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Linzess (linaclotide) - 3 indications
Scroll down for more information on each indication:
- Irritable bowel syndrome with constipation (IBS-C) in adults; approved August of 2012
- Chronic idiopathic constipation (CIC) in adults; approved August of 2012
- Functional constipation (FC) in pediatric patients 6 to 17 years of age; approved June of 2023
General Information
Linzess (linaclotide) is a guanylate cyclase-C (GC-C) agonist. Linzess activates the GC-C receptor in the intestine. Activation of GC-C is thought to result in increased intestinal fluid secretion and accelerated transit and a decrease in the activity of pain-sensing nerves in the intestine.
Linzess is specifically indicated for the treatment of:
- Irritable bowel syndrome with constipation (IBS-C) in adults;
- Chronic idiopathic constipation (CIC) in adults;
- Functional constipation (FC) in pediatric patients 6 to 17 years of age
Linzess is supplied as a tablet for oral administration. Scroll down for recommended dosing/administration for each indication.
Mechanism of Action
Linzess (linaclotide) is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.
Side Effects
Adverse reactions associated with the use of Linzess may include, but are not limited to, the following:
- diarrhea
- abdominal pain
- flatulence
- abdominal distension
The Linzess drug label comes with the following Black Box Warning for the risk of serious dehydration in pediatric patients less than 2 years of age. Linzess is contraindicated in patients less than 2 years of age; in neonatal mice, linaclotide caused deaths due to dehydration.
Indication 1 - irritable bowel syndrome with constipation (IBS-C) in adults
approved August of 2012
Dosing/Administration
The recommended dose of Linzess for irritable bowel syndrome with constipation is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.
Clinical Trial Results
The FDA approval of Linzess for irritable bowel syndrome with constipation was based on two double-blind, placebo-controlled, randomized, multicenter trials, Trial 1 (n=800) and Trial 2 (n=804). All subjects met the Rome II criteria for IBS. The subjects received Linzess 290 mcg or placebo. 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, subjects were allowed to continue stable doses of bulk laxatives or stool softeners. The four 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 subject had to have at least a 30% reduction from baseline in mean abdominal pain, at least three complete spontaneous bowel movements (CSBMs) and an increase of at least one CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the two 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 subject had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least one 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, subjects did not have to have at least three CSBMs per week.
In both trials, the proportion of subjects who were responders to Linzess 290 mcg was statistically significantly higher than with placebo.
Efficacy Responder Rates: at Least 9 Out of 12 Weeks:
Trial 1 combined responder endpoint: Linzess: 12.1% responders vs. placebo: 5.1% responders. Trial 2 combined responder endpoint: Linzess: 12.7% responders vs. placebo: 3.0% responders.
Efficacy Responder Rates: at Least 6 Out of 12 Weeks:
Trial 1 combined responder endpoint: Linzess: 33.6% responders vs. placebo: 21.0% responders. Trial 2 combined responder endpoint: Linzess: 33.7% responders vs. placebo: 13.9% responders.
In both trials improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment period. For change from baseline in the 11-point abdominal pain scale, Linzess 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). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs per week in both trials. During the 4-week randomized withdrawal period in Trial 1, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on Linzess 290 mcg. In the Linzess-treated arm re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional 4 weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM frequency and abdominal pain levels that were similar to the levels observed in patients taking Linzess during the treatment period.
For the 9 out of 12 weeks combined primary responder endpoint, a subject had to have at least a 30% reduction from baseline in mean abdominal pain, at least three complete spontaneous bowel movements (CSBMs) and an increase of at least one CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the two 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 subject had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least one 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, subjects did not have to have at least three CSBMs per week.
In both trials, the proportion of subjects who were responders to Linzess 290 mcg was statistically significantly higher than with placebo.
Efficacy Responder Rates: at Least 9 Out of 12 Weeks:
Trial 1 combined responder endpoint: Linzess: 12.1% responders vs. placebo: 5.1% responders. Trial 2 combined responder endpoint: Linzess: 12.7% responders vs. placebo: 3.0% responders.
Efficacy Responder Rates: at Least 6 Out of 12 Weeks:
Trial 1 combined responder endpoint: Linzess: 33.6% responders vs. placebo: 21.0% responders. Trial 2 combined responder endpoint: Linzess: 33.7% responders vs. placebo: 13.9% responders.
In both trials improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment period. For change from baseline in the 11-point abdominal pain scale, Linzess 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). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs per week in both trials. During the 4-week randomized withdrawal period in Trial 1, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on Linzess 290 mcg. In the Linzess-treated arm re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional 4 weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM frequency and abdominal pain levels that were similar to the levels observed in patients taking Linzess during the treatment period.
Indication 2 - Chronic idiopathic constipation (CIC) in adults
approved August of 2012
Dosing/Administration
The recommended dose of Linzess for chronic idiopathic constipation is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.
Clinical Trial Results
The FDA approval of Linzess for the treatment of chronic idiopathic constipation was based on two double-blind, placebo-controlled, randomized, multicenter clinical trials, Trial 3 (n=642) and Trial 4 (n=630). All subjects met modified Rome II criteria for functional constipation. The subjects received Linzess 145 mcg, 290 mcg, or placebo once daily. 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, subjects were allowed to continue stable doses of bulk laxatives or stool softeners. Efficacy of Linzess was assessed using overall responder analysis and change-from-baseline endpoints. A CSBM overall responder in the CIC trials was defined as a subject who had at least three CSBMs and an increase of at least one CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. In Trials 3 and 4, the proportion of subjects who were CSBM responders was statistically significantly greater with the Linzess 145 mcg dose than with placebo. Linzess 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the 145 mcg dose. The following data is for the approved 145 mcg dose of Linzess:
CSBM Overall Responder at Least 9 Out of 12 Weeks:
Trial 3: Linzess 145 mcg: 20.3% responders vs. placebo 3.3% responders. Trial 4: Linzess 145 mcg: 15.5% responders vs. placebo 5.6% responders.
In both trials CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs. In both trials, Linzess also resulted in significantly greater improvements compared with placebo in stool frequency and stool consistency. During the 4-week randomized withdrawal period in Trial 3, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of Linzess taken during the treatment period. In Linzess-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional four weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM and SBM frequency similar to the levels observed in subjects taking Linzess during the treatment period.
CSBM Overall Responder at Least 9 Out of 12 Weeks:
Trial 3: Linzess 145 mcg: 20.3% responders vs. placebo 3.3% responders. Trial 4: Linzess 145 mcg: 15.5% responders vs. placebo 5.6% responders.
In both trials CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs. In both trials, Linzess also resulted in significantly greater improvements compared with placebo in stool frequency and stool consistency. During the 4-week randomized withdrawal period in Trial 3, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of Linzess taken during the treatment period. In Linzess-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional four weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM and SBM frequency similar to the levels observed in subjects taking Linzess during the treatment period.
Indication 3 - Functional constipation (FC) in pediatric patients 6 to 17 years of age
approved June of 2023
Dosing/Administration
The recommended dosage of Linzess is 72 mcg orally once daily.
Clinical Trial Results
FDA approval of Linzess for FC was based on results of a large, multicenter, double-blind, Phase III study evaluating Linzess in patients ages 6-17 years-old with functional constipation. A total of 328 patients received the study treatment, randomized in a 1:1 ratio between Linzess 72 mcg or placebo. In this pivotal study, linaclotide showed a statistically significant and clinically meaningful improvement compared to placebo in 12-week SBM frequency rate (SBMs/week), the primary endpoint. Linaclotide-treated patients demonstrated a greater than two-fold least squares mean change from baseline in SBMs/week (2.6) compared to placebo.
Approval Date: 2012-08-01
Company Name: AbbVie and Ironwood Pharmaceuticals
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