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A Clinical Overview
Irritable Bowel
Syndrome with
Constipation (IBS-C)
CONSTELLA® (linaclotide) is
indicated for the treatment of irritable
bowel syndrome with constipation
(IBS-C) in adults.1
Chronic Idiopathic
Constipation (CIC)
CONSTELLA® (linaclotide) is indicated
for the treatment of chronic idiopathic
constipation (CIC) in adults.1
Over 295,000 cumulative patient-years of experience globally2
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Irritable Bowel Syndrome with Constipation (IBS-C)
Action and Clinical Pharmacology*
• IBS-C is a functional bowel disorder1
• In IBS-C, abdominal pain and discomfort are associated with altered
defecation1
• Etiology and pathophysiology are poorly understood and appear to be
multifactorial resulting in:1
– Visceral hypersensitivity
– Alteration in GI motility
– Psychosocial factors
• Treatment is aimed at:1
– Relief of abdominal symptoms – abdominal pain, discomfort and bloating
– Normalization of bowel movements
– Improvement of quality of life
* Clinical significance has not been established.
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Chronic Idiopathic Constipation (CIC)
Action and Clinical Pharmacology*
• CIC is a functional GI disorder1
• Patients with CIC report multiple bowel and abdominal symptoms:
– Straining, gas, hard stools, abdominal discomfort, infrequent bowel movements, bloating,
sense of incomplete evacuation, abdominal pain1
• Treatment is aimed at:
– Normalizing bowel movements – frequency and consistency
– Relieving abdominal symptoms
* Clinical significance has not been established.
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CONSTELLA®:
A 14-Amino Acid Peptide That Acts Locally in the Bowel
to Accelerate GI Transit and Reduce Intestinal Pain1*
CFTR=cystic fibrosis transmembrane conductance regulator; cGMP=cyclic guanosine
monophosphate; GC-C=guanylate cyclase-C
* Clinical significance has not been established.
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CONSTELLA® – Action and Clinical Pharmacology*
CONSTELLA® is –
Pharmacokinetics –
• minimally absorbed with low systemic
availability following oral administration2
• metabolized within the GI tract to its principle,
active metabolite. Both linaclotide and the
metabolite are proteolytically degraded within
the intestinal lumen to smaller peptides and
naturally occurring amino acids2
• No drug interaction studies have been
performed. It is thought that linaclotide is
unlikely to interact with concomitantly
administered medications based on the
observed:
Patients with hepatic or renal impairment –
• CONSTELLA® has not been specifically studied
in patients with hepatic or renal impairment.
No effect on metabolism or clearance of
linaclotide or its metabolite is expected in
patients with hepatic or renal impairment2
* Clinical significance has not been established.
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– Minimal systemic exposure to linaclotide
or its principle metabolite
– Extensive metabolism of both peptides
within the GI tract
– Lack of interaction with common drug
metabolizing enzymes (e.g., cytochrome
P450) and drug transporting enzymes
(e.g., P-glycoprotein transporters)
CONSTELLA®:
Four Pivotal Phase 3 Clinical Trials in IBS-C and CIC1
Trial Number
Description
Trial 1: published in the AJG*
Trial 2: published in the AJG*
Trial 3: published in the NEJM†
Trial 4: published in the NEJM†
Multicentre,
randomized,
controlled
trials
Duration
No. of Patients
(CONSTELLA®/placebo)
12+4 weeks
N=800 (405/395)
26 weeks
N=804 (401/403)
12+4 weeks
N=642 (433/209)
12 weeks
N=630 (415/215)
Study parameters are available at http://www.actavis.ca/specialty/products/constella
* AJG=American Journal of Gastroenterology
† NEJM=New England Journal of Medicine
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IBS-C: Demonstrated Early and Sustained
Reduction in Abdominal Pain1*
Statistically Significant Separation from Placebo Observed at Week 1
and Sustained across the 26-week Treatment Period1,2
Mean Percentage Improvement in Abdominal Pain by Week over 26 Weeks
(secondary endpoint)1,2
Week 1: Significant separation
from placebo (p<0.001)1*
Weeks 6-9: Maximum effect was
seen and maintained until the end of
the study vs. baseline, p<0.001)1,2*
Week 26: 50% reduction vs.
baseline1,2* (p<0.001)2
* Abdominal pain score based on 11-point numerical rating scale (0=none, 10=very severe).1
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In IBS-C: Significant Improvement
Reported in Abdominal Bloating1,2
At Week 12: 29% Reduction in Bloating
from Baseline vs. 15% Placebo2
Mean Change from Baseline in Abdominal Bloating, Weeks 1-12
(secondary endpoint)1,2*†
* Analysis based on first 12 weeks of treatment, Trial 2. 1
† Abdominal bloating was measured daily using an 11-point numerical rating scale (0=none, 10=very severe).1
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IBS-C: Demonstrated Improvement in
Bowel Movement Frequency – Weekly SBMs
(secondary endpoint)1
SBMs/week, change vs.
baseline at week 12:
SBMs reported within 24 hours
of first dose:
Trial 1: 3.9 CONSTELLA® vs. 1.1 placebo;
Trial 2: 4.0 CONSTELLA® vs. 1.3 placebo
(p<0.0001)1
• In a pooled analysis of Trials 1 and 2, 67% of
patients had an SBM within 24 hours of the
first dose of CONSTELLA® vs. 42% placebo
(p<0.0001)1
• In Trial 1, 58% of CONSTELLA®-treated
patients had an increase of ≥2 SBMs per
week from baseline for at least 6 of 12
weeks vs. 29% placebo (p<0.0001,
secondary endpoint)3
SBM=spontaneous bowel movement (occurring in the absence of laxative use)1
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CIC: Significant Improvement Reported
in Abdominal Bloating and Discomfort
Lembo AJ, et al.,
New England Journal of Medicine 2011
Improvement Reported
in Abdominal Discomfort
(secondary endpoint)
Improvement Reported
in Abdominal Bloating
(secondary endpoint)
34% of patients treated with CONSTELLA®
had a decrease in abdominal discomfort
vs. 21% placebo (p=0.003)4*
Twice as many CONSTELLA®-treated
patients had a decrease in bloating score:
30% CONSTELLA® vs. 15% placebo
(p<0.001)4*
Trial 3
* Decrease of ≥0.5 points in score for 9/12 weeks.4
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CIC: No Worsening Reported in SBM Frequency
During the Randomized Withdrawal Period1,2
For CONSTELLA®-treated patients re-randomized to placebo, SBM frequency returned
toward baseline within 1 week, with no evidence of rebound worsening1,2
Mean SBM Frequency by Week: 12-Week Treatment Period and 4-Week RW Period
(secondary endpoint, Trial 3)1,2
CONSTELLA® 290 mcg is not
recommended for the treatment
of CIC
RW=randomized withdrawal; SBM=spontaneous bowel movement
(occurring in the absence of laxative use)1
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CIC: Significant Improvements Reported
in Bowel Movement Frequency
(SBMs)
SBM frequency
An increase of 3.4 SBMs/week was
reported with CONSTELLA® vs.
1.1 with placebo (mean change
from baseline, p<0.0001)1,2*
Mean Number of SBMs/Week at Week 122
(secondary endpoint)
SBM=spontaneous bowel movement (occurring in the absence of laxative use)1
* Analysis based on Trial 4.
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CONSTELLA®:
+3.4 SBMs from baseline vs.
+1.1 placebo (p<0.0001)1,2
Quality of Life in IBS-C – Significant
Improvements Reported with CONSTELLA® vs.
Placebo (p<0.05 for QOL parameters assessed in IBS-C)1
IBS-C: QOL Results for CONSTELLA®
(secondary endpoint, responder analyses, pooled ITT population)
IBS-QOL parameter*
0- to 100-point scale
CONSTELLA® 290 mcg
n=805
placebo
n=797
≥10-point improvement (%)
IBS-C-QOL overall score
Dysphoria
Body image
Health worry
Food avoidance
Social reaction
Sexual
Relationships
Interference with activity
64.3d
62.0b
71.7d
67.6d
57.4d
52.5b
54.2c
41.6b
54.7a
52.5
53.6
59.5
56.1
46.6
44.5
44.4
34.7
48.5
CONSTELLA® 290 mcg
n=805
placebo
n=797
≥14-point improvement (%)
53.8d
56.2d
62.1d
67.6d
57.4d
42.4c
37.9d
41.6b
47.5b
39.0
45.7
43.2
56.1
46.6
32.9
26.9
34.7
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; ITT=intent-to-treat
* The Irritable Bowel Syndrome – Quality of Life (IBS-QOL) instrument evaluates eight dimensions on a 0- to 100-point scale: dysphoria, interference with activity, body image,
health worry, food avoidance, social reaction, sexual, relationships. Assessments were made at baseline and at week 12 in the Phase 3 trials of CONSTELLA® 290 mcg vs.
placebo in treatment of patients with IBS-C.1
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Quality of Life in CIC – Significant Improvements
Reported with CONSTELLA® vs. Placebo
(p<0.05 for QOL parameters assessed in CIC)1
CIC: QOL Results for CONSTELLA®
(secondary endpoint, responder analyses, pooled ITT population)
PAC-QOL parameter*
0- to 4-point scale
CONSTELLA® 145 mcg
n=430
placebo
n=423
≥1-point improvement (%)
PAC-QOL overall score
Satisfaction
Physical discomfort
Worries/concerns
Psychosocial discomfort
43.6b
53.8b
55.4b
48.1b
24.7a
23.4
28.3
30.8
26.7
18.6
p≤0.05, b p<0.0001(vs. placebo, CMH test)
PAC-QOL=Patient Assessment of Constipation – Quality of Life
a
* The Patient Assessment of Constipation – Quality of Life (PAC-QOL) instrument evaluates four dimensions on a 0- to 4-point scale: physical discomfort, psychosocial discomfort,
worries/concerns and satisfaction.1
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IBS-C and CIC: Safety Profile Evaluated in
4,370 Patients in Phase 2 and 3 Clinical Trials1
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Adverse Reactions:
Pooled IBS-C and CIC Clinical Trials
IBS-C and CIC Trials: Most Common Adverse Reactions
(incidence ≥4% and greater than placebo)1
Adverse Reaction
Diarrhea (%)
Abdominal pain (%)
Flatulence (%)
IBS-C Trials
CONSTELLA®
290 mcg/day
n=807
19.8
5.1
4.3
IBS-C:
Severe diarrhea:
2.0% of IBS-C patients (vs. <1% placebo)1
Discontinuations due to diarrhea:
5.3% in IBS-C patients (vs. <1% placebo)1
Overall discontinuations:
9.4% of IBS-C patients (vs. 2.9% placebo)1
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CIC Trials
placebo
n=798
3.0
3.3
1.9
CONSTELLA®
145 mcg/day
n=430
16.0
4.0
5.6
CIC:
Severe diarrhea:
1.8% of CIC patients (vs. <1% placebo)1
Discontinuations due to diarrhea:
4.2% in CIC patients (vs. <1% placebo)1
Overall discontinuations:
7.6% of CIC patients (vs. 4.3% placebo)1
placebo
n=423
4.7
3.1
5.2
CONSTELLA®:
Simple, Once-Daily Dosing for IBS-C and CIC in Adults1
Taken orally once daily on an empty stomach,
at least 30 minutes prior to the first meal of the day.1
•
•
•
Improvement of bowel symptoms should occur within the first week of CONSTELLA®
treatment; improvement of abdominal symptoms may take longer.1
No dosage adjustments required for patients with hepatic or renal impairment. 1
Physicians should periodically assess the need for continued treatment with CONSTELLA®.1
* Exceeding the daily dose of 145 mcg for the treatment of CIC is not expected to
increase efficacy. The 290 mcg dose is not recommended for the treatment of CIC. 1
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American Gastroenterological Association (AGA)
Strong Recommendation for Linaclotide5
IBS-C
American Gastroenterological Association Institute Guideline on the
Pharmacological Management of Irritable Bowel Syndrome
The AGA recommends using linaclotide
(over no drug treatment) in patients with IBS-C.
Strong recommendation*
High-quality evidence5
Comment: Patients who place a high value
on avoiding diarrhea and avoiding higher
out-of-pocket expenses associated with
linaclotide may prefer alternate treatments.5
Recommendations based on GRADE (Grading of Recommendations Assessment, Development and Evaluation). www.gradeworkinggroup.org.5
* Implications of strong guideline recommendations for clinicians: most patients should receive the recommended course of action. Adherence to this
recommendation according to guidelines could be used as a quality criterion or a performance indicator. 5
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American College of Gastroenterology (ACG)
Strong Recommendations for Linaclotide6
IBS-C and CIC
American College of Gastroenterology Monograph on the Management
of Irritable Bowel Syndrome and Chronic Idiopathic Constipation
Linaclotide is superior to placebo for the
treatment of constipation-predominant IBS.
Recommendation: strong*
Quality of evidence: high6†
Linaclotide is effective in chronic idiopathic
constipation.
Recommendation: strong*
Quality of evidence: high6†
Recommendations based on GRADE (Grading of Recommendations Assessment, Development and Evaluation). www.gradeworkinggroup.org.6
* “Strong” recommendations represent a “recommendation that can apply to most patients in most circumstances and further evidence is unlikely to
change our confidence in the estimate of treatment effect.”6
† Interpretation of high quality of evidence: further research is very unlikely to change our confidence in the estimate of effect.6
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CONSTELLA®: For the Treatment
of IBS-C and CIC in Adults
• Demonstrated Efficacy in IBS-C and CIC
• Demonstrated Safety Profile
• The First-in-Class Guanylate Cyclase-C (GC-C) Agonist1*
– A 14-amino acid peptide shown to act locally in the bowel to accelerate GI transit and reduce
intestinal pain1†
• Simple, Once-Daily Dosing1
– IBS-C patients: 290 mcg
– CIC patients: 145 mcg‡
– Taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day
• Strong Recommendations for Linaclotide:
– For IBS-C – from the American Gastroenterological Association5
– For IBS-C and CIC – from the American College of Gastroenterology6
* Comparative clinical significance has not been established.
† Clinical significance has not been established.
‡ Exceeding the daily dose of 145 mcg for the treatment of CIC is not expected to increase efficacy.
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Clinical use:
Clinical studies of CONSTELLA® did not include
sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger
subjects.
CONSTELLA® is contraindicated in children under
6 years of age and is not recommended for use in
children between 6 and 18 years of age as the safety
and efficacy of CONSTELLA® in pediatric patients have
not been established.
Contraindications:
•
Pediatric patients under 6 years of age
•
Patients with known or suspected mechanical
gastrointestinal obstruction
Most serious warnings and precautions:
Children: Not recommended in children between 6 and
18 years of age
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Other relevant warnings and precautions:
•
Diarrhea most common adverse reaction; may cause
serious diarrhea
•
Use in pregnant women only if the potential benefit
justifies the potential risk to the fetus
•
Caution should be exercised when CONSTELLA® is
administered to nursing women
For more information:
Please consult the Product Monograph at www.actavis.ca/
NR/rdonlyres/94008767-D103-460E-B854-766C324A3CE8/0/
CONSTELLA_ProductMonograph.pdf for important
information relating to adverse reactions, food interactions
and dosing information not discussed in this piece. The
Product Monograph is also available by calling Actavis
Specialty Pharmaceuticals at 1-855-892-8766.
References: 1. CONSTELLA® (linaclotide) Product Monograph, Forest Laboratories Canada Inc., May 12, 2014. 2. Data on file, Forest Laboratories Canada Inc. 3. Rao S, et al.
A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.
Am J Gastroenterol 2012;107:1714-24. 4. Lembo AJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011;365:527-36. 5. Weinberg DS, et al.
American Gastroenterological Association Institute guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014;147:1146-8. 6. Ford AC,
et al. for the Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome
and chronic idiopathic constipation. Am J Gastroenterol 2014;109:S2-S26.
CONSTELLA® is a registered trademark of Ironwood Pharmaceuticals, Inc. used under license by Allergan, Inc. or its affiliates.
©2015 Allergan. All rights reserved.