Ironwood Announces Updates Designed to Strengthen IW-3718 Phase III Program for Refractory Gastroesophageal Reflux Disease (GERD)

– Changed primary endpoint to continuous from current responder endpoint, in-line with recent FDA guidance and very similar to IW-3718 Phase IIb trial –

– Conducting early assessment of IW-3718-302, one of two identical Phase III trials; expect to report outcome of assessment in 4Q 2020 –

– Ironwood to host conference call today at 8:30 a.m. Eastern Time –

BOSTON–(BUSINESS WIRE)–Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD), a leading GI-focused healthcare company, today announced that it has reached alignment with the U.S. Food and Drug Administration (FDA) on certain updates to its Phase III clinical program evaluating IW-3718 in adults with refractory gastroesophageal reflux disease (GERD). The updates are as follows:

• The primary endpoint for the two identical trials – IW-3718-301 and IW-3718-302 – has been changed from the previous responder endpoint to a continuous endpoint.
• Ironwood plans to stop enrollment of study subjects into IW-3718-302 and to conduct a blinded early assessment of efficacy in that trial; the company expects to report the outcome of this assessment in the fourth quarter of 2020.

“Following discussions with the FDA, we are making important updates that we believe will strengthen the overall Phase III program despite the enrollment delays we have seen due to the COVID-19 pandemic,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of drug development at Ironwood. “These updates are designed to maintain the scientific integrity of the trials without adding risk to the development program. (Read more…)”

“We believe IW-3718 represents an exciting opportunity, if approved, to bring a medicine to the estimated 8 to 10 million adult Americans with refractory GERD in need of treatment options for their highly bothersome symptoms of heartburn and regurgitation despite being on PPI therapy,” said Tom McCourt, president of Ironwood. “We are working with the FDA to advance IW-3718 quickly and safely, given the high unmet need in this patient population.”

Ironwood is also in discussions with the FDA regarding its request for long-term safety data for IW-3718 in refractory GERD patients. Ironwood has provided a detailed overview of the existing long-term safety data for colesevelam and is working closely with the FDA to determine whether any additional data is needed in connection with a New Drug Application (NDA) submission for IW-3718.

Ironwood’s Phase III program comprises two identical randomized, double-blind, placebo-controlled, multicenter trials of IW-3718, its gastric retentive formulation of a bile acid sequestrant, for the potential treatment of patients with refractory GERD. Patients evaluated in these trials must demonstrate evidence of pathological acid reflux. Patients enrolled in the trials continue to take proton pump inhibitors (PPIs) and are randomized to placebo or IW-3718 1500 mg twice a day for eight weeks.

Phase III Primary Endpoint

The primary endpoint for the Phase III trials is now the assessment of change from baseline to week 8 in weekly heartburn severity scores.

The original primary endpoint was an overall heartburn responder (defined as a patient who experiences at least a 45% reduction from baseline in heartburn severity for at least four out of eight weeks, including at least one of the last two weeks), which has been moved to become one of the key secondary endpoints, along with a change in weekly regurgitation frequency and the proportion of heartburn-free days.

Ironwood’s decision to change the primary endpoint was primarily based on recent FDA guidance indicating the FDA’s preference for continuous endpoints over responder endpoints. The new endpoint is very similar to the primary endpoint in the IW-3718 Phase IIb clinical trial and the previous key secondary endpoint in the Phase III trials, which both assessed percent change from baseline to week 8 in weekly heartburn severity score.

“An assessment of continuous endpoints is a rigorous method of measuring clinical response in studies evaluating compounds for GERD and other gastrointestinal conditions,” said Michael Vaezi, M.D., Ph.D., professor of medicine, division of gastroenterology and hepatology, director of the Center for Swallowing and Esophageal Disorders at Vanderbilt University Medical Center and an investigator for the studies. “Retaining the overall heartburn responder as a key secondary endpoint, combined with the other primary and key secondary endpoints, helps to elucidate whether IW-3718 could bring a clinically meaningful improvement in symptom relief to this patient population.”

Early Assessment of IW-3718-302

In line with new FDA guidance on statistical considerations for trials impacted by COVID-19, Ironwood plans to stop enrollment of study subjects into IW-3718-302 and conduct an early assessment of the data, leveraging a well-powered data set. The data is expected to remain blinded to Ironwood and be assessed by an independent data monitoring committee (IDMC) using pre-specified criteria that are consistent with certain of the study’s new primary and key secondary endpoints. Ironwood expects to report the outcome of the early assessment in the fourth quarter of 2020. IW-3718-301 is continuing to enroll patients.

Under the planned assessment, the IDMC will make a non-binding recommendation to Ironwood. If the IDMC determines the data meet all pre-specified criteria, Ironwood plans to remain blinded to the IW-3718-302 data and continue enrollment of the IW-3718-301 trial, with the goal of announcing top-line results from both trials in the first half of 2021. If the IDMC determines the data do not meet all pre-specified criteria, Ironwood plans to unblind and evaluate the data from IW-3718-302 and determine next steps for the program.

Long-Term Safety Data

The FDA requested that additional long-term safety data for IW-3718 be included in connection with a New Drug Application (NDA) submission. In response to this request, Ironwood has provided a detailed overview of the existing colesevelam long-term safety data to the FDA and is working closely with the FDA to determine whether a long-term safety study is needed to provide additional safety data with an NDA submission.

Colesevelam – the active ingredient in IW-3718 – has a demonstrated safety profile, having been used for more than two decades as a treatment for high cholesterol and with long-term safety data for up to 50 weeks. In addition, IW-3718 1500 mg was well tolerated in previous clinical trials, including the Phase IIb clinical trial. In that trial, there were no treatment-related serious adverse events reported with IW-3718 1500 mg; the most common adverse event reported overall was constipation.

Ironwood does not believe the FDA’s request is due to new safety signals with IW-3718; including long-term safety data is common practice for some therapeutic candidates being developed for long-term, chronic or repeat intermittent use. Ironwood plans to provide additional updates when it has more clarity.

Ironwood Conference Call Today at 8:30 a.m. ET:

Ironwood will host a conference call and webcast at 8:30 a.m. Eastern Time on Tuesday, July 21, 2020. Individuals interested in participating in the call should dial (833) 350-1432 (U.S. and Canada) or (647) 689-6932 (international) using conference ID number 9462189. To access the webcast, please visit the Investors section of Ironwood’s website at www.ironwoodpharma.com at least 15 minutes prior to the start of the call to ensure adequate time for any software downloads that may be required. The call will be available for replay via telephone starting at approximately 11:30 a.m. Eastern Time, on July 21, 2020 running through 11:59 p.m. Eastern Time on August 4, 2020. To listen to the replay, dial (800) 585-8367 (U.S. and Canada) or (416) 621-4642 (international) using conference ID number 9462189. The archived webcast will be available on Ironwood’s website for 14 days beginning approximately one hour after the call has completed.

About IW-3718

IW-3718 is a novel, gastric-retentive investigational formulation of colesevelam, a bile-acid sequestrant, developed by Ironwood using the proprietary Acuform® drug delivery formulation technology licensed from Assertio Therapeutics, Inc. IW-3718 is designed to maintain the bile-acid sequestrant in the stomach over an extended period of time where it is positioned to intercept bile before it reaches the esophagus. Data from non-clinical and clinical studies collectively support the extended release and gastric-retentive profile of IW-3718.

About Refractory Gastroesophageal Reflux Disease (GERD)

An estimated 8 to 10 million adult Americans and more than 60 million adults globally suffer from refractory gastroesophageal reflux disease (GERD), meaning they continue to experience symptoms such as heartburn and regurgitation despite receiving treatment with a proton pump inhibitor (PPI). One of the largest and most diverse population-based surveys on gastrointestinal symptoms found that more than half (54.1 percent) of GERD patients taking PPIs still reported persistent symptoms.¹ While PPIs suppress production of stomach acid, Ironwood’s clinical research demonstrates that reflux of bile from the intestine into the stomach and esophagus may play a key role in the ongoing symptoms of refractory GERD. There are no FDA-approved treatment options for these patients.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD) is a GI-focused healthcare company dedicated to creating medicines that make a difference for patients living with GI diseases. We discovered, developed and are commercializing linaclotide, the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). We are also advancing IW-3718, a gastric retentive formulation of a bile acid sequestrant being developed for the potential treatment of refractory gastroesophageal reflux disease. IW-3718 is first-in-category product candidate currently in Phase III clinical trials.

Ironwood was founded in 1998 and is headquartered in Boston, Mass. For more information, please visit our website at www.ironwoodpharma.com or www.twitter.com/ironwoodpharma; information that may be important to investors will be routinely posted in both these locations.

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 our plans to stop enrollment of study subjects into IW-3718-302 and conduct an early assessment of efficacy in that trial, including the IDMC assessment of the trial data, the timing of receipt of outcomes of such assessment, and the nature of the recommendation; next steps for the IW-3718 trial following receipt of the IDMC’s non-binding recommendation; the scientific integrity, risk profile and power of, and our ability to expeditiously and efficiently advance, the IW-3718 program; the potential use of, and demand for, IW-3718; the anticipated timing of clinical developments and the timing and top-line results of the IW-3718 Phase III trials, including due to the impacts of the COVID-19 pandemic and the recommendation of the IDMC evaluating IW-3718-302; the outcome of our discussions with the FDA regarding potentially including long-term safety data as part of an NDA and whether a long-term safety study is needed to provide additional safety data with an NDA submission; our ability to continue enrolling patients in IW-3718-301; the safety and tolerability of IW-3718; the size of the potential refractory GERD population. These forward-looking statements (except as otherwise noted) 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 safety, efficacy and tolerability of IW-3718; the effectiveness and timing of our development efforts; the risk that our clinical programs, studies and development plans may not progress or develop as anticipated, including that studies are delayed or discontinued, or that regulatory submissions are delayed, for any reason, such as safety, tolerability, enrollment, manufacturing, economic or other reasons, including due to the impacts of the COVID-19 pandemic; the risk that findings from our completed nonclinical and clinical studies may not be replicated in the IW-3718-301 and IW-3718-302 studies, our interpretation of the results of those studies are not shared by the FDA or the results of those studies are not consistent; the risk that the therapeutic opportunities IW-3718 are not as we expect; decisions by regulatory and judicial authorities, including the FDA changing its views; the risk that we may never get sufficient patent protection for IW-3718, that patents may not provide adequate protection from competition, or that we are not able to successfully protect such patents; the risk that financial and operating results may differ from our projections; 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; 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, 2020 and in our subsequent SEC filings. In addition, the COVID-19 pandemic and the associated containment efforts have had a serious adverse impact on the economy, the severity and duration of which are uncertain. Government stabilization efforts will only partially mitigate the consequences. The extent and duration of the impact on our business and operations is highly uncertain. Factors that will influence the impact on our business, operations and financial results include the duration and extent of the pandemic, the extent of imposed or recommended containment and mitigation measures, and the general economic consequences of the pandemic. The pandemic could have a material adverse impact on our business, operations and financial results for an extended period of time.

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¹ Delshad, S.D., Almario, C.V., Chey, W.D. & Spiegel, BMR. (2019). Prevalence of Gastroesophageal Reflux Disease and Proton Pump Inhibitor-Refractory Symptoms. Gastroenterology. S0016-5085(19)41941-0.

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