Tenapanor is associated with earlier and sustained symptom relief in IBS-C: a post hoc analysis

Abstract

Background:

In patients with irritable bowel syndrome with constipation (IBS-C), rapid, sustained relief from constipation and abdominal symptoms, such as pain, discomfort, and bloating, can improve quality of life.

Objective:

This post hoc analysis evaluates the time to constipation and abdominal symptom relief achieved with tenapanor.

Design:

Post hoc analysis of data pooled from three randomized placebo-controlled studies (phase IIb, T3MPO-1, and T3MPO-2) of tenapanor 50 mg twice daily in patients with IBS-C.

Methods:

The time to first response for complete spontaneous bowel movement (CSBM) frequency, abdominal pain, discomfort, bloating, and 3-item abdominal score (AS3) were assessed. The AS3 was derived as the average of the weekly scores for abdominal pain, discomfort, and bloating. Cumulative incidences of response over time were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to assess the effect of baseline and demographic characteristics on the time to first response.

Results:

Among 1372 patients with IBS-C (684 tenapanor; 688 placebo), median time to first CSBM response was 2 weeks, and median time to abdominal pain, discomfort, bloating, or AS3 response was 4–5 weeks in those treated with tenapanor, with 67.8%–76.7% achieving first response in CSBM frequency and abdominal symptoms by week 12. These time frames were shorter than those observed with the placebo (4 weeks for CSBM and 6–8 weeks for pain, discomfort, bloating, and AS3), of whom 59.1%–69.4% achieved the first response in CSBM and abdominal symptoms by week 12. Higher weekly response rates were observed with tenapanor than with placebo for all endpoints in each week of the 12-week treatment period.

Conclusion:

This novel post hoc analysis demonstrates that, compared with placebo, tenapanor reduces the time to first response in CSBM frequency and abdominal symptoms and consistently increases the weekly response rate during 12 weeks of treatment.

Trial registration:

NCT01923428; NCT02621892; NCT02686138.

Plain language summary

Tenapanor reduces time to relief in irritable bowel syndrome with constipation

Why was the study done? People with irritable bowel syndrome with constipation (IBS-C) often have symptoms such as hard or infrequent stools (constipation), stomach discomfort, abdominal pain, and bloating, which can be very bothersome. This study looked at how quickly a medicine called tenapanor can help relieve these symptoms.

What did the researchers do? Tenapanor is used to treat adults with IBS-C. We combined the data collected from 1372 adults with IBS-C in three clinical trials. We used these data to find out how long it took for people to feel relief from their symptoms with tenapanor compared with a placebo (a pill containing no active medicine).

What did the researchers find? People who took tenapanor felt relief from their IBS-C symptoms faster than those who took the placebo. On average, stool symptom relief and abdominal symptom relief began within 2 weeks and 4 to 5 weeks for those who took tenapanor compared with 4 weeks and 6 to 8 weeks for those on placebo, respectively. By week 12 of treatment, more people who took tenapanor had improvements in their bowel movements and other symptoms than those on placebo. Weekly improvements in these outcomes were also seen more consistently with tenapanor versus placebo throughout the 12-week treatment period.

What do the findings mean? Tenapanor may help people with IBS-C feel better sooner and keep feeling better over time.

Introduction

Irritable bowel syndrome (IBS) is a disorder of gut–brain interaction (DGBI) characterized by abdominal pain and altered bowel habits, ¹ with an estimated prevalence of 6.1%–8.8% among adults in the United States.^2,3 Approximately one-third of patients with IBS are diagnosed with the constipation predominant subtype (IBS-C) ² and have reduced stool frequency, hard or lumpy stools,^1,4 and more bothersome abdominal pain than other IBS subtypes. ⁵ Other symptoms reported by patients with IBS-C include abdominal discomfort, bloating, cramping, and fullness. ⁶

Patients with IBS-C have a substantial symptom burden, which significantly impairs their quality of life. ⁷ In a study of patients with prevalent gastrointestinal conditions, those with IBS-C demonstrated a higher total symptom burden the year before and the year after the index consultation than patients with active inflammatory bowel disease (IBD), inactive IBD, or gastroesophageal reflux disease (GERD). ⁸ In a US-wide survey of participants self-reporting IBS-C symptoms (Rome IV criteria; n = 910), abdominal discomfort was the most reported symptom experienced in the past 7 days (71%), followed by abdominal pain (66%); the latter was ranked as the most bothersome symptom (34%). ⁷ Most participants reported seeking medical care for symptoms (92%). ⁷ Furthermore, in comparison with matched controls, the health impact of IBS-C increased presenteeism (occurring when an employee continues to work despite a medical illness that will prevent them from fully functioning; 28% vs 18%), work productivity loss (32% vs 23%), and daily activity impairment (38% vs 24%). ⁷

Tenapanor is a first-in-class, minimally absorbed inhibitor of intestinal sodium/hydrogen exchanger isoform 3 approved for the treatment of IBS-C in adults.^9–11 Inhibition of this antiporter reduces absorption of dietary sodium, thereby increasing retention of sodium and water within the intestinal lumen, which softens stool consistency and accelerates intestinal transit.^11,12 Preclinical studies demonstrated that tenapanor alleviates abdominal pain by reducing visceral hypersensitivity through normalization of colonic sensory neuronal excitability and transient receptor potential cation channel subfamily V member 1 currents. ¹³ Tenapanor may also reduce abdominal pain by increasing the transepithelial electrical resistance of intestinal epithelial cells, which leads to decreased intestinal permeability to macromolecules. ¹³

In two phase III randomized controlled trials (T3MPO-1 (NCT02621892); T3MPO-2 (NCT02686138)), a significantly greater proportion of patients receiving tenapanor met the US Food and Drug Administration (FDA) recommended primary endpoint than those in the placebo group (T3MPO-1: 27.0% vs 18.7%; T3MPO-2: 36.5% vs 23.7%, respectively).^14,15 The primary endpoint required a reduction of ⩾30% in average weekly worst abdominal pain and an increase of ⩾1 weekly complete spontaneous bowel movement (CSBM) from baseline, both in the same week, for ⩾6 of the first 12 treatment weeks.^14,15 Based on these findings, the FDA approved tenapanor for the treatment of IBS-C in adults. ⁹

Patients with IBS-C welcome rapid and sustained relief of their chronic symptoms. In a study of patient experiences, 20.8% (97/467) of patients with IBS-C reported a symptom duration of 5–10 years, while 56.1% (262/467) had lived with symptoms for >10 years. ¹⁶ Unfortunately, according to data from a US survey of patients with IBS-C, many patients remain dissatisfied with the control of bowel-related symptoms (47.4% (431/910)) and abdominal symptoms (45.9% (417/910)) and thus seek novel treatment options. ⁷

A 2024 post hoc analysis of data pooled from phase IIb (NCT01923428), T3MPO-1, and T3MPO-2 studies of tenapanor demonstrated improvements in abdominal pain, discomfort, bloating, cramping, and fullness as early as the first week of treatment. ¹⁷ This study also demonstrated that during the first 12 weeks of treatment, the change from baseline in the 3-item abdominal score (AS3; a composite score of abdominal pain, bloating, and discomfort), the weekly response rate of achieving a reduction from baseline of ⩽2 points in AS3, and 6/12- and 9/12-week response rates for AS3 were all significantly greater with tenapanor than placebo in the pooled population. ¹⁷ Furthermore, a significant association between the weekly CSBM status and the weekly AS3 response status was observed in each week. ¹⁷ However, providers and patients often question when symptom relief will occur, especially from bloating, which is a prevalent symptom that is excluded from the FDA-recommended endpoint. Patients and providers also question whether a longer course of therapy will lead to greater symptom relief. These questions have not been addressed in previous studies of tenapanor, which focused on the FDA responder endpoint for IBS-C. To characterize the time to onset of CSBM and abdominal symptom relief achieved with tenapanor, we performed a post hoc analysis of pooled data from the phase IIb, T3MPO-1, and T3MPO-2 studies to evaluate the time to onset of tenapanor’s effect on bowel function and abdominal symptoms in patients with IBS-C.

Methods

Patients and study design

Study methodologies for the phase IIb, T3MPO-1, and T3MPO-2 studies have been described previously (Supplemental Figure 1).^14,15,18 Eligible patients were adults diagnosed with IBS-C using Rome III criteria. To assist patients with reporting abdominal symptoms, the Diary for IBS Symptoms-Constipation^6,19 was developed by the IBS Working Group of the Critical Path Institute’s Patient-Reported Outcome Consortium, with FDA guidance on patient-reported outcomes and review board approval from the Research Triangle Institute. The AS3 is a composite score of abdominal pain, bloating, and discomfort reported in the Diary for IBS Symptoms-Constipation. ¹⁹ The AS3 has previously been used in the post hoc analysis examining how tenapanor improved abdominal symptoms. ¹⁷ A treatment satisfaction questionnaire was administered at week 12 in the phase IIb study and at weeks 4, 8, and 12 in the T3MPO-1 and T3MPO-2 studies. Treatment satisfaction was scored using the following scale: 1 = not at all satisfied, 2 = a little satisfied, 3 = moderately satisfied, 4 = quite satisfied, and 5 = very satisfied. Data from the responses of the patients were pooled from week 4 of the T3MPO-1 and T3MPO-2 studies. The treatment satisfaction score was summarized as a categorical and continuous variable.

For this post hoc analysis, data were pooled from patients who had received tenapanor 50 mg twice daily (BID) or placebo BID for up to 12 weeks (phase IIb and T3MPO-1) or 26 weeks (T3MPO-2). All patients included in the intention-to-treat (ITT) analysis set were randomized to treatment and received ⩾1 dose of tenapanor or placebo. In all three studies, data on daily CSBMs and abdominal symptoms were collected using an interactive voice response system phone diary. Symptom severity was rated using an 11-point scale (0 = none; 10 = very severe; Supplemental Methods). Diarrhea was managed according to the package insert and institutional guidelines.

Endpoints and statistical analysis

This post hoc analysis evaluated the time to first response to tenapanor for IBS-C symptoms (CSBM frequency, abdominal pain, discomfort, bloating, and AS3 response) within the first 12 weeks of treatment. A CSBM response was defined as an increase of ⩾1 from baseline in average weekly CSBMs. Abdominal pain, bloating, discomfort, and AS3 responses were defined as a decrease of ⩾30% from baseline in the weekly score of the corresponding abdominal variable. For each abdominal symptom, the weekly score was calculated for any week with ⩾4 days of symptom reporting by averaging the daily scores and multiplying by 7 to standardize to a 7-day score. Invalid weeks with <4 days of reporting were considered nonresponding weeks for each endpoint. AS3 was calculated as the average of weekly scores for abdominal pain, discomfort, and bloating.

For the pooled ITT analysis set, log-rank tests were conducted to compare the time to first response and the time to first sustained response within the first 12 weeks between the tenapanor and placebo groups. For each IBS-C symptom, the sustained response was defined as achieving the corresponding weekly response for 2 consecutive weeks. Cumulative incidences of response and sustained response for both treatment groups were estimated using the Kaplan–Meier method. The same analysis of the time to first response was repeated for subgroups defined by age at informed consent (<50, 50 to <65, ⩾65 years), sex (female, male), race (Black, White, Other), ethnicity (Hispanic or Latino, non-Hispanic or non-Latino), baseline body mass index (BMI; <30, ⩾30 kg/m²), and history of GERD based on reported medical history and prior medications (yes, no). A Cox proportional hazards model, with treatment, sex, race, ethnicity, and history of GERD as categorical factors, and age at informed consent and baseline BMI as continuous factors, was used to assess the effect of tenapanor on the time to first response while adjusting for demographic and baseline characteristics. Sex and age were selected for further analysis as numerous studies report a higher prevalence of IBS in women than in men, and a lower prevalence of IBS in patients aged >50 years. ²⁰ Race and ethnicity were included for subgroup analyses because of their potential influence on treatment response, as previous research has shown distinct genetic variations in IBS-C according to ethnicity ²¹ and differential responses to treatments for chronic constipation, such as prucalopride, in Asian patients compared to those from other racial and ethnic populations. ²² Moreover, emerging evidence suggests that IBS-C may present differently across these populations.^2,23 A history of GERD was selected for further analysis as patients with IBS-C often have a coexisting functional gastrointestinal disorder.^24,25 BMI was included for subgroup analysis as BMI and symptom severity were both found to negatively correlate with physical health in patients with IBS-C. ²⁶ In addition, the weekly response rate in each week up to week 12 was calculated for both treatment groups. For the subset of patients in the pooled ITT analysis set who completed the treatment satisfaction questionnaire at the end of week 4 (i.e., the pooled ITT analysis set with week 4 treatment satisfaction), the proportion of patients with any response within the first 4 weeks of treatment was calculated by treatment satisfaction category (not at all satisfied, a little satisfied, moderately satisfied, quite satisfied, or very satisfied) for both treatment groups. No multiplicity adjustment was applied, as these post hoc analyses were exploratory in nature and not intended to formally control the Type I error rate.

Safety assessments were evaluated for the pooled safety analysis set (i.e., all randomized and treated patients) using pooled adverse event (AE) data from each study over the entire randomized treatment period. In addition, the median time to first onset, median duration of first onset, and exposure-adjusted incidence rate per patient-year, derived as the number of patients with diarrhea divided by the total person-years of exposure, were estimated for TEAEs of diarrhea during the randomized treatment period.

Results

Patient disposition, demographics, and baseline characteristics

The pooled ITT analysis set included 1372 patients with IBS-C: 684 patients received tenapanor, and 688 patients received placebo. Demographic and baseline characteristics of the pooled ITT population were similar between the tenapanor and placebo groups (Table 1). Most patients within the pooled population were women (82.4%; 1131/1372). The mean (standard deviation (SD)) age was 45.3 (13.3) years at informed consent. The mean (SD) weekly CSBM frequency at baseline was 0.16 (0.41), and the mean (SD) weekly scores of abdominal pain, discomfort, bloating, and AS3 were 6.25 (1.66), 6.45 (1.67), 6.59 (1.79), and 6.43 (1.64), respectively.

Table 1.

Patient demographics and baseline characteristics (pooled ITT analysis set).

	Placebo (N = 688)	Tenapanor 50 mg BID (N = 684)	Overall (N = 1372)
Age at informed consent, mean (SD), y	45.0 (13.5)	45.7 (13.1)	45.3 (13.3)
Sex, n (%)
Female	572 (83.1)	559 (81.7)	1131 (82.4)
Race, n (%)
Asian	14 (2.0)	24 (3.5)	38 (2.8)
Black or African American	214 (31.1)	195 (28.5)	409 (29.8)
White	442 (64.2)	452 (66.1)	894 (65.2)
Other a	18 (2.6)	13 (1.9)	31 (2.3)
Ethnicity, n (%)
Hispanic  Non-Hispanic	190 (27.6) 498 (72.4)	199 (29.1) 485 (71.0)	389 (28.4) 983 (71.7)
Body mass index, mean (SD), kg/m2	29.9 (6.8)	30.0 (7.0)	30.0 (6.9)
Duration of IBS symptoms before randomization, mean (SD), y b	11.6 (11.9)	11.2 (11.6)	11.4 (11.7)
Baseline weekly score for abdominal symptoms and CSBM, mean (SD)
Pain	6.27 (1.65)	6.24 (1.67)	6.25 (1.66)
Discomfort	6.45 (1.68)	6.45 (1.67)	6.45 (1.67)
Bloating	6.57 (1.82)	6.61 (1.77)	6.59 (1.79)
AS3	6.43 (1.64)	6.43 (1.65)	6.43 (1.64)
CSBM frequency	0.16 (0.40)	0.16 (0.42)	0.16 (0.41)

^aIncludes American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, Multiple, and Unknown categories.

^bSix patients in the T3MPO-1 study did not report the start date of their IBS symptoms. Thus, the mean (SD) duration of IBS symptoms before randomization of the pooled ITT analysis set is reported for the following numbers of patients: placebo (N = 684), tenapanor (N = 682), and overall (N = 1366).

AS3, 3-item abdominal score; BID, twice daily; CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome; ITT, intention-to-treat; SD, standard deviation; y, year.

Time to first CSBM response

In the pooled ITT analysis set, the median (95% confidence interval (CI) time to first CSBM response was shorter with tenapanor (2 (2–3) weeks) vs placebo (4 (4–5) weeks; log-rank test p < 0.0001, interquartile range = 9 weeks). The estimated probability of achieving the first CSBM response by week 2 was 52.3% with tenapanor and 36.3% with placebo, increasing to 76.7% and 69.4% by week 12, respectively (Figure 1; Supplemental Table 1).

Figure 1.

Time to first CSBM response Kaplan–Meier curve in the pooled ITT analysis set. The CSBM response was defined as achieving an increase of ⩾1 in average weekly CSBMs from baseline.

CSBM, complete spontaneous bowel movement; ITT, intention-to-treat.

Time to first abdominal pain, bloating, discomfort, and AS3 response

Tenapanor reduced the median (95% CI) time to first abdominal pain, discomfort, bloating, and AS3 response in the pooled ITT analysis set (4 (3–4), 4 (4–5), 5 (4–6), and 4 (4–5) weeks, respectively), relative to those observed with placebo treatment (6 (5–7), 6 (5–8), 8 (6–9), and 7 (7–9) weeks, respectively; log-rank test p < 0.0001). Among patients treated with tenapanor, the estimated probabilities of achieving a response in abdominal pain, discomfort, bloating, and AS3 increased with treatment duration to 67.8%–72.3% by week 12 and were consistently higher than in patients treated with placebo across all study weeks (Figure 2; Supplemental Table 1).

Figure 2.

Time to first (a) pain, (b) discomfort, (c) bloating, and (d) AS3 response Kaplan–Meier curves in the pooled ITT analysis set. Abdominal pain, discomfort, bloating, and AS3 responses were defined as achieving a decrease of ⩾30% from baseline in the weekly score of the abdominal variable. For each abdominal symptom, the weekly score was calculated as the average of scores recorded during a week with ⩾4 days of reporting for the given symptom. AS3 was calculated as the average of weekly scores for abdominal pain, discomfort, and bloating.

AS3, 3-item abdominal score; ITT, intention-to-treat.

Time to first sustained response

In the pooled ITT analysis set, the median (95%) time to first sustained CSBM response was shorter with tenapanor (6 (5–7) weeks) than with placebo (inestimable median, interpreted as >12 weeks (10 − inestimable (>12)) weeks; log-rank test p < 0.0001; Figure 3(a)). The cumulative probability of achieving a sustained CSBM response by week 12 was 62.2% with tenapanor versus 49.0% with placebo.

Figure 3.

Kaplan–Meier curves of the time to first 2 consecutive weeks of sustained response in the first 12 weeks of treatment for (a) CSBMs, (b) abdominal pain, (c) discomfort, (d) bloating, and (e) AS3 in the pooled ITT analysis set.

AS3, 3-item abdominal score; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat.

Tenapanor also reduced the time to first sustained response in abdominal symptoms (log-rank test p values < 0.0001). The median (95% CI) time to first sustained response was 6 (5–7) weeks for abdominal pain, 6 (6–7) weeks for abdominal discomfort, 7 (7–9) weeks for abdominal bloating, and 7 (6–8) weeks for AS3 relative to that observed with placebo (11 (9 − inestimable (>12)), 11 (10 − inestimable (>12)) 12 (10 − inestimable (>12)), and 12 (10 − inestimable (>12)) weeks, respectively; Figure 3(b)–(e), respectively). The cumulative probability of achieving a sustained response in abdominal pain, discomfort, bloating, and AS3 by week 12 was greater with tenapanor (65.1%, 63.6%, 60.8%, and 63.9%, respectively) than with placebo (53.0%, 52.1%, 50.1%, and 51.5%, respectively).

Factors affecting the time to first response

Kaplan–Meier analyses for subgroups defined by age at informed consent, sex, race, ethnicity, baseline BMI, and history of GERD also demonstrated a higher estimated probability of achieving the first response with tenapanor versus placebo across all study weeks among all subgroups, with the exception of the “age ⩾65 years” subgroup in abdominal pain and discomfort responses, and the “race other than Black or African American and White” (“Race: Other”) subgroup in abdominal bloating (Supplemental Tables 2–6). The findings in these two subgroups could be affected by small sample sizes.

In the subgroup of patients aged <50 years (n = 828), the estimated probabilities of achieving the first response in patients treated with tenapanor increased with treatment to 69.5%–78.6% by week 12 and were consistently higher than in patients receiving placebo across all study weeks (p ⩽ 0.0003; Supplemental Figure 2). In patients aged <50 years, tenapanor improved the median time to first response by 2–3 weeks for CSBM (2 vs 4 weeks with placebo; log-rank test p < 0.0001), abdominal pain (4 vs 6 weeks; log-rank test p = 0.0002), bloating (5 vs 8 weeks; log-rank test p = 0.0001), discomfort (4 vs 6 weeks; log-rank test p = 0.0003), and AS3 (4 vs 7 weeks; log-rank test p = 0.0001). In the largest subgroup of interest, female patients (n = 1112), the estimated probabilities of achieving the first response in patients treated with tenapanor increased with treatment to 69.1%–77.1% by week 12 and were consistently higher than in patients receiving placebo across all study weeks (log-rank test p ⩽ 0.0002; Supplemental Figure 3). In female patients, tenapanor improved the median time to first response by 1–2 weeks for CSBM (2 vs 4 weeks; log-rank test p < 0.0001), abdominal pain (4 vs 5 weeks; log-rank test p = 0.0002), discomfort (4 vs 6 weeks; log-rank test p = 0.0001), bloating (5 vs 7 weeks; log-rank test p = 0.0002), and AS3 (4 vs 6 weeks; log-rank test p < 0.0001). Similar results were observed in subgroups defined by ethnicity, baseline BMI, and history of GERD.

A Cox proportional hazards model was used to assess the effect of tenapanor on the time to first response while adjusting for demographic and baseline characteristics. Among all factors, treatment was the most significant factor, with the probability of achieving the first response 31.8%–35.2% higher in patients treated with tenapanor than in patients receiving placebo over time (p < 0.0001; hazard ratios (HRs): 1.318–1.352; Supplemental Table 7). For CSBM, ethnicity was the second most significant factor (p = 0.0002; HR = 0.75; 95% CI: 0.643–0.875), with the probability of achieving the first response 25.0% lower in Hispanic or Latino patients than non-Hispanic or non-Latino patients over time. For abdominal pain, discomfort, and AS3, sex was the second most significant factor, with the probability of achieving the first response 21.9%–31.5% higher in female patients than in male patients over time (p = 0.0044–0.0390; HRs: 1.219–1.315; Supplemental Table 7).

Weekly response rates

Weekly CSBM and abdominal symptom response rates with tenapanor and placebo up to week 12 are presented in Figure 4. Compared with placebo, consistently higher weekly response rates were observed with tenapanor for CSBM, abdominal pain, discomfort, bloating, and AS3 in each study week of the 12-week treatment. Per-week absolute differences for weekly response rates are presented in Table 2.

Figure 4.

Weekly response rates of (a) CSBM, (b) abdominal pain, (c) discomfort, (d) bloating, and (e) AS3 with tenapanor treatment per week from weeks 1 to 12 in the pooled ITT analysis set. The weekly CSBM response is defined as achieving an increase of ⩾1 in average weekly CSBMs from baseline, and the weekly abdominal pain, discomfort, bloating, and AS3 responses are defined as achieving a decrease of 30% or more in the weekly score of the corresponding abdominal variable. For each abdominal symptom, the weekly score was calculated as the average of the scores recorded during a week with ⩾4 days of reporting for the given symptom. AS3 was calculated as the average of weekly scores for abdominal pain, discomfort, and bloating.

AS3, 3-item abdominal score; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat.

Table 2.

Differences in response rate between treatment groups and NNT (pooled ITT analysis set).

Week	CSBM		Abdominal pain		Discomfort		Bloating		AS3
	Abs diff (95% CI), %	NNT, n	Abs diff (95% CI), %	NNT, n	Abs diff (95% CI), %	NNT, n	Abs diff (95% CI), %	NNT, n	Abs diff (95% CI), %	NNT, n
1	18.5 (0.13–0.24)	6	9.7 (0.06–0.14)	11	10.6 (0.07–0.15)	10	11.0 (0.07–0.15)	10	9.8 (0.06–0.14)	11
2	17.1 (0.12–0.22)	6	9.8 (0.05–0.15)	11	11.3 (0.06–0.16)	9	10.8 (0.06–0.16)	10	11.5 (0.07–0.16)	9
3	14.2 (0.09–0.20)	8	9.9 (0.05–0.15)	11	9.9 (0.05–0.15)	11	10.2 (0.05–0.15)	10	9.0 (0.04–0.14)	12
4	14.4 (0.09–0.2)	7	12.6 (0.07–0.18)	8	13.42 (0.08–0.19)	8	12.81 (0.07–0.18)	8	14.04 (0.09–0.2)	8
5	16.9 (0.11–0.22)	6	17.0 (0.11–0.23)	6	15.3 (0.20–0.21)	7	13.1 (0.08–0.19)	8	16.1 (0.11–0.22)	7
6	15.3 (0.10–0.21)	7	13.2 (0.08–0.19)	8	14.0 (0.08–0.20)	8	12.6 (0.07–0.18)	8	14.4 (0.09–0.20)	7
7	14.6 (0.09–0.20)	7	15.0 (0.09–0.21)	7	15.6 (0.10–0.21)	7	13.3 (0.08–0.19)	8	15.8 (0.10–0.22)	7
8	14.1 (0.08–0.20)	8	16.1 (0.10–0.22)	7	15.2 (0.10–0.21)	7	13.6 (0.08–0.19)	8	16.7 (0.11–0.22)	6
9	14.5 (0.09–0.20)	7	16.5 (0.11–0.22)	7	17.0 (0.11–0.23)	6	12.6 (0.07–0.19)	8	16.1 (0.10–0.22)	7
10	12.9 (0.07–0.19)	8	11.7 (0.06–0.18)	9	12.8 (0.07–0.19)	8	12.3 (0.07–0.18)	9	13.4 (0.08–0.19)	8
11	11.8 (0.06–0.18)	9	14.8 (0.09–0.21)	7	15.0 (0.09–0.21)	7	13.2 (0.07–0.19)	8	15.4 (0.10–0.21)	7
12	11.8 (0.06–0.18)	9	13.9 (0.08–0.20)	8	14.2 (0.08–0.20)	8	11.0 (0.05–0.17)	10	13.5 (0.08–0.19)	8

Abs diff, absolute difference; AS3, 3-item abdominal score; CI, confidence interval; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat; NNT, number needed to treat.

Patient-reported treatment satisfaction

In the pooled ITT analysis set with week 4 treatment satisfaction, the proportion of patients who were not at all satisfied with their first 4 weeks of treatment was much lower in the tenapanor group (36/536; 6.7%) than in the placebo group (121/566, 21.4%); while the proportion of patients who were very satisfied with their first 4 weeks of treatment was higher in the tenapanor group (95/536, 17.7%) than in the placebo group (54/566, 9.5%). Among the five treatment satisfaction categories, the “not at all satisfied” and “very satisfied” categories had the smallest and the largest proportions of patients with any response within first 4 weeks, respectively, with a range of 24.8%–80.5% for CSBM, 24.2%–74.5% for abdominal pain, 19.7%–72.5% for abdominal discomfort, 17.8%–74.5% for abdominal bloating, and 18.5%–73.8% for AS3.

Safety

Safety outcomes for tenapanor studies in IBS-C have been previously reported.^14,15,18 Tenapanor was generally well tolerated with an acceptable safety profile. Table 3 provides an overview of the AEs that occurred in the pooled safety analysis set. Drug-related AEs were reported in 138 patients (20.0%) receiving tenapanor and 59 patients (8.5%) receiving placebo. No deaths occurred in these studies. The study drug-related AEs were mostly gastrointestinal in nature, with diarrhea and flatulence as the only AEs reported for ⩾2% of patients receiving tenapanor. The most common study drug-related AE was diarrhea, which occurred in 93 patients (13.5%) receiving tenapanor and 10 patients (1.4%) receiving placebo during the randomized treatment periods. Diarrhea was typically transient (⩽1 week’s duration) and mild to moderate in severity. The median time to first diarrhea onset was 4.5 days in patients treated with tenapanor and 15.5 days in patients treated with placebo. The median duration of the first diarrhea was 8 days with tenapanor and 3 days with placebo. The exposure-adjusted incidence rate of diarrhea was 49.4 per 100 patient-years in the tenapanor treatment group and 7.3 per 100 patient-years in the placebo treatment group. In the pooled safety analysis set, the overall incidence rates of TEAEs leading to study drug discontinuation were 7.2% (50/691) in patients receiving tenapanor and 1.2% (8/691) in patients receiving placebo.

Table 3.

Overview of TEAEs (pooled safety analysis set).

TEAEs, n (%)	Placebo (N = 691)	Tenapanor 50 mg BID (N = 691)	Overall (N = 1382)
Any TEAE	236 (34.2)	298 (43.1)	534 (38.6)
Study drug-related TEAEs	59 (8.5)	138 (20.0)	197 (14.3)
Serious TEAEs	7 (1.0)	8 (1.2)	15 (1.1)
Deaths	0	0	0
Study drug-related TEAEs by preferred term a
Diarrhea	10 (1.4)	93 (13.5)	103 (7.5)
Flatulence	11 (1.6)	15 (2.2)	26 (1.9)
TEAEs leading to study drug discontinuation by preferred term b	8 (1.2)	50 (7.2)	58 (4.2)
Diarrhea	4 (0.6)	42 (6.1)	46 (3.3)

^aTEAEs by the preferred term occurring in ⩾2.0% of patients in the tenapanor group and at a higher incidence than in the placebo group.

^bTEAEs leading to study drug discontinuation by the preferred term occurring in ⩾2.0% of patients in the tenapanor group and at a higher incidence than in the placebo group.

BID, twice daily; TEAE, treatment-emergent adverse events.

Discussion

Patients with IBS-C frequently have significant gastrointestinal symptom burden, which negatively affects the quality of life and places a significant burden on healthcare resources.^7,16,27,28 Rapid and sustained relief from gastrointestinal symptoms should benefit patients with IBS-C and potentially decrease healthcare visits and unnecessary tests, all while promoting treatment adherence.

Here, we demonstrate that tenapanor significantly reduced the time to onset of symptom relief in patients with IBS-C, with a median time to first response of 2 weeks for CSBMs and 4–5 weeks for abdominal symptoms. In addition, the higher probabilities of achieving a response in CSBMs and abdominal symptoms over the course of treatment with tenapanor compared with placebo, as well as the higher chance of achieving a response within the first 3 months of tenapanor treatment, support the benefit of long-term treatment with tenapanor. Previous studies have demonstrated the efficacy of tenapanor in improving CSBM frequency and alleviating abdominal symptoms during 12- and 26-week studies.^14,15 However, this post hoc analysis is the first to assess the time to respond to tenapanor in relieving multiple individual IBS-C symptoms.

The rapid CSBM response and more gradual abdominal symptom responses after tenapanor treatment are confirmed by the mean change from baseline reported in two individual trials.^14,15 This difference may be due to mechanistic differences between tenapanor-mediated CSBM improvement and tenapanor-mediated abdominal symptom improvement, which have not yet been fully characterized. ¹³ These results are consistent with other FDA-approved medications used to treat patients with IBS-C^29–31, and highlight the complex pathophysiology that underlies the generation and expression of IBS symptoms. Importantly, continued therapy through week 12 allowed for a greater percentage of patients to achieve a clinically meaningful response, which may be related to interindividual variability in the degree and nature of pathophysiological disturbances that may respond to tenapanor treatment. This is important information for healthcare providers, as discontinuing therapy too early may significantly reduce the likelihood of potential responders having symptom improvement. For example, stopping tenapanor at week 4 because of an apparent incomplete response for abdominal pain would prevent nearly 25% of patients from achieving a more complete response between weeks 4 and 12. From a clinical perspective, patients with IBS-C should be informed about the variability in the times to symptom response, both for overall and individual symptoms. Furthermore, given the complex pathophysiology of DGBIs, in which symptoms of pain are driven largely by visceral and central hypersensitivity, mechanisms that take time to develop, it behooves clinicians to set reasonable expectations with patients about symptom relief from abdominal pain in particular.

Abdominal bloating has been reported by patients with IBS as the second most bothersome symptom after abdominal pain, with women generally reporting higher rates than men.^32–35 In a study examining predictors of patient-assessed IBS severity, patient reports of abdominal pain and bloating were found to correlate with IBS severity. ³² The cause and pathophysiology of abdominal bloating are complex and poorly understood. ³⁵ Furthermore, there is no validated management algorithm to treat bloating in patients with IBS-C; thus, treatment is empirical. ³⁶ In a systematic review and meta-analysis of FDA-approved drug efficacy for IBS-C, all of the drugs studied, including linaclotide, lubiprostone, tegaserod, and tenapanor, were significantly more efficacious than placebo for reducing bloating. ³⁶ This post hoc analysis further demonstrates that patients treated with tenapanor had a higher probability of achieving the first abdominal bloating response over time than patients treated with placebo, with an earlier median time to first response (5 vs 8 weeks). In addition, the weekly bloating response rates in patients treated with tenapanor were consistently higher than those in patients treated with placebo.

Among all factors assessed in the Cox model for each time-to-response endpoint, treatment was the most significant factor, with a higher probability of achieving the first response with tenapanor than with placebo over time. Ethnicity was found to be the second most significant factor affecting the time to first CSBM response. Thus, genetic factors may be an important component of treatment responses; however, these studies did not analyze the genetic disposition of the patients. Sex was found to be the second most significant factor affecting the time to first response for all abdominal variables. These observations suggest that both social and biological factors may influence responses to pharmacological therapy. Future studies involving larger IBS patient populations with diverse ethnicities, coupled with extensive multiomic analyses, may allow for a more nuanced interpretation of the time to onset of response.

Of note, the time to first response in CSBMs and abdominal symptoms after tenapanor treatment may be affected by the presence of other comorbidities, specifically additional DGBIs, which were not assessed in this post hoc analysis. For example, patients with multiple overlapping DGBIs typically respond worse to therapeutic interventions than patients with only a single DGBI. ³⁷ Further real-world studies incorporating patients with IBS and other DGBIs would help assess whether these factors affect the time to first response in tenapanor treatment.

In this pooled analysis, tenapanor demonstrated a safety profile consistent with the results demonstrated in the parent trials.^14,15,18 Diarrhea, the most common AE in patients treated with tenapanor, is typically transient, lasting up to 1 week and predominantly mild-to-moderate in severity. ³⁸

Post hoc analyses may have limitations associated with pooling data from multiple trials that differ in patient populations and methods. As stringent criteria are used to enroll patients with IBS-C into clinical trials, this post hoc analysis may not be representative of real-world populations. Furthermore, study drug adherence is higher in clinical trials than in clinical practice; hence, further studies will be necessary to determine the time to first response of tenapanor in real-world settings.

This post hoc analysis demonstrates that a longer duration of tenapanor therapy will benefit more patients with improved CSBM frequency and relief from abdominal symptoms. Patient education on variability in the time to response may help treatment adherence and, ultimately, improve the quality of life.