in males and females in the 0.5, 2.5, and 5 mg/kg/day dose groups on PND 25 and correlated with the decrements in body weight noted in these groups. Lower spleen, thymus, and/or ovarian weights were noted at the 0.5, 2.5, and 5 mg/kg/day doses. IBSRELA-related gastrointestinal distension and microscopic bone findings of increased osteoclasts, eroded bone, and/or decreased bone in the sternum and/or femorotibial joint were noted in males and females in the 0.5, 2.5, and 5 mg/kg/day dose groups.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Box Warning; Sections 4, 5.1, 8.2]

Of the 1203 patients in placebo-controlled clinical trials of IBSRELA, 100 (8%) were 65 years of age and older. No overall differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

IBSRELA® (tenapanor) Tablets US Prescribing Information. Waltham, MA: Ardelyx, Inc. [Section 8.5]