More Than a Third of Surveyed IBS-C Patients Reported That Their Symptoms Worsened During COVID-19 According to New Survey Findings Presented by Ironwood Pharmaceuticals at Digestive Disease Week® (DDW)

– Ironwood also presented results of a separate survey of nearly 90,000 Americans that highlights the prevalence and burden of multiple GI diseases –

– Preclinical data presented at DDW highlight linaclotide’s effect on visceral hypersensitivity, which plays a key role in IBS-C –

- Ironwood’s DDW presentations feature four posters of distinction –

Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD), a GI-focused healthcare company, presented new findings at the Digestive Disease Week® (DDW) 2021 virtual meeting from a survey highlighting disease burden and care-seeking behavior among adult patients with irritable bowel syndrome with constipation (IBS-C) during the COVID-19 pandemic.

The poster presentation, titled Disease Burden and Care-Seeking Behavior for IBS-C Patients in the United States in the Era of COVID-19 (presentation number Fr014), summarized data from a cross-sectional online general health survey of 130 adults with IBS-C conducted from August through October 2020. More than a third of surveyed IBS-C patients indicated their symptoms had worsened during the COVID-19 pandemic. Additionally, nearly a quarter reported cancelling healthcare visits due to COVID-19. Also, nearly half (46%) of surveyed IBS-C patients reported that they did not seek care from a healthcare provider in the past year for their symptoms.

“As a physician, my biggest takeaway from this survey is that while IBS-C patients’ symptoms have been exacerbated during the COVID-19 pandemic, they are unfortunately not speaking with their doctors, and hence the disease continues to have a wide impact despite availability of prescription treatment options,” said Brian E. Lacy, M.D., Ph.D., Gastroenterology, Neurogastroenterology, the Mayo Clinic. “It is critical for patients to recognize they have a legitimate medical condition that needs treatment and to take that step of speaking with their physician – either in person or through a telehealth appointment.”

Other key findings from the survey, which was conducted in collaboration with researchers from the Mayo Clinic, the Acumen Health Research Institute and the International Foundation for Functional Gastrointestinal Disorders, include:

• Surveyed IBS-C patients reported a significantly higher proportion of moderate-to-severe anxiety and depression and significantly lower health-related quality of life (HRQoL) than surveyed patients without IBS-C.
• Absenteeism and presenteeism were also significantly higher among surveyed IBS-C patients versus those without IBS-C.
• 25% of surveyed IBS-C patients reported currently taking a prescription medication whereas 68.5% reported currently taking an OTC for their IBS-C symptoms.
• Most common bothersome symptoms in the past seven days included abdominal discomfort, abdominal pain, straining, abdominal bloating and incomplete bowel movements.

Ironwood Pharmaceuticals also presented six other posters at the meeting, four of which were posters of distinction. These include findings from the “National GI Survey II,” a separate survey of nearly 90,000 Americans, as well as pre-clinical data on the impact of the guanylate cyclase (GC-C) agonist linaclotide on visceral hypersensitivity, which is believed to play a key role in IBS-C.¹

"The data at DDW spotlight a harsh reality, which is that GI diseases continue to be widely prevalent and exact a vast burden on patients in the United States, creating a significant medical need,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of drug development at Ironwood. “Ironwood is committed to understanding these diseases at both a clinical and pathological level in order to advance scientific knowledge on how to address them. An example is our focus on the science of visceral hypersensitivity, which causes increased pain originating from internal organs. Our strong preclinical data suggest that GC-C agonists may play a role in addressing this huge medical problem, and we look forward to exploring the potential of this class of therapeutics in addressing visceral pain conditions.”

Results from “National GI Survey II”

In a series of three posters, Christopher Almario, M.D., MSHPM, Cedars Sinai Medical Center, presented findings from the National GI Survey II – a nationwide audit of GI symptoms in nearly 90,000 adult Americans, which was conducted from May to June 2020. The survey was conducted in collaboration with researchers from Cedars-Sinai and the University of Michigan.

• A poster titled Prevalence and Burden of Illness of Rome IV Irritable Bowel Syndrome in the U.S. (poster of distinction; presentation number Su085) showed that Rome IV-positive IBS is more prevalent (7.4%) compared to prior estimates (approximately 5%). The authors noted that additional research is needed to understand if this higher prevalence is in part related to the COVID-19 pandemic, as social distancing may have levied a psychological toll on many individuals, leading to alterations in the gut-brain axis and a propensity to either develop IBS or gain greater awareness of symptoms. The poster also noted that people with IBS commonly experience other symptoms on top of their cardinal IBS symptoms. Those with IBS with diarrhea (IBS-D) or mixed IBS (IBS-M) were more likely to report excess gas, heartburn, regurgitation, nausea/vomiting, pelvic pain or bowel incontinence versus those with IBS-C, but symptom severity scores for abdominal pain were largely similar among groups. 73.8% of IBS patients reported that they had ever sought care for their cardinal IBS symptoms (abdominal pain, constipation, or diarrhea), 19.4% had ever sought care via telehealth, and 59.7% had sought care in the past 12 months. Those with IBS-D and IBS-M were less likely to have sought care versus those with IBS-C.

• A second poster titled Prevalence of Bowel Disorders in Multiple Sclerosis and Parkinson’s Disease (poster of distinction; presentation number Fr080) showed that Rome IV chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and IBS-C are common among those with multiple sclerosis (MS) and Parkinson’s disease (PD), and that these patients have more severe constipation versus the general population. Those with MS had higher odds for having CIC, OIC and IBS-C, versus those without MS. While those with PD were more likely to have CIC versus those without PD, no association was seen for OIC or IBS-C in PD patients. Those with MS were more likely to report constipation and fecal incontinence in the seven days prior to taking the survey. 81.2% of patients with MS and 84.1% of patients with PD were taking an OTC or prescription medication for constipation. One third (34.9%) of patients with MS and half (46.6%) of those with PD, respectively, had not discussed their constipation with a provider. The authors noted that, given the negative impact of constipation on daily life, improved efforts by clinicians to proactively assess for and treat constipation in those with MS and PD are needed.

• A third poster titled Prevalence and Burden of Illness of Rome IV Chronic Idiopathic Constipation, Opioid-Induced Constipation, and Opioid-Exacerbated Constipation in the U.S. (presentation number Fr438) showed that Rome IV-positive CIC is more common (6.7%), while Rome IV OIC (2.1%) and opioid-exacerbated constipation (OEC) (0.5%) are less prevalent; these data are consistent with prior reports. The survey also noted that those with OIC and OEC were more likely to currently be taking a prescription constipation medication versus those with CIC. In fact, only 5.6% of those with CIC reported being on prescription constipation medication. Moreover, those with OIC and OEC were more likely to have ever sought care and – in fact – did seek care in the past 12 months for their constipation symptoms compared to those with CIC.

Impact of Linaclotide on Visceral Hypersensitivity

• A poster of distinction titled Colorectal nociceptive processing in the rostral and caudal ventromedial medulla is increased in a mouse model of chronic visceral hypersensitivity and is reversed by chronic linaclotide treatment (presentation number Su136) presented by Andrea Harrington, Flinders University, Adelaide, South Australia, suggested that colonic nociceptive (relating to pain) processing after colitis is enhanced in specific medullary brain regions that are known to have direct roles in modulating spinal cord pain signaling. The study also demonstrated that enhanced activation in these medullary regions is effectively reduced by targeting peripheral hypersensitivity with chronic linaclotide treatment.
  
  
• Another poster of distinction titled Intracolonic Administration of Linaclotide Relieves Visceral Hypersensitivity by Inhibiting Chronic Psychological Stress- Induced Activation of Central Nociceptive Pathways in Rats (presentation number Su134) presented by Casey Ligon, The University of Oklahoma Health Sciences Center, provided preclinical evidence that intracolonic administration of linaclotide inhibits stress-induced colonic and bladder hypersensitivity by altering neuronal activation within the spinal cord and supraspinal pain modulation circuitry.

Effect of MD-7246 on IBS-D

A poster titled Impact of MD-7246 on Irritable Bowel Syndrome with Diarrhea: Phase 2 Results (presentation number Su090) presented by Anthony Lembo, M.D., Beth Israel Deaconess Medical Center, expanded on topline results from a Phase II trial of MD-7246 in patients with IBS-D, which were presented by Ironwood in May 2020. While MD-7246 did not show statistically significant benefit in abdominal pain when compared to placebo in patients with IBS-D, a post-hoc analyses identified a significant, positive treatment effect in daily abdominal pain during 50% of days on treatment for the MD-7246 300 µg group versus placebo in patients diagnosed with IBS-D more than six months prior to study enrollment.

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 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 chronic constipation. In China, (including Hong Kong and Macau) Ironwood’s partner Astra Zeneca markets linaclotide under the brand name LINZESS for the treatment of adults with IBS-C. Ironwood is also partnered with AbbVie for development and commercialization of linaclotide in all other territories worldwide. 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) 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). Under the guidance of our seasoned industry leaders, we continue to build upon our history of GI innovation and challenge what has been done before to shape what the future holds. 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.

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 prevalence and burden of multiple GI diseases, including the scope of unmet medical need; the potential impact of GC-C agonists, including linaclotide, on visceral pain conditions; the disease burden, care-seeking behavior and size of the potential IBS-C patient population; the development and commercial potential of linaclotide; and the potential effect of MD-7246 on abdominal pain in certain IBS-D patients and the design, timing and results of clinical and preclinical studies. 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 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 Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, and in our subsequent SEC filings.

¹ J Neurogastroenterol Motil. 2016 Oct; 22(4): 558–574.

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