Ironwood Pharmaceuticals Reports Positive Topline Data from Phase III Trial of LINZESS® (linaclotide) in Pediatric Patients Aged 6-17 with Functional Constipation
Ironwood Pharmaceuticals announced positive topline results from a Phase III trial of linaclotide in pediatric patients aged 6-17 with functional constipation (FC). The study met its primary and secondary endpoints, demonstrating significant improvements in spontaneous bowel movements and stool consistency compared to placebo. Linaclotide was generally well-tolerated, with diarrhea being the most common side effect. There are currently no FDA approved pediatric treatments for FC, affecting 4-6 million children in the U.S. Ironwood and partner AbbVie may file for a supplemental New Drug Application (sNDA).
- Phase III trial met primary and secondary endpoints for linaclotide in children with FC.
- Significant improvement in spontaneous bowel movements (SBMs) and stool consistency compared to placebo.
- Linaclotide was well-tolerated, consistent with previous studies.
- No FDA-approved prescription treatments for pediatric FC, indicating unmet market need.
- Diarrhea, reported in 4.3% of linaclotide-treated participants, was the most common adverse effect.
– Study met primary and secondary endpoints –
– Results add to body of data supporting the safety of linaclotide for this patient population –
– There are currently no FDA approved prescription pediatric therapies for Functional Constipation (FC); FC affects an estimated 4 to 6 million children ages 6 to 17 in
– Ironwood and its partner, AbbVie, to evaluate a potential supplemental New Drug Application (sNDA) submission –
“Functional constipation is one of the most common gastrointestinal complaints in pediatric patients, one that significantly impacts young patients’ lives. Despite its high prevalence, FC remains challenging to treat because there are no FDA approved prescription treatments for children,” said
In this study, a total of 330 patients were randomized in a 1:1 ratio between linaclotide or placebo. Topline data indicate that 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 (2.220) compared to placebo (1.050) (p<0.0001). Stool consistency, as assessed by Bristol Stool Form Scale (BSFS) scores, which was the secondary endpoint, also showed an improvement at weeks 12 with linaclotide compared to placebo. The least squares mean change from baseline at week 12 was 1.108 and 0.685 points, respectively (p=0.0001). The BSFS is a 7-point scale ranging from 1 (separate hard, difficult-to-pass lumps) to 7 (liquid stools).
Overall, linaclotide (72 mcg) was well tolerated. The most frequently reported treatment-emergent adverse event was diarrhea, which occurred in
“We are excited by the results of this Phase III trial and are focused on identifying an expeditious regulatory path forward, with our partner AbbVie, to support delivering this potential first functional constipation therapeutic to pediatric patients ages 6-17 in need,” said
“Our vision for LINZESS has always been simple but powerful – keep patients at the center of everything we do,” said
These data are from the FC cohort of the Phase III, multicenter, randomized, double-blind, parallel-group, safety, and efficacy study of linaclotide vs. placebo in children ages 6-17 years with FC. Participants in the FC cohort must have fulfilled modified Rome III Criteria for child/adolescent FC.
Ironwood expects to share these Phase III trial data at upcoming scientific meetings and via peer-reviewed publications.
LINZESS is developed and marketed by Ironwood and AbbVie in
About Linaclotide
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. In
LINZESS Important Safety Information
INDICATIONS AND USAGE
LINZESS (linaclotide) is indicated in adults for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC).
IMPORTANT SAFETY INFORMATION
WARNING: 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 nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration. |
Contraindications
- LINZESS is contraindicated in patients less than 2 years of age due to the risk of serious dehydration.
- LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
Warnings and Precautions
Pediatric Risk
- LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice, linaclotide increased fluid secretion as a consequence of age-dependent elevated GC-C agonism resulting in mortality within the first 24 hours due to dehydration. There was no age-dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established.
Diarrhea
-
Diarrhea was the most common adverse reaction in LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar in the IBS-C and CIC populations. Severe diarrhea was reported in
2% of 145 mcg and 290 mcg LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC patients. If severe diarrhea occurs, dosing should be suspended, and the patient rehydrated.
Common Adverse Reactions (incidence ≥
-
In IBS-C clinical trials: diarrhea (
20% vs3% placebo), abdominal pain (7% vs5% ), flatulence (4% vs2% ), headache (4% vs3% ), viral gastroenteritis (3% vs1% ) and abdominal distension (2% vs1% ). -
In CIC trials of a 145 mcg dose: diarrhea (
16% vs5% placebo), abdominal pain (7% vs6% ), flatulence (6% vs5% ), upper respiratory tract infection (5% vs4% ), sinusitis (3% vs2% ) and abdominal distension (3% vs2% ). In a CIC trial of a 72 mcg dose: diarrhea (19% vs7% placebo) and abdominal distension (2% vs <1% ).
Please see full Prescribing Information including Boxed Warning: http://www.allergan.com/assets/pdf/linzess_pi
About
Founded in 1998,
We routinely post information that may be important to investors on our website at www.ironwoodpharma.com. In addition, follow us on Twitter and on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the clinical utility of LINZESS as a treatment option for pediatric patients aged 6-17 with FC; the efficacy and safety of linaclotide in FC and IBS in pediatric patients; the potential for linaclotide to provide therapeutic benefit to patients suffering from FC; and the potential for an sNDA submission for linaclotide. These forward-looking statements speak only as of the date of this press release, and Ironwood undertakes no obligation to update these forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include those related to the effectiveness of development and commercialization efforts by us and our partners; preclinical and clinical development, manufacturing and formulation development of linaclotide and our product candidates; the risk that clinical programs and studies may not progress or develop as anticipated, including that studies are delayed or discontinued for any reason, such as safety, tolerability, enrollment, manufacturing, economic or other reasons; the risk that findings from our completed nonclinical and clinical studies may not be replicated in later studies; the risk that we or our partners are unable to obtain, maintain or manufacture sufficient LINZESS or our product candidates, or otherwise experience difficulties with respect to supply or manufacturing; the efficacy, safety and tolerability of linaclotide and our product candidates; the risk that the therapeutic opportunities for LINZESS or our product candidates are not as we expect; decisions by regulatory and judicial authorities; the risk that we may never get sufficient patent protection for linaclotide and other product candidates, that patents for linaclotide or other products may not provide adequate protection from competition, or that we are not able to successfully protect such patents; developments in the intellectual property landscape; challenges from and rights of competitors or potential competitors; the risk that the development of either our clinical pediatric programs in IBS-C and functional constipation and/or IW-3300 is not successful or that any of our product candidates is not successfully commercialized; the risk that our planned investments do not have the anticipated effect on our company revenues; the risk that we are unable to manage our expenses or cash use, or are unable to commercialize our products as expected; the impact of the COVID-19 pandemic; and the risks listed under the heading "Risk Factors" and elsewhere in Ironwood's Annual Report on Form 10-K for the year ended
1 Robin, Samantha G. et al., Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria,
View source version on businesswire.com: https://www.businesswire.com/news/home/20220906005224/en/
Media:
bcalitri@ironwoodpharma.com
Investors:
gmartini@ironwoodpharma.com
mroache@ironwoodpharma.com
Source:
FAQ
What were the results of the Phase III trial for IRWD's linaclotide?
What is the significance of linaclotide for pediatric patients with functional constipation?
What side effects were noted in the linaclotide trial for pediatric patients?
How many children in the U.S. are affected by functional constipation?