Abdominal pain improved 56% with CR1 300 mcg relative to placebo in this trial
Companies separately announced Phase IIb data with linaclotide colonic release-2 (CR2) supporting investigation in additional GI indications associated with abdominal pain
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Linaclotide IR (LINZESS®) is currently
"Abdominal pain is usually the most difficult symptom to treat in
patients with IBS-C. When that pain is not treated sufficiently, then
that drives the patient back into my office again and again," said
The double-blind, placebo-controlled, dose-ranging Phase IIb trial randomized 532 adult patients with IBS-C into one of eight possible treatment arms. The trial was exploratory in nature and comparisons to placebo were evaluated using nominal p-values. In the trial, CR1 300 mcg demonstrated improvement on the three prespecified key efficacy endpoints as follows:
- 6/12 APC+1 Responder: the percentage of patients to report at least a 30% reduction from baseline in abdominal pain and an increase of at least one complete spontaneous bowel movement (CSBM) from baseline, both in the same week for at least 6 out of 12 weeks, was 38.8% for CR1 300 mcg compared to 21.2% for placebo and 31.8% for IR 290 mcg.
- Change from Baseline in Abdominal Pain: the average weekly change in abdominal pain from baseline to week 12 was -2.14 for CR1 300 mcg compared to -1.37 for placebo and -1.94 for IR 290 mcg, as measured on an 11-point scale. This translates to a 56.2% improvement in abdominal pain with CR1 300 mcg relative to placebo.
- Change from Baseline in CSBM Frequency: the average weekly change in CSBM frequency from baseline to week 12 was 1.78 for CR1 300 mcg compared to 1.11 for placebo and 2.11 for IR 290 mcg. This translates to a 59.3% improvement in CSBM frequency with CR1 300 mcg relative to placebo.
In this trial, CR1 300 mcg showed a numerically greater reduction in abdominal pain than IR 290 mcg each week beginning at week 5 and continuing for the remainder of the 12 week study, with a mean percent reduction from baseline at week 12 of 49.5% for CR1 300 mcg compared to 26.2% for placebo and 40.6% for IR 290 mcg. Additionally, patients treated with linaclotide CR1 300 mcg reported improvement in other abdominal and bowel symptoms commonly experienced by IBS-C patients, including abdominal discomfort and bloating.
The most common adverse event was diarrhea, which was reported in 10.4% of patients on CR1 300 mcg compared to 1.5% of patients on placebo and 13.6% of patients on IR 290 mcg. All diarrhea adverse events reported were mild or moderate in severity, with discontinuation resulting from diarrhea occurring in 3.0% of CR1 300 mcg patients compared to no placebo patients and 6.1% of IR 290 mcg patients.
Additional data from the Phase IIb trial are expected to be shared at upcoming scientific meetings and via peer-reviewed publications.
"Relief of abdominal pain is a key benefit motivating physicians to
choose LINZESS for patients suffering from IBS-C, and it is the primary
driver of patient satisfaction," said
"LINZESS is the market-leading
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Patients in the double-blind, placebo-controlled, dose-ranging Phase IIb clinical trial were randomized to one of eight groups: one group received placebo, one group received linaclotide 290 mcg (approved formulation), three groups received various doses of linaclotide CR1 (30 mcg, 100 mcg or 300 mcg), and three groups received various doses of linaclotide CR2 (30 mcg, 100 mcg or 300 mcg). The 290 mcg approved formulation was included as a reference group for this study. The trial was designed to evaluate the safety and efficacy of each linaclotide colonic release dose and formulation relative to placebo; the statistical power was based on a linear dose response. Additional objectives included assessing how the two colonic release formulations compared to each other and to the approved 290 mcg formulation of linaclotide. All doses were administered orally, once daily for 12 weeks.
About Irritable Bowel Syndrome with Constipation
Irritable bowel syndrome with constipation (IBS-C) is a functional
gastrointestinal disorder in which individuals experience hallmark
symptoms of abdominal pain and infrequent bowel movements (less than
three times per week). While estimates vary, as many as 13 million
adults in the
Linaclotide is a guanylate cyclase‐C (GC‐C) agonist that is thought to
work in two ways based on nonclinical studies. Linaclotide binds to the
GC-C receptor locally, within the intestinal epithelium. Activation of
GC-C results in increased intestinal fluid secretion and accelerated
transit and a decrease in the activity of pain-sensing nerves in the
intestine. The clinical relevance of the effect on pain fibers, which is
based on nonclinical studies, has not been established. Linaclotide is
marketed by Ironwood and
LINZESS Important Safety Information
WARNING: PEDIATRIC RISK
LINZESS is contraindicated in pediatric patients under 6 years of age. In nonclinical studies, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration in young juvenile mice. Use of LINZESS should be avoided in pediatric patients 6 through 17 years of age. The safety and efficacy of LINZESS has not been established in pediatric patients under 18 years of age.
- LINZESS is contraindicated in pediatric patients under 6 years of age.
- LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
Warnings and Precautions
- LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences.
- Use of LINZESS should be avoided in pediatric patients 6 through 17 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use of LINZESS should be avoided in pediatric patients 6 through 17 years of age.
- Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of LINZESS-treated patients. The incidence of diarrhea was similar in the IBS-C and CIC populations.
- Patients should be instructed to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider. The healthcare provider should consider dose suspension and rehydration.
- In IBS-C clinical trials, the most common adverse reactions in LINZESS-treated patients (incidence ≥2% and greater than placebo) were diarrhea (20% vs 3% placebo), abdominal pain (7% vs 5%), flatulence (4% vs 2%), headache (4% vs 3%), viral gastroenteritis (3% vs 1%) and abdominal distension (2% vs 1%).
- In CIC clinical trials, the most common adverse reactions in LINZESS-treated patients (incidence ≥2% and greater than placebo) were diarrhea (16% vs 5% placebo), abdominal pain (7% vs 6%), flatulence (6% vs 5%), upper respiratory tract infection (5% vs 4%), sinusitis (3% vs 2%) and abdominal distension (3% vs 2%).
Please see full Prescribing Information including Boxed Warning: http://www.allergan.com/assets/pdf/linzess_pi
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This press release contains forward-looking statements. Investors are
cautioned not to place undue reliance on these forward-looking
statements, including statements about the topline assessment of the
data from the Phase IIb clinical trial of CR1; the development and
regulatory plans for CR1, and the timing thereof, including further
investigation and advancement of CR1, engaging with the
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