Once-Weekly Apraglutide Showed Consistent Treatment Effect Across Baseline Demographics and Disease Characteristics in Adults with Short Bowel Syndrome with Intestinal Failure (SBS-IF), According to New STARS Phase III Data from Ironwood at ACG 2024

– New safety and tolerability data show high treatment compliance with apraglutide, low incidence of injection site reactions and adverse events associated with GI tolerability –

– Findings reinforce the clinical profile of once-weekly apraglutide; Ironwood expects to complete U.S. regulatory submission in Q1 2025 –

– One apraglutide poster recognized as presidential poster recipient –

– New linaclotide data shed light on treatment outcomes across patient demographics –

Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, will present new findings at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting and Postgraduate Course from subgroup analyses of the primary endpoint of the pivotal Phase III clinical trial, STARS, evaluating the treatment effect of apraglutide by baseline demographics and disease-specific characteristics in adults with short bowel syndrome with intestinal failure (SBS-IF). The data, which will be unveiled during an oral presentation tomorrow, October 29, from 8:30 am – 8:40 am ET, indicate that apraglutide showed a consistent treatment effect across subgroups: gender, age, body weight, region, race, ethnicity and SBS characteristics – including length of remnant bowel. These findings build on previously announced positive data from the phase III pivotal trial.

SBS-IF, a rare chronic debilitating malabsorptive condition in which patients are dependent on parenteral support (PS), affects an estimated 18,000 adult patients in the U.S., Europe and Japan. Apraglutide is the first and only investigational once-weekly GLP-2 analog that has successfully demonstrated positive results in a Phase III placebo-controlled study. Ironwood is working to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and marketing applications to other regulatory agencies for apraglutide for the treatment of adult patients with SBS who are dependent on PS.

STARS represents the largest Phase III trial in SBS-IF conducted to date, and the only study that pre-specified patient stratification based on remnant bowel anatomy. Ironwood previously reported that the STARS clinical trial met its primary endpoint of relative change from baseline in actual weekly PS volume at week 24 vs. placebo (-25.5% vs. -12.5%; p=0.001). The new subgroup analyses examined the primary endpoint by demographics for the overall population, which included patients with stoma and colon-in- continuity: gender, age (<65 and ≥65 years old), body weight (<50 and ≥50 kgs), region (EU, USA or rest of world), race (Asian, Caucasian or other), ethnicity (Hispanic/Latino or not) and SBS characteristics (PS volume, length of remnant bowel and time from SBS diagnosis at baseline). Analyses showed consistent treatment effect for apraglutide vs. placebo across subgroups of varying baseline demographics and SBS characteristics in the overall population. Significance in favor of apraglutide was shown in body weight, PS volume at baseline, and length of remnant small bowel, in addition to other subgroups.

“SBS-IF is a rare condition, but it is extremely variable in terms of patient demographics and the way in which they present,” said Kishore R Iyer, MBBS, FRCS (Eng), FACS, Director of Adult and Pediatric Intestine Rehabilitation & Transplantation at The Mount Sinai Hospital in New York, Coordinating Principal Investigator of the trial, paid scientific advisor to Ironwood and chair of the scientific steering committee for the STARS clinical trial. “The analyses from STARS are critically important in helping us confirm consistency of treatment effect across different subgroups in the largest SBS-IF study ever conducted. The consistency across different baseline volumes and lengths of remnant bowel is especially noteworthy, given that this disease characteristic has a significant impact on treatment and prognosis.”

Topline results from STARS were previously announced in February 2024, and the topline data was also presented at Digestive Disease Week® (DDW) in May.

In addition to the STARS Phase III oral presentation, Ironwood and its collaborators presented new safety findings from the STARS study, with this abstract receiving a Presidential Poster Award.

“As we work to make apraglutide available as potentially the first once-weekly treatment option for patients with SBS who are dependent on PS, we are focused on continuing to educate the SBS community on the potential of this compound across profiles of adult patients given the known patient heterogeneity,” said Michael Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of research and drug development at Ironwood Pharmaceuticals. “Patient demographic analyses play a key role in understanding the impact of any medication, and our focus on these analyses extends to all our data at ACG this year.”

In addition to the apraglutide data, Ironwood is also featuring linaclotide data at ACG.

More details on these data are provided below.

Safety Data from STARS

“Safety and Tolerability of Once-Weekly Glucagon-like Peptide-2 Analog Apraglutide in Patients with Short Bowel Syndrome and Intestinal Failure (SBS-IF): Results from a Global, Phase 3, Randomized, Double-Blind Trial” (poster number 1521, Presidential Poster Award) was presented by Mena Boules, M.D., Ironwood Pharmaceuticals. This analysis showed that apraglutide had a safety profile consistent with previous apraglutide studies, with no new safety concerns. Incidence of AEs, serious AEs and AEs of Grade ≥ 3 was similar between treatment arms. Dose interruptions due to AEs were also similar between apraglutide and placebo (10.9% vs 11.3%). The incidence of AEs associated with gastrointestinal (GI) tolerability was low and similar between treatment arms. Most frequently reported AE was nausea (apraglutide 13.6% vs placebo 11.3%). Incidence of subjects with GI polyps was also low (apraglutide n=4 [3.6%] vs placebo n=2 [3.8%]); all polyps could be removed during colonoscopy, with no apraglutide discontinuations due to GI tolerability symptoms or GI polyps. GI stoma complication was reported in 7.3% of apraglutide vs 3.8% of placebo patients. There were no cases of complete GI obstruction or malignancies. The incidence of injection site reactions was similar between apraglutide and placebo. There was one death in the apraglutide arm (sudden cardiac death, unrelated). More than 98% of patients had ≥ 80% treatment compliance in both treatment arms. Most patients entered the long-term, open-label STARS Extend trial at the end of the study (apraglutide 92% vs placebo 89%).

Linaclotide Treatment Outcomes by Patient Demographic

• “Efficacy, Safety and Time to Response of Linaclotide in Adult Patients With Chronic Idiopathic Constipation: A Post Hoc Subgroup Analysis by Age” (poster number P0615) was presented by Lin Chang, M.D., Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles. The results showed that linaclotide-treated patients with CIC tended to show greater and faster improvement in bowel and abdominal symptoms compared with placebo and had similar safety profiles across age groups (< 65 and ≥ 65 yrs) for both linaclotide doses (72 mcg or 145 mcg). The authors noted that the small sample size for patients aged ≥ 65 years should be considered when interpreting these data.

Two studies will be presented by Baha Moshiree, M.D., Division of Gastroenterology, Advocate Health Wake Forest Medical University, Charlotte.

• “Efficacy and Safety of Linaclotide in Patients With Chronic Idiopathic Constipation: A Post Hoc Analysis of Phase 3 Clinical Study Data Assessing Primary and Additional Endpoints by Race and Ethnicity, and by Age” (poster number P2334). The study showed that linaclotide improved complete spontaneous bowel movement (CSBM) responder rates and CIC symptoms, and had a similar safety profile, across most races/ethnicities and ages in CIC patients. The authors note that small sample sizes for Asian and other patient groups (and some age subgroups) limit data interpretation and highlight the need to recruit more diverse populations in clinical studies.

• “Impact of Weight on the Efficacy, Time to Response and Safety of Linaclotide in Adults With Chronic Idiopathic Constipation or Irritable Bowel Syndrome With Constipation: Post Hoc Descriptive Analysis by Body Mass Index” (poster number P4073). The study showed that linaclotide improved bowel symptoms in patients with CIC and IBS-C and was similarly efficacious in those with normal weight, overweight or obesity. Treatment-emergent adverse events (TEAEs) were consistent with the known safety profile of linaclotide.

About STARS

The STARS (STudy of ApRaglutide in SBS) pivotal Phase III trial represents the largest Phase III trial in SBS-IF to date.

This global, multicenter, double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of weekly subcutaneous injections of apraglutide in adult patients with SBS-IF. STARS randomized 164 patients 2:1 and 163 were dosed to receive either once-weekly apraglutide or placebo. Patients were stratified approximately 50/50 by remnant bowel anatomy (stoma vs. colon-in continuity) and evaluated over 24 weeks (stoma and colon-in-continuity subpopulations) and 48 weeks (colon-in-continuity subpopulation only). The primary endpoint was relative change from baseline in actual weekly PS volume at week 24. Key secondary endpoints included patients who achieved a reduction from baseline of at least 1 day/week off PS at week 24 (overall population); relative change from baseline in actual weekly PS volume at week 24 (stoma subpopulation); patients who achieved a reduction from baseline of at least 1 day/week off PS at week 48 (colon-in-continuity subpopulation); and patients reaching enteral autonomy at week 48 (colon-in-continuity subpopulation).

The study was conducted in 18 countries with enrollment from 68 study sites.

About Short Bowel Syndrome

SBS is a serious and chronic condition where there is diminished absorptive capacity for fluids and/or nutrients, sometimes requiring dependence on parenteral support to maintain health. Short bowel syndrome typically occurs because of extensive intestinal resection, and patients with SBS who are dependent on parenteral support, also referred to as SBS with intestinal failure (SBS-IF), often experience significant quality of life impact and are at risk of severe complications such as infection. An estimated 18,000 adult patients suffer from SBS-IF in the U.S., Europe and Japan, and have chronic dependence on PS, which significantly impacts quality of life and carries the risk of severe complications such as infection. Many of these patients often require chronic PS infusions for 10+ hours per day. And up to 7 days a week. SBS-IF is associated with frequent complications, significant morbidity and mortality, high economic burden, and an impaired quality of life.

About Apraglutide

Apraglutide is an investigational, next-generation, long-acting synthetic GLP-2 analog being developed for a range of rare gastrointestinal diseases where GLP-2 can play a central role in addressing disease pathophysiology, including short bowel syndrome with intestinal failure (SBS-IF) and Acute Graft-Versus-Host Disease (aGVHD).

About LINZESS (Linaclotide)

LINZESS® is the #1 prescribed brand in the U.S. for the treatment of adult patients with irritable bowel syndrome with constipation (“IBS-C”) or chronic idiopathic constipation (“CIC”), based on IQVIA data. LINZESS is a once-daily capsule that helps relieve the abdominal pain, constipation, and overall abdominal symptoms of bloating, discomfort and pain associated with IBS-C in adults, as well as the constipation, infrequent stools, hard stools, straining, and incomplete evacuation associated with CIC in adults. LINZESS relieves constipation in children and adolescents aged 6 to 17 years with functional constipation. The recommended dose is 290 mcg for IBS-C patients and 145 mcg for CIC patients, with a 72 mcg dose approved for use in CIC depending on individual patient presentation or tolerability. In children with functional constipation aged 6 to 17 years, the recommended dose is 72 mcg.

LINZESS is not a laxative; it is the first medicine approved by the FDA in a class called GC-C agonists. LINZESS contains a peptide called linaclotide that 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. The clinical relevance of the effect on pain fibers, which is based on nonclinical studies, has not been established.

In the United States, Ironwood and AbbVie co-develop and co-commercialize LINZESS for the treatment of adults with IBS-C or CIC. In Europe, AbbVie markets linaclotide under the brand name CONSTELLA® for the treatment of adults with moderate to severe IBS-C. In Japan, Ironwood's partner, Astellas, markets linaclotide under the brand name LINZESS for the treatment of adults with IBS-C or CIC. Ironwood also has partnered with AstraZeneca for development and commercialization of LINZESS in China, and with AbbVie for development and commercialization of linaclotide in all other territories worldwide.

LINZESS Important Safety Information

INDICATIONS AND USAGE

LINZESS® (linaclotide) is indicated for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults and functional constipation (FC) in children and adolescents 6 to 17 years of age. It is not known if LINZESS is safe and effective in children with FC less than 6 years of age or in children with IBS-C less than 18 years of age.

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

• 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 guanylate cyclase (GC-C) agonism, which was associated with increased 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.

Diarrhea

• In adults, 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.
• In children and adolescents 6 to 17 years of age, diarrhea was the most common adverse reaction in 72 mcg LINZESS-treated patients in the FC double-blind placebo-controlled trial. Severe diarrhea was reported in <1% of 72 mcg LINZESS treated patients. If severe diarrhea occurs, dosing should be suspended and the patient rehydrated.

Common Adverse Reactions (incidence ≥2% and greater than placebo)

• In IBS-C or CIC adult patients: diarrhea, abdominal pain, flatulence, and abdominal distension.
• In FC pediatric patients: diarrhea.

Please see full Prescribing Information including Boxed Warning: https://www.rxabbvie.com/pdf/linzess_pi.pdf

LINZESS® and CONSTELLA® are registered trademarks of Ironwood Pharmaceuticals, Inc. Any other trademarks referred to in this press release are the property of their respective owners. All rights reserved.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD), an S&P SmallCap 600® company, is a leading gastrointestinal (GI) healthcare company on a mission to advance the treatment of GI diseases and redefine the standard of care for GI patients. We are pioneers in the development of LINZESS® (linaclotide), the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). LINZESS is also approved for the treatment of functional constipation in pediatric patients ages 6-17 years-old. Ironwood is also advancing apraglutide, a next-generation, long-acting synthetic GLP-2 analog being developed for rare gastrointestinal diseases, including short bowel syndrome with intestinal failure (SBS-IF), as well as several earlier-stage assets. Building upon our history of GI innovation, we keep patients at the heart of our R&D and commercialization efforts to reduce the burden of GI diseases and address significant unmet needs.

Founded in 1998, Ironwood Pharmaceuticals is headquartered in Boston, Massachusetts, with a site in Basel, Switzerland.

We routinely post information that may be important to investors on our website, www.ironwoodpharma.com. In addition, you can follow us on X and LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the assessment of the data from the Phase III STARS clinical trial of apraglutide; the efficacy, safety and tolerability of apraglutide; Ironwood’s plan to submit an NDA and marketing applications to other regulatory filings for apraglutide and the expected timing to complete U.S. regulatory submission; the estimated adult population who suffer from SBS-IF in the U.S., Europe and Japan; that the findings from the Phase III STARS clinical trial reinforce the clinical profile of once-weekly apraglutide and confirm consistency of treatment effect across different subgroups; and the potential of apraglutide to be available as the first once-weekly treatment option for patients with SBS who are dependent on PS. 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 our products and product candidates; the risk that clinical programs and studies, including for products and product candidates 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 studies and clinical trials may not be replicated in later trials and earlier-stage clinical trials may not be predictive of the results we may obtain in later-stage clinical trials or of the likelihood of regulatory approval; the risk that apraglutide will not be approved by the FDA or other regulatory agencies; the risk of competition or that new products may emerge that provide different or better alternatives for treatment of the conditions that our products are approved to treat; the efficacy, safety and tolerability of linaclotide and our product candidates; the risk that the commercial and therapeutic opportunities for LINZESS, apraglutide or our other product candidates are not as we expect; decisions by regulatory and judicial authorities; the risk we may never get additional patent protection for linaclotide, apraglutide and other product candidates, that patents for linaclotide, apraglutide or other products may not provide adequate protection from competition, or that we are not able to successfully protect such patents; the risk that the development of any of our products is not successful or that any of our product candidates does not receive regulatory approval or is not successfully commercialized; outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including abbreviated new drug application litigation; and the risks listed under the heading “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the year ended December 31, 2023, and in our subsequent Securities and Exchange Commission filings.

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Media: Beth Calitri, 978-417-2031 [e-mail] Smitha Dwarakanath, 201-616-8099 [e-mail] Investors: Greg Martini, 617-374-5230 [e-mail] Matt Roache, 617-621-8395 [e-mail]