Ironwood Pharmaceuticals Announces Positive Topline Results from Global Phase III Trial of Once-Weekly Apraglutide in Adults with Short Bowel Syndrome with Intestinal Failure (SBS-IF)

– Apraglutide met the primary endpoint of relative change from baseline in actual weekly parenteral support (PS) volume at week 24, driven by both stoma and colon-in-continuity populations –

– Apraglutide also showed a clinically meaningful improvement at week 24, with patients achieving at least one day off PS per week –

– Apraglutide was generally well-tolerated, and the safety profile was consistent with previously-reported studies of apraglutide in this patient population –

– Ironwood to submit new drug application and other regulatory filings for apraglutide as a once-weekly GLP-2 analog for use in adult patients with SBS who are dependent on PS –

– Ironwood to host conference call and webcast today at 8:00 a.m. ET –

Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today announced positive topline results from its pivotal Phase III STARS trial, which evaluated the efficacy and safety of once-weekly subcutaneous apraglutide in reducing parenteral support (PS) dependency in adult patients with short bowel syndrome with intestinal failure (SBS-IF). SBS-IF, a rare and severe organ failure condition in which patients are dependent on PS, affects an estimated 18,000 adult patients in the U.S., Europe, and Japan. Based on these results, Ironwood plans to submit a new drug application (NDA) and other regulatory filings for apraglutide for use in adult patients with SBS who are dependent on PS.

The 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. The trial met its primary endpoint of relative change from baseline in actual weekly PS volume at week 24, comparing apraglutide versus placebo (-25.5% vs. -12.5%; p=0.001).

“Reducing dependency on parenteral support and easing treatment burden are important goals for every patient with SBS-IF,” 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 Trial. “The STARS topline results are significant as this is the first successful Phase III placebo-controlled study in SBS-IF patients with a GLP-2 analog with once-weekly dosing.”

In addition, there were four key secondary endpoints evaluated in statistical hierarchy. Apraglutide demonstrated statistical significance for the first two key secondary endpoints, with more patients in the combined population achieving at least one day/week off PS relative to baseline at week 24 versus placebo (43.0% vs. 27.5%; p=0.040) and more patients treated with apraglutide versus placebo demonstrating improvement in relative change from baseline in actual weekly PS volume at week 24 in the stoma population (-25.6% vs. -7.8%; p<0.001). The third and fourth key secondary endpoints were specific to colon-in-continuity patients in assessing at least one day/week off PS versus baseline and reaching enteral autonomy at week 48, both of which were not achieved. Apraglutide was numerically favorable but not statistically significant relative to placebo for improving days off PS (51.8% versus 44.4%) and reaching enteral autonomy in seven out of 56 (12.5%) patients versus two out of 27 (7.4%) patients on placebo.

Apraglutide was generally well-tolerated. Topline safety results were generally consistent with the safety profile demonstrated in apraglutide studies to date.

“Patients with SBS-IF bear the dual burden of a devastating condition and a complex treatment regimen that includes hours of parenteral support, which significantly impacts their quality of life and carries a risk of severe complications such as infection,” said Michael Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of research and drug development at Ironwood Pharmaceuticals. “We believe these results demonstrate the potential for apraglutide to improve the standard of care for all adult patients with SBS dependent on parenteral support as the only GLP-2 with once-weekly administration, if approved. We are thankful to the patients and clinical investigators involved in the largest study of a GLP-2 analog in SBS-IF and will work with regulators on next steps with the goal of making apraglutide available to those living with this severe condition.”

Ironwood looks forward to presenting additional data from the STARS study at upcoming medical conferences later this year.

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 enrolled 164 patients and dosed 163 stratified approximately 50/50 (stoma vs. colon-in continuity), then evaluated them over 24 weeks (stoma and colon-in-continuity populations) and 48 weeks (colon-in-continuity population only). Patients were randomized 2:1 to either once weekly apraglutide or placebo. 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 of PS at week 24 (all patients); relative change from baseline in actual weekly PS volume at week 24 (stoma population); patients who achieved a reduction from baseline of at least 1 day/week of PS at week 48 (colon-in-continuity population); and patients reaching enteral autonomy at week 48 (colon-in-continuity population).

The study was conducted in 18 countries with 68 active sites.

About Short Bowel Syndrome (SBS)

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 chronically 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. Those with the most severe SBS-IF require PS infusions for up to 10 to 15 hours per day. SBS-IF is associated with frequent complications, significant morbidity and mortality, high economic burden and an impaired quality of life.

Conference Call

Ironwood will host a conference call and webcast today, Thursday, February 29, 2024 at 8:00 a.m. Eastern Time to discuss the topline results. Individuals interested in participating in the call should dial (800) 715-9871 (U.S. and Canada) or (646) 307-1963 (international) using conference ID number and event passcode 2684639. To access the webcast, please visit the Investors section of Ironwood’s website at www.ironwoodpharma.com. The call will be available for replay via telephone starting at approximately 11:30 a.m. Eastern Time on February 29, 2024, running through 11:59 p.m. Eastern Time on March 14, 2024. To listen to the replay, dial (800) 770-2030 (U.S. and Canada) or (609) 800-9909 (international) using conference ID number 2684639. The archived webcast will be available on Ironwood’s website for 1 year beginning approximately one hour after the call has completed.

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 (SBS) and Acute Graft-Versus-Host Disease (aGVHD).

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD), an S&P SmallCap 600® company, is a leading global 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), which is the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) and is also indicated 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) dependent on PS 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.

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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 assessment of the data from the Phase III STARS clinical trial of apraglutide; the efficacy and safety of apraglutide; Ironwood’s plan to submit an NDA and other regulatory filings for apraglutide; the estimated adult population who suffer from SBS-IF in the U.S., Europe and Japan; the belief that the clinical trial results demonstrate the potential for apraglutide to improve the standard of care for all adult patients with SBS dependent on PS and the potential availability of apraglutide. 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 apraglutide; 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 completed nonclinical and clinical studies may not be replicated in later studies; the risk that the FDA may not approve our NDA submission; 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 risk that healthcare reform and other governmental and private payor initiatives may have an adverse effect upon or prevent our products’ or product candidates’ commercial success; the efficacy, safety and tolerability of our product candidates; the risk that the commercial and therapeutic opportunities for our product candidates are not as we expect; the risk that we are unable to successfully partner with other companies to develop and commercialize products or product candidates; decisions by regulatory and judicial authorities; the risk we may never get additional patent protection for our product candidates, that patents for our 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 apraglutide 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; challenges from and rights of competitors or potential competitors; 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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