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Constella - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Constipation, Chronic, Constipation, Irritable Bowel Syndrome
Class: Guanylate cyclase-C agonists
Form: Capsules
Ingredients: linaclotide, calcium chloride dihydrate, gelatin, hypromellose, iron oxide black, iron oxide yellow, L-leucine, microcrystalline cellulose, shellac glaze, titanium dioxide

Pharmaceutical information

Drug Substance

Proper name: Linaclotide
Chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl- L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide)
Molecular formula: C59H79N15O21S6
Molecular weight: 1526.8
Structural formula: Linaclotide is a 14-amino acid peptide with the following sequence:
Physicochemical properties: Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%).

Clinical trials

Irritable Bowel Syndrome with Constipation (IBS-C)

Study Demographics and Trial Design

The efficacy of CONSTELLA (linaclotide) for the treatment of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with CONSTELLA 290 mcg or placebo once daily, and were evaluated for efficacy. A summary of trial designs and patient demographics is presented in Table 1 below. In the two pivotal trials, 77% of patients were White, 19% were Black, and 12% were Hispanic.

Table 1: Summary of Patient Demographics for Clinical Trials Supporting Efficacy of CONSTELLA in the Treatment of IBS-C (Intention-to-Treat [ITT] Population)
Trial# Trial Design/Duration Oral Dosage Study Subjects(N)
[Female/Male (F/M)]
Mean Age (Range) Mean Baseline Characteristics
1 12-week, randomized, multicenter, double-blind, placebo-controlled, Plus 4-week randomized withdrawal (RW) period CONSTELLA 290 mcg, once daily N=800
[F=724; M=76]
43.5 (18-84) CSBMs/week: 0.2 (0.0-2.9)

Abdominal paina(min, max): 5.6 (2.8-10)
2 26-week, randomized, multicenter, double-blind, placebo-controlled CONSTELLA 290 mcg, once daily N=804
[F=720; M=84]
44.3 (18-87) CSBMs/week: 0.2 (0.0-2.9)

Abdominal paina(min, max): 5.6 (2.9-10)

a Abdominal pain score based on 11-point numerical rating scale (NRS) (0=none, 10=very severe)
CSBM=Complete Spontaneous Bowel Movement

All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria:

  • a mean abdominal pain score of at least 3 on a 0-to10-point numeric rating scale
  • less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and
  • less than or equal to 5 SBMs per week.

The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take bismuth, prokinetic agents, or other drugs to treat IBS-C including laxatives (except for bisacodyl, the protocol-specified rescue medication).

Study Results

Efficacy of CONSTELLA was assessed using overall responder analyses (primary endpoints) and change-from-baseline analyses (secondary endpoints). Results for endpoints were based on information provided daily by patients in electronic diaries, via an interactive voice response system.

Primary Endpoints

The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.

In the two pivotal trials (Trials 1 and 2) CONSTELLA demonstrated statistically superior benefits, for the primary endpoint, compared to placebo in the treatment of IBS-C. In both trials, the proportion of patients who were responders to CONSTELLA 290 mcg was statistically significantly higher than with placebo. The primary efficacy results are shown in Table 2 below.

Table 2: Primary Efficacy of CONSTELLA in IBS-C (ITT Population)
Primary Responder Endpoints Trial 1 Trial 2
CONSTELLA
290 mcg
(N=405)
Placebo
(N=395)
Treatment
Difference
[95% CI]
CONSTELLA
290 mcg
(N=401)
Placebo
(N=403)
Treatment
Difference
[95% CI]
9/12 Week Combined Responder (Abdominal Pain and CSBM Responder) 12.1%b 5.1% 7.0%
[3.2%,10.9%]
12.7c 3.0% 9.7%
[6.1%,13.4%]
CSBM Responder (≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 19.5c 6.3% 13.2%
[8.6%,17.7%]
18.0c 5.0% 13.0%
[8.7%,17.3%]
Abdominal Pain Responder (≥ 30% Reduction) 34.3%a 27.1% 7.2%
[0.9%,13.6%]
38.9%c 19.6% 19.3%
[13.2%,25.4%]
6/12 Week Combined Responder (Abdominal Pain and CSBM Responder) 33.6%c 21.0% 12.6%
[6.5%,18.7%]
33.7%c 13.9% 19.8%
[14.0%,25.5%]

a p≤0.05, b p<0.001, c p<0.0001
Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2
CI = Confidence Interval, CSBM=Complete Spontaneous Bowel Movement

Secondary Endpoints

The secondary efficacy endpoints consisted of both responder and change from baseline assessments. The responder endpoints were based on a patient being a CSBM weekly responder or an abdominal pain responder for at least 6 out of the first 12 weeks of treatment. For the 6 out of 12 weeks CSBM responder endpoint, a patient had to have an increase of at least 1 CSBM from baseline for at least 6 out of the first 12 weeks of treatment. For the abdominal pain responder, a patient had to have at least a 30% reduction from baseline in mean abdominal pain.

The change from baseline secondary endpoints were the change from baseline in 12-week CSBM and SBM frequency rate, stool consistency, severity of straining, abdominal pain at its worst, abdominal discomfort, bloating and percent of abdominal pain-free days.

In Trial 1 and 2, for the 6/12 week CSBM and abdominal pain endpoints, statistically significantly more patients receiving CONSTELLA 290 mcg were responders versus placebo (Table 3).

Table 3: Secondary Efficacy of CONSTELLA in IBS-C (6/12 Week Responder Endpoints, ITT Population)
Secondary Responder Endpoints Trial 1 Trial 2
CONSTELLA
290 mcg
(N=405)
Placebo
(N=395)
Treatment
Difference(%)
[95% CI]
CONSTELLA
290 mcg
(N=401)
Placebo
(N=403)
Treatment
Difference(%)
[95% CI]
CSBM Responder (Increase ≥ 1 CSBM from Baseline) 48.6%c 29.6% 19.0%
[12.4%,25.7%]
47.6%c 22.6% 25.1%
[18.7%,31.4%]
Abdominal Pain Responder (≥ 30% Abdominal Pain Reduction) 50.1%b 37.5% 12.7%
[5.8%,19.5%]
48.9%c 34.5% 14.4%
[7.6%,21.1%]

a p≤0.05, b p<0.001, c p<0.0001
Note: Analyses based on first 12 weeks of treatment for Both Trials 1 and 2
CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement

For change-from-baseline endpoints, patients who received CONSTELLA 290 mcg across the 2 trials demonstrated statistically significantly greater improvements compared with patients receiving placebo in both abdominal symptoms (pain, discomfort and bloating) and bowel

symptoms (straining, stool frequency and consistency) (Table 4). In a pooled analysis of Trials 1 and 2, 67% of CONSTELLA-treated patients had an SBM within 24 hours of taking their first dose versus 42% of placebo patients (p < 0.0001).

Table 4: Secondary Efficacy of CONSTELLA in IBS-C (Mean Change from Baseline,ITT Population)
Trial 1 Trial 2
12-week Parameter CONSTELLA
290 mcg
(N=405)
Placebo
(N=395)
LSMD
[95% CI]
CONSTELLA
290 mcg
(N=401)
Placebo
(N=403)
LSMD
[95% CI]
CSBMs/Week 2.3c 0.7 1.6
(1.2,1.9)
2.2c 0.7 1.5
(1.2,1.9)
SBMs/Week 3.9c 1.1 2.8
(2.3,3.2)
4.0c 1.3 2.7
(2.3,3.2)
Stool Consistency
(BSFS Score)
2.1c 0.7 1.4
(1.3,1.6)
1.9c 0.6 1.3
(1.1,1.5)
Straining (5-point Ordinal scale) -1.3%c -0.7 -0.7
(-0.8,-0.5)
-1.2c -0.7 -0.6
(-0.7,-0.5)
Abdominal Pain at its Worst (11-point NRS) -1.9c -1.1 -0.7
(-1.0,-0.5)
-1.9c -1.1 -0.8
(-1.0,-0.5)
Abdominal Discomfort (11-point NRS) -2.0c -1.2 -0.7
(-1.0,-0.5)
-1.9c -1.1 -0.8
(-1.1,-0.6)
Bloating (11-point NRS) -1.9c -1.1 -0.8
(-1.1,-0.6)
-1.9c -1.0 -0.9
(-1.1,-0.6)
Percent of Abdominal Pain-free Days 9.8a 5.3 4.5
(1.9,7.2)
10.5b 4.8 5.7
(2.9,8.5)

a p≤0.05, b p<0.001, c p<0.0001
Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2
BSFS=Bristol Stool Form Scale, CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement,
LSMD=Least Squares Mean Difference, SBM=Spontaneous Bowel Movement, NRS=Numerical Rating Scale

In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods. For change from baseline in the 11-point abdominal pain scale, CONSTELLA 290 mcg began to separate from placebo in the first week. Maximum effects were seen at Weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at Week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale).

The maximum effect on CSBM frequency occurred within the first week. For the change from baseline in CSBM frequency at Week 12, the difference between placebo and CONSTELLA was approximately 1.5 CSBMs per week in both trials.

The proportions of patients who met response criteria of increasing levels of symptom improvement compared to baseline over 12 weeks of treatment were analyzed for both abdominal pain and CSBMs. At each level, a statistically significantly greater proportion of patients treated with CONSTELLA 290 mcg met the response criterion compared to placebo patients (Figure 1).

Figure 1: Percentage of Patients with Specified Improvements in (a) Abdominal Pain and (b) CSBMs over the First 12 Weeks of Treatment in IBS-C (Trials 1 & 2, Pooled ITT Population)


CSBM=Complete Spontaneous Bowel Movement

Figure 2 presents results for improvement in abdominal pain (% change from baseline) for each of the 26 weeks of treatment in Trial 2. CONSTELLA 290 mcg demonstrated a statistically significant separation from placebo that was present at the first week and sustained across the 26 weeks of the treatment period (p < 0.001 at all time-points during the treatment period). Similar results for improvement in CSBM frequency were demonstrated throughout the 26-week treatment period. Maximum effect on CSBM frequency occurred by Week 1, but the effect on abdominal pain continued to increase over the first 6 to 8 weeks.

Figure 2: Trial 2 - Mean Percentage Improvement in Abdominal Pain by Week over 26 Weeks in IBS-C


CI=Confidence Interval

During the 4-week randomized withdrawal period in Trial 1, patients who received CONSTELLA during the 12-week treatment period were re-randomized to receive placebo or continue treatment on CONSTELLA 290 mcg. In CONSTELLA-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week with no evidence of rebound worsening compared to baseline. Patients who continued on CONSTELLA maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to CONSTELLA had an increase in CSBM frequency and abdominal pain levels that were similar to the levels observed in patients taking CONSTELLA during the treatment period.

Quality of Life Assessment

The Irritable Bowel Syndrome-Quality of Life (IBS-QOL) instrument was utilized in the Phase 3 pivotal trials to assess the impact of IBS on a patient’s quality of life. The IBS-QOL evaluated 8 dimensions: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual, and relationships on a 0 to 100 point scale. A pooled analysis of the IBS- QOL data at Week 12 demonstrated that a higher proportion of patients receiving CONSTELLA 290 mcg were responders versus placebo for the overall score and the 8 subscale scores (all p<0.05). Table 5 provides an overview of the IBS-QOL responder data from Trials 1 and 2.

Table 5: Quality of Life Results for CONSTELLA in IBS-C (Responder Analyses,Pooled ITT Population)
IBS-QOL Parameter CONSTELLA
290 mcg
N=805
Placebo
N=797
CONSTELLA
290 mcg
N=805
Placebo
N=797
% of Patients with ≥10 point
improvement
% of patients with ≥14 point
improvement
IBS-QOL Overall Score 64.3%d 52. 5% 53.8%d 39.0%
Dysphoria 62.0%b 53.6% 56.2%d 45.7%
Body Image 71. 7%d 59.5% 62.1%d 43.2%
Health Worry 67.6%d 56.1% 67.6%d 56.1%
Food Avoidance 57.4%d 46.6% 57.4%d 46.6%
Social Reaction 52.5%b 44. 5% 42.4%c 32.9%
Sexual 54.2%c 44.4% 37.9%d 26.9%
Relationships 41.6%b 34.7% 41.6%b 34.7%
Interference with Activity 54.7%a 48.5% 47.5%b 39.0%

a p<0.05, b p <0.01, c p <0.001, d p<0.0001(vs. placebo, CMH test)
IBS-QOL=Irritable Bowel Syndrome-Quality of Life

Chronic Idiopathic Constipation (CIC)

Study Demographics and Trial Design

The efficacy of CONSTELLA for the treatment of CIC was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with the recommended 145 mcg dose of CONSTELLA, the 290 mcg dose of CONSTELLA, or placebo once daily, and were evaluated for efficacy. A summary of trial designs and patient demographics is presented in Table 6 below. In the two pivotal trials, 76% of patients were White, 22% were Black, and 10% were Hispanic.

Table 6: Summary of Patient Demographics for Clinical Trials Supporting Efficacy of CONSTELLA in the Treatment of CIC (ITT Population)
Trial# Trial
Design/Duration
Oral Dosage Study Subjects (N)
[Female/Male
(F/M)]
Mean Age
(Range)
Mean Baseline
Characteristics
3 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group
Plus4-week randomized withdrawal (RW) period
CONSTELLA
145 mcg or
290 mcg once
daily
N=642
[F=561; M=81]
48.0 (18-85) CSBMs/week:
0.3 (0.0-2.9)
4 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group CONSTELLA
145 mcg or
290 mcg once
daily
N=630
[F=570; M=60]
47.6 (20-83) CSBMs/week:
0.3 (0.0-2.4)

CSBM=Complete Spontaneous Bowel Movement

All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 spontaneous bowel movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:

  • Straining during greater than 25% of bowel movements
  • Lumpy or hard stools during greater than 25% of bowel movements
  • Sensation of incomplete evacuation during greater than 25% of bowel movements

Patients were also required to have less than 3 complete spontaneous bowel movements (CSBMs) per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take bismuth, prokinetic agents, or other drugs to treat chronic constipation including laxatives (except for bisacodyl, the protocol-specified rescue medication).

Study Results

Efficacy of CONSTELLA was assessed using overall responder analysis (primary endpoint) and change-from-baseline analyses (secondary endpoints). Results for endpoints were based on information provided daily by patients in electronic diaries, via an interactive voice response system.

Both doses of CONSTELLA were statistically superior to placebo for the primary and secondary endpoints in each pivotal trial, with no incremental benefit of the 290 mcg dose over the 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose.

Primary Endpoint

The primary efficacy endpoint was the proportion (%) of patients who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period.

In the two pivotal trials (Trials 3 and 4), CONSTELLA demonstrated statistically superior benefits, for the primary endpoint, compared to placebo in the treatment of CIC. In both trials, the proportion of patients who were CSBM responders was statistically significantly greater with CONSTELLA than with placebo. Results are summarized in Tables 7 and 8.

Table 7: Trial 3 - Primary Efficacy of CONSTELLA in CIC (ITT Population)
Trial 3
Placebo
(N=209)
CONSTELLA
145 mcg
(N=217)
Treatment
Difference
[95% CI]
CONSTELLA
290 mcg
(N=216)
Treatment
Difference
[95% CI]
CSBM Responder (≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 3.3% 21.2%a 17.8%
[11.9%,23.8%]
19.4%a 16.1%
[10.3%,21.9%]

a p<0.0001
CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement


Table 8: Trial 4 - Primary Efficacy of CONSTELLA in CIC (ITT Population)
Trial 4
Placebo
(N=215)
CONSTELLA
145 mcg
(N=213)
Treatment
Difference
[95% CI]
CONSTELLA
290 mcg
(N=202)
Treatment
Difference
[95% CI]
CSBM Respondera,b (≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 6.0% 16.0%a 9.9%
[4.1%,15.8%]
21.3%b 15.2%
[8.8%,21.7%]

a p≤0.05, b p<0.0001
CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement

Secondary Endpoints

The secondary efficacy endpoints were the change from baseline in 12-week CSBM and SBM frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and constipation severity.

Patients who received CONSTELLA across the 2 trials demonstrated statistically significantly greater improvements compared with patients receiving placebo for all secondary endpoints, including change from baseline in 12 week CSBM and SBM frequency, stool consistency (as measured by the Bristol Stool Form Scale (BSFS)), severity of straining, abdominal discomfort, bloating and constipation severity (Tables 9 and 10).

CSBM frequency reached maximum level during Week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at Week 12, the difference between placebo and CONSTELLA was approximately 1.5 CSBMs.

Table 9: Trial 3 - Secondary Efficacy of CONSTELLA in CIC (Mean Change from Baseline, ITT Population)
12-Week
Parameter
Placebo
(N=209)
CONSTELLA
145 mcg
(N=217)
LSMD
(95% CI)
CONSTELLA
290 mcg
(N=216)
LSMD
(95% CI)
CSBMs/week 0.5 1.9c 1.5 (1.0, 1.9) 2.0c 1.6 (1.2, 2.0)
SBMs/week 1.1 3.0c 2.0 (1.4, 2.5) 3.0c 1.9 (1.4, 2.5)
Stool
Consistency*
0.6 1.9c 1.3 (1.1, 1.5) 1.8c 1.3 (1.0, 1.5)
Severity of
Straining**
-0.5 -1.1c -0.6 (-0.7, -0.5) -1.2c -0.6 (-0.8, -0.5)
Abdominal
Discomfort**
-0.3 -0.5b -0.2 (-0.3, -0.1) -0.4a -0.1 (-0.2, 0.0)
Bloating** -0.2 -0.5c -0.2 (-0.3, -0.1) -0.4a -0.2 (-0.3, -0.1)
Constipation
Severity**
-0.3 -0.9c -0.6 (-0.8, -0.5) -0.8c -0.5 (-0.7, -0.4)

a p≤0.05,b p<0.001,c p<0.0001
*BSFS Score, **5-point Ordinal Scale
BSFS=Bristol Stool Form Scale, CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement, LSMD=Least Squares Mean Difference, SBM=Spontaneous Bowel Movement


Table 10: Trial 4 - Secondary Efficacy of CONSTELLA in CIC (Mean Change from Baseline, ITT Population)
12-Week
Parameter
Placebo
(N=215)
CONSTELLA
145 mcg
(N=213)
LSMD
(95% CI)
CONSTELLA
290 mcg
(N=202)
LSMD
(95% CI)
CSBMs/week 0.6 2.0b 1.4 (0.9, 1.9) 2.7b 2.0 (1.5, 2.6)
SBMs/week 1.1 3.4b 2.3 (1.7, 3.0) 3.7b 2.6 (1.9, 3.2)
Stool
Consistency*
0.6 1.8b 1.3 (1.0, 1.5) 2.0b 1.4 (1.2, 1.7)
Severity of
Straining**
-0.6 -1.1b -0.6 (-0.7, -0.4) -1.2b -0.7 (-0.8, -0.5)
Abdominal
Discomfort**
-0.3 -0.5a -0.2 (-0.3, -0.1) -0.5b -0.2 (-0.3, -0.1)
Bloating** -0.2 -0.4a -0.2 (-0.3, -0.1) -0.5b -0.3 (-0.4, -0.1)
Constipation
Severity**
-0.3 -0.9b -0.6 (-0.8, -0.5) -1.0b -0.6 (-0.8, -0.5)

a p<0.001,b p<0.0001
*BSFS Score, **5-point Ordinal Scale
BSFS=Bristol Stool Form Scale, CI=Confidence Interval, CSBM=Complete Spontaneous Bowel Movement, LSMD=Least Squares Mean Difference, SBM=Spontaneous Bowel Movement

The proportions of patients who met response criteria of increasing levels of stool frequency compared to baseline (i.e., increases of >0, ≥1, ≥2, ≥3, ≥4, ≥5, and ≥6 CSBMs per week) over 12 weeks of treatment were analyzed. At each level, a statistically significantly greater proportion of patients treated with either dose of CONSTELLA met the response criterion compared with placebo patients (Figure 3).

Figure 3: Percentage of CIC Patients with Incremental Increases in CSBM Frequency (Trials 3 & 4, Pooled ITT Population)


p≤0.0001 for all comparisons of linaclotide vs placebo
CSBM=Complete Spontaneous Bowel Movement

For CSBM and SBM frequency, each dose of CONSTELLA demonstrated a statistically significant separation from placebo that was present at the first week and sustained across the 12 weeks of the treatment period (p < 0.001 for each dose vs. placebo at all time-points) for both trials.

During the 4-week randomized withdrawal period in Trial 3, patients who received CONSTELLA during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of CONSTELLA taken during the treatment period. In CONSTELLA-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week with no evidence of rebound worsening compared to baseline. Patients who continued on CONSTELLA maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to CONSTELLA had an increase in CSBM and SBM frequency similar to the levels observed in patients taking CONSTELLA during the treatment period (Figure 4).

Figure 4: Trial 3 - Mean (a) CSBM and (b) SBM Frequency by Week Over the 12- week Treatment Period and 4-week Randomized Withdrawal Period


CSBM=Complete Spontaneous Bowel Movement, SBM=Spontaneous Bowel Movement

Quality of Life Assessment

The Patient Assessment of Constipation – Quality of Life (PAC-QOL) instrument was utilized in the Phase 3 pivotal trials to assess the impact of constipation on a patient’s quality of life. The PAC-QOL evaluated 4 dimensions: physical discomfort, psychosocial discomfort, worries/concerns, and satisfaction on a 0 to 4 point scale. A pooled analysis of the PAC-QOL data at Week 12 demonstrated that a higher proportion of patients receiving CONSTELLA 145 mcg or CONSTELLA 290 mcg were responders versus placebo for the overall score and the 4 subscale scores (all p<0.05). Table 11 provides an overview of the pooled PAC-QOL responder data from Trials 3 and 4.

Table 11: Quality of Life Results for CONSTELLA in CIC (Responder Analyses, Pooled ITT Population)
PAC-QOL
Parameter
CONSTELLA 145 mcg
N=430
CONSTELLA 290 mcg
N=418
Placebo
N=423
% of Patients with ≥1 point improvement
PAC-QOL Overall
Score
43.6%b 41.0%b 23.4%b
Satisfaction 53.8%b 52.3%b 28.3%b
Physical Discomfort 55.4%b 54.6%b 30.8%b
Worries/Concerns 48.1%b 45.1%b 26.7%b
Psychosocial
Discomfort
24.7%a 29.1%b 18.6%b

a p≤0.05, b p<0.0001(vs. placebo, CMH test)
PAC-QOL=Patient Assessment of Constipation-Quality of Life

Detailed pharmacology

Animal Pharmacology

In vitro pharmacodynamics

Several competitive binding studies were conducted using radiolabled pSTa (E. coli heat-stable enterotoxin derived from a porcine source) to confirm the molecular target of linaclotide and characterize its binding to guanylate cyclase-C (GC-C). Linaclotide and its active primary metabolite, MM-419447, each bound with similar high affinities to human colon carcinoma T84 cells, which are known to express high levels of GC-C. The binding was found to be pH- independent. Linaclotide bound to rat intestinal epithelial cells and brush-border membranes with high affinity, providing further evidence that linaclotide binds to GC-C. A study using intestinal mucosal membranes from wild-type (WT) and GC-C knock-out (KO) mice showed high affinity binding of linaclotide to GC-C in intestinal mucosal membranes from WT mice, but not those from GC-C KO mice, confirming that the GC-C is the molecular target of linaclotide.

Upon binding to GC-C, both linaclotide and its active metabolite stimulate the production of cGMP intracellularly, in a concentration-dependent manner, with similar minimal effective concentrations in human T84 cells. In human colonic adenocarcinoma (Caco-2) cell monolayers, linaclotide increased intracellular cGMP and induced both basolateral (submucosal) and apical (lumenal) cGMP efflux. This bidirectional cGMP efflux was inhibited by several known efflux transporter inhibitors, demonstrating that intracellular cGMP is actively transported out from intestinal epithelial cells.

In vivo pharmacodynamics

The pharmacological activities of linaclotide and MM-419447 have been characterized in a number of studies in rodent models of intestinal secretion, GI transit, and visceral pain. Linaclotide and MM-419447 stimulated a significant, dose-dependent increase in intestinal secretion in suckling mice with equal potency at a minimal effective dose of 2.5 mcg /kg. In adult mice and rats, using a loop-ligation assay, linaclotide stimulated a significant increase in intestinal fluid secretion, accompanied by a significant increase in luminal cGMP secretion. The effect of linaclotide on intestinal fluid and cGMP secretion is GC-C dependent since the effect was only observed in WT mice, but not in GC-C KO mice.

In mice, linaclotide at oral doses of 25 mcg /kg (single dose) and 60 mcg /kg, QD (5-day repeat dosing) significantly induced GI transit in WT mice, but not in GC-C KO mice. In Sprague- Dawley rats, both linaclotide at 6.25 mcg /kg, p.o. and MM-419447 at 12.5 mcg/kg, p.o. produced a significant increase in GI transit.

In addition to its effect on intestinal secretion and GI transit, linaclotide significantly reduced visceral hypersensitivity. In a model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity in WT mice linaclotide (0.01 mcg /kg, p.o.) reduced visceral hyperalgesia but had no effect in GC-C KO mice. In models of both inflammation- and stress-induced (i.e., partial restraint, water avoidance) visceral hyperalgesia in rats, linaclotide produced antinociceptive effects, without affecting the colonic tone. However, a clear dose-response relationship was not observed.

Safety pharmacology

Linaclotide tested at 10 and 100 μM concentrations exhibited negligible and not statistically significant inhibition (10 μM = 3.7% ± 2.0%; 100 μM = 0.9 ± 0.8%; vehicle = 0.7 ± 0.3%) of the human ether-a-go-go-related gene (hERG) channel current when tested in vitro in stably transfected human embryonic kidney (HEK) cells. In an in vivo safety pharmacology study, linaclotide did not produce any noticeable adverse respiratory or cardiovascular effects in dogs after administration of intravenous doses of up to 5 mg/kg.

Animal pharmacokinetics

Following oral dosing, linaclotide is minimally absorbed in all studied species, including mice, rats, and monkeys, with a low absolute oral bioavailability (≤ 0.2%).

While the predominant mechanism of clearance of orally administered linaclotide and its active primary metabolite is through proteolytic degradation in the lumen of the intestine, fecal recovery studies in rats have shown that a small amount of active peptide (≤ 1%), predominately in the form of the active metabolite, is excreted in the feces. These results also demonstrate that despite early rapid metabolism and degradation of linaclotide and MM-419447 in the proximal small intestine, some active peptide is available to interact with GC-C throughout the entire intestinal tract, including the colon.

Although very little active peptide is absorbed into systemic circulation after oral administration, when given intravenously in rats, both linaclotide and MM-419447 are rapidly cleared by at least two pathways. The kidney is a major clearance organ for systemically circulating linaclotide and MM-419447, and studies have indicated the presence of additional, non-renal pathways of clearance, including biliary clearance.

Human Pharmacology

Pharmacodynamics

Orally administered linaclotide acts on the luminal surface of the intestine. The pharmacodynamics of orally administered linaclotide was evaluated in healthy subjects and patients through bowel symptom assessments of stool, severity of straining associated with bowel movements, stool frequency, and stool weight. Because the form of the feces largely depends on the time spent in the colon (i.e., slower transit results in harder stool form), stool consistency is a surrogate for GI transit. Single (29 mcg to 2897 mcg) and repeated once daily doses (29 mcg to 966 mcg) of linaclotide softened stools and decreased straining with bowel movements in healthy subjects relative to placebo, with more profound effects noted following doses ≥ 290 mcg.

In a food-effect study, healthy subjects treated for seven days with once-daily linaclotide (290 mcg) administered after a high-fat breakfast had looser stools and increased stool frequency compared with fasted patients, suggesting that food increases the pharmacodynamic effect of linaclotide.

Oral administration of linaclotide (97 mcg or 966 mcg) for five days to IBS-C patients, softened stools, increased stool frequency, improved ease of passage, and decreased time to first bowel movement, with a dose-dependent response for stool consistency. In addition to its effects on bowel movement parameters in these IBS-C patients, linaclotide was found to increase colonic transit using radiographic techniques.

Pharmacokinetics

Plasma concentrations of linaclotide and its active primary metabolite, MM-419447, were not generally measurable in humans, following oral administration of linaclotide, as expected for a peptide with a low permeability profile. There were no detectable plasma concentrations of linaclotide or MM-419447 in > 99% of linaclotide-dosed participants whose plasma was analyzed during clinical trials, regardless of participant gender, age, or race. Consequently, standard PK parameters could not be calculated for linaclotide or MM-419447.

While the predominant mechanism of clearance of orally administered linaclotide and its active primary metabolite is through proteolytic degradation in the intestine, fecal recovery studies in humans have shown that a small amount of active peptide, predominately in the form of the metabolite, is excreted in the feces (≤ 6%). These results also demonstrate that despite the early rapid metabolism and degradation of linaclotide and MM-419447 in the proximal small intestine, some active peptide is available to interact with GC-C throughout the entire intestinal tract, including the colon.

No clinical studies assessing drug-drug interactions were conducted. Linaclotide has a low permeability coefficient in Caco-2 cells and is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes. At clinically relevant concentrations, linaclotide is not a substrate for P-glycoprotein (P-gp) and does not inhibit common efflux and uptake transporters, including P-gp. The observed minimal systemic exposure to linaclotide and MM-419447 following oral administration of linaclotide, the extensive metabolism of both peptides within the GI tract, and the lack of interaction with common drug-transporting and drug-metabolizing enzymes have led to the conclusion that linaclotide is unlikely to interact with concomitantly administered medications.

Toxicology

Single-dose Toxicity

In rats, there was no detectable systemic exposure to linaclotide at single oral dose levels of up to 5.0 mg/kg (lower limit of quantitation [LLOQ] was 3 ng/mL). There were no linaclotide-related effects observed on survival, body weight, food consumption, clinical observations, or macroscopic evaluations. The No-Observed-Adverse-Effect-Level (NOAEL) was determined to be ≥ 5.0 mg/kg in rats (both sexes) given linaclotide as a single oral dose.

Cynomolgus monkeys were administered a single oral dose of linaclotide at dose levels of 0.5, 1.5, 3.0, and 5.0 mg/kg. Monkeys receiving a single oral dose ≥ 1.5 mg/kg exhibited changes in stool consistency (non-formed and/or liquid feces), qualitatively reduced food consumption, and/or abdominal distention. There were no significant changes in individual body weight data for these animals. A monkey dosed orally for five consecutive days at 1.5 mg/kg/day exhibited non-formed and liquid feces over the course of the dosing period, with mild abdominal distention occurring on the fourth dosing day. These results demonstrated that linaclotide was well tolerated by Cynomolgus monkeys following a single oral dose at dose levels up to 5.0 mg/kg. Clinical signs related to the exaggerated pharmacological effects of linaclotide on stool consistency were observed at oral doses of ≥ 1.5 mg/kg/day.

Repeat-dose Toxicity

Repeated-dose studies of orally administered linaclotide have been conducted in mice, rats and monkeys. In Good Laboratory Practice (GLP) two-week repeated-dose oral toxicity studies in rats and monkeys, the administration of linaclotide at dose levels of 20 mg/kg/day in rats and 5 mg/kg/day in monkeys was associated with no noteworthy findings in rats and reversible changes in stool consistency in monkeys. In a GLP 7-day repeated-dose intravenous toxicity study in monkeys, the administration of linaclotide at a dose level of 15 mg/kg/day was associated with stool consistency changes.

In GLP repeated-dose oral toxicity studies in rats and monkeys, linaclotide did not produce findings considered to be adverse when administered for up to 13 weeks at doses up to 100 mg/kg/day in rats and up to 5 mg/kg/day in monkeys. Reversible changes in stool consistency were observed in monkeys and are the exaggerated pharmacological effect of linaclotide. During a GLP 13-week repeated-dose oral toxicity study in mice, mortality related to linaclotide administration was observed at dose levels ≥ 100 mg/kg/day. Linaclotide-related microscopic changes were noted in the lymphoid system (spleen and thymus), GI tract (stomach, cecum), kidney, and heart at doses ≥ 100 mg/kg/day in both males and females. The no-observed-adverse-effect-level (NOAEL) for linaclotide in mice was 20 mg/kg/day administered orally once daily for 13 weeks.

Based upon the increased sensitivity of mice to linaclotide administration, mice were chosen as the species for the GLP 26-week repeated-dose oral toxicity study in rodents. In the 26-week toxicity study, mortality was observed early in the study in the high dose (100/80 mg/kg/day) group. However, no linaclotide-related clinical pathology changes, gross or microscopic findings were noted at any dose level in either sex. Based on the mortality observed, the NOAEL was 20 mg/kg/day in mice administered linaclotide orally for 26 weeks.

In the GLP 39-week study in monkeys, changes in stool consistency (watery feces) were present at all dose levels evaluated in both sexes and were consistent with the exaggerated pharmacological effects of linaclotide. Repeated daily oral dosing for up to 39 weeks did not result in any apparent decrease in the pharmacological effects of linaclotide on stool consistency during the dosing interval and the effects on stool consistency were reversible upon discontinuation of dosing. Two monkeys (one male in the mid dose group and one female in the high dose group) were euthanized moribund due to severe watery feces (e.g., diarrhea) and associated progressive dehydration. Mortality in these monkeys was considered to be related to exaggerated pharmacology of linaclotide. Clinical observations and histopathologic findings in the large intestine (colon, cecum and rectum) identified the GI system as target organs in both animals euthanized moribund. In other animals in this study which survived until scheduled necropsy, there were no linaclotide-related clinical pathology changes, nor any gross or microscopic findings. Based on mortality, the NOAEL was determined to be 5 mg/kg/day in monkeys administered linaclotide orally for 39 weeks.

Genotoxicity

Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes.

Carcinogenicity

In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3,500 mcg/kg/day or in mice at doses up to 6,000 mcg/kg/day.

Reproductive and Developmental Toxicity

Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100 mg/kg/day.

Studies in Juvenile Animals

In a range-finding tolerability study, when administered orally for 5 days, linaclotide was tolerated at higher dose levels in juvenile mice when treatment was initiated on Day 21 post-partum compared to Day 14 or Day 7. In mice, younger animals were more sensitive to linaclotide-related mortality. In the definitive GLP 9-week repeated-dose oral toxicity study in juvenile mice initiated on Day 7 post-partum, there was an increase in mortality after administration of 1 or 2 doses of linaclotide at 10 mcg/kg/day through Day 9 post-partum. However the 10 mcg/kg/day dose level was well tolerated after Day 9 post-partum for the remaining treatment period in surviving juvenile mice, with no linaclotide-related adverse effects or microscopic findings and no effects on the physical development or neurobehavioral assessments. Based on the mortality observed, the NOAEL was determined to be 3 mcg/kg/day in juvenile mice administered linaclotide orally once daily for 9 weeks. The increased sensitivity of juvenile mice to linaclotide may be related to the increased expression of intestinal GC-C receptors in young animals or possibly other factors such as those related to an immature GI system [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, Special Populations, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Teratology Studies

The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100 mg/kg/day in rats and 40 mg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40 mg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5 mg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice.