Ironwood Pharmaceuticals Announces Positive Results from its Phase II Exploratory STARGAZE Trial of Apraglutide in Patients with Steroid-Refractory Gastrointestinal Acute Graft-versus-Host Disease (SR GI aGVHD)

– First prospective trial of a glucagon-like peptide (GLP-2) analog in SR GI aGVHD –

– Results up to Day 91 show that apraglutide in SR GI aGVHD was well-tolerated with an acceptable safety profile, the study’s primary objective –

– Exploratory secondary efficacy data showed lower GI tract responses maintained through Day 91 in SR GI aGVHD patients treated with apraglutide and standard of care –

Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today announced positive, primary results up to Day 91 for its Phase II exploratory STARGAZE trial evaluating apraglutide in patients with steroid-refractory gastrointestinal acute Graft-versus-Host Disease (SR GI aGVHD). The primary objective of the trial was to evaluate the safety and tolerability of once-weekly apraglutide, a next-generation, long-acting glucagon-like peptide-2 (GLP-2) analog, in SR GI aGVHD patients treated with standard of care, including systemic corticosteroids and ruxolitinib. This was a first-of-its-kind study combining a GLP-2 analog with immunosuppressive therapy in patients with SR GI aGVHD.

The safety and tolerability observed in this trial was consistent with the standard of care and known safety of GLP-2 analogs, as well as observed events in the GVHD population. The emerging safety profile of apraglutide in the SR GI aGVHD population was monitored by an independent safety review committee that endorsed the continuation of the study without modification.

In addition to evaluating safety, secondary endpoints evaluated efficacy using lower GI and all-organ responses, indicative of organ-level improvement from baseline per the Mount Sinai Acute GVHD International Consortium (MAGIC) grading system. The majority of patients responded to treatment by Day 28 and Day 56. All lower GI responders at Day 28 maintained their response through Days 56 and 91, considering available organ staging assessments.

“The findings presented here are an important step forward for patients with SR GI aGVHD given limited duration of response with currently approved agents,” said Robert Zeiser, M.D., Professor of Hematology and Oncology at the University of Freiburg and Principal Investigator for the STARGAZE study. “Given its potential GI effect on tissue regeneration and function, apraglutide may have a role in the advanced management of acute GI GVHD through a non-immunosuppressive approach, and we look forward to longer-term findings in this patient population.”

aGVHD is a rare, life-threatening condition that occurs when immune cells of the donor (the graft) attack a recipient’s (host) healthy cells after an allogeneic hematopoietic stem cell transplant (HSCT). The condition typically affects the skin, GI tract, and liver. GI aGVHD, is a leading cause of morbidity and mortality following HSCT with approximately 70% of aGVHD cases having GI involvement. While treatment options exist for aGVHD, a significant number of patients do not respond to 1^st line therapy, such as corticosteroids. Despite receiving 2^nd line therapy, many patients also do not maintain response over time, with significant non-relapse mortality (NRM) after six months.

“These results from the first-of-its-kind STARGAZE trial in a population of patients with SR GI aGVHD add to the body of evidence about the safety and tolerability profile of apraglutide,” said Michael Shetzline, M.D., Ph.D., Senior Vice President, Chief Medical Officer and Head of Research and Development at Ironwood Pharmaceuticals. “Other studies have shown that GLP-2 promotes intestinal healing and regeneration, and we look forward to further understanding the data from this trial given the high unmet medical need of these patients who suffer from high morbidity and mortality.”

Additional data from the STARGAZE trial are expected to be presented at an upcoming medical congress. The STARGAZE study will continue through its two-year endpoint, where apraglutide will be re-evaluated for safety and efficacy.

About STARGAZE

STARGAZE (Study of Apraglutide in Graft-versus-Host Disease) is a randomized, single-blind, Phase II exploratory trial designed to evaluate weekly dosing of apraglutide in combination with standard of care, including systemic corticosteroids and ruxolitinib in patients with steroid-refractory GI aGVHD for up to 90 days with a follow-up period lasting up to two years after the first dose. STARGAZE is the first prospective trial of a glucagon-like peptide (GLP-2) analog focusing on patients with steroid-refractory GI aGVHD. The trial enrolled 31 patients and at this primary analysis, evaluated them for safety and tolerability, pharmacokinetics, and efficacy, including response rate, duration of response, and survival-related outcomes. This study’s population consisted of more than 87% Grade III and IV patients, the most severe cohort as measured by the Mount Sinai Acute Graft Versus Host Disease International Consortium (MAGIC) scale.

About Acute Graft-Versus-Host Disease (aGVHD)

Acute Graft-Versus-Host Disease (aGVHD) is a severe condition which occurs when immune cells from the donor attack a recipient’s healthy cells after an allogeneic hematopoietic stem cell transplant (HSCT), the standard last-line treatment for many forms of blood cancer. aGVHD typically emerges within the first 100 days post-transplant and predominantly affects the skin, gastrointestinal (GI) tract and liver. GI GvHD is one of the leading causes of morbidity and mortality following HSCT. The predominant manifestations of GI GVHD are abdominal pain and diarrhea. The diarrhea is secretory, occurs independently of oral intake and can be profound and incessant, with up to several liters of output and more than 10 episodes per day, often requiring parenteral support to feed and hydrate patients. More than 26,000 allogeneic HSCTs take place in the U.S., Europe and Japan annually and aGVHD occurs in an estimated 30-50% of patients. While treatment options exist for aGVHD, a significant number of patients do not respond to 1^st line therapy, such as corticosteroids. Despite receiving 2^nd line therapy, many patients also do not maintain response over time, with significant non-relapse mortality (NRM) after six months.

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 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), 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 II exploratory STARGAZE trial of apraglutide in patients with steroid-refractory GI aGVHD and the continuation of the study through its two-year endpoint; the safety, tolerability and efficacy of apraglutide in this trial; the potential effect of apraglutide on intestinal healing, function and regeneration; and the therapeutic potential of apraglutide for the treatment of aGVHD. 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 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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