First-Ever U.S. Pivotal Phase 3 Clinical Study in Eosinophilic Esophagitis (EoE) Completes: Takeda's Investigational Therapy Meets Co-Primary & Key Secondary Efficacy Endpoints

LEXINGTON, Mass., Oct. 28, 2019 /PRNewswire/ -- Takeda Pharmaceuticals U.S.A., Inc., ("Takeda") (TSE:4502/NYSE:TAK) announced today that Budesonide Oral Suspension (BOS), its investigational therapy for the treatment of eosinophilic esophagitis (EoE), achieved co-primary and key secondary efficacy outcomes with statistical significance compared to placebo in the first of two pivotal Phase 3 studies. Positive results on clinical endpoints were presented from a randomized, double-blind, placebo-controlled trial that investigated the safety and efficacy of BOS over 12 weeks of treatment among adolescent and adult patients aged 11 to 55.¹ This is the first pivotal Phase 3 study investigating an EoE treatment ever to be reported in the United States (U.S.)² and is the largest EoE clinical trial program conducted to date, globally.^3,4 Results on histologic, symptomatic and endoscopic endpoints were presented today during a Presidential Plenary Session of the 2019 American College of Gastroenterology Annual Scientific Meeting (Oct 25-30, San Antonio, TX).¹ BOS is an investigational, novel mucoadherent topical corticosteroid formulation being evaluated in the United States for the treatment of EoE in adolescents and adults.

"I am very much looking forward to presenting positive results on the clinical endpoints of this Phase 3 trial of Budesonide Oral Suspension, the first U.S. Phase 3 study in patients with EoE to assess histologic, dysphagia, and endoscopic response to a medical treatment," said Ikuo Hirano, MD, Professor of Medicine, Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine. "Patients with EoE have long suffered with dysphagia and esophageal inflammation in the absence of an FDA-approved treatment. The results from this Phase 3 study of a medication specifically designed for esophageal delivery in EoE are promising in addressing an unmet need in the management of EoE."

EoE is a rare,⁵ chronic immune-mediated disease of the esophagus that occurs when eosinophils accumulate in the esophagus, resulting in inflammation.⁶ It is estimated that approximately 1 in 2,000 people in the U.S. has EoE.⁷ Children, adolescents and adults with EoE can experience difficulty eating and/or swallowing, potentially resulting in discomfort and pain.⁸ EoE that is uncontrolled can lead to esophageal remodeling and fibrosis, resulting in dysmotility and/or food impaction.⁹ 

In this clinical study, patients aged 11 to 55 years with EoE and dysphagia were randomized 2:1 to receive 2.0 mg BOS or placebo twice daily for 12 weeks. Following a placebo lead-in period of up to six weeks, a total of 318 patients received at least one dose of double-blind therapy (BOS, n=213; placebo, n=105). The co-primary efficacy endpoints of this study were histologic response and dysphagia symptom response after an initial 12 weeks of therapy. Histologic response was measured as having a peak eosinophil count less than or equal to six eosinophils per high-powered field, and dysphagia symptom response was measured as a greater than or equal to 30 percent reduction from baseline to final treatment as assessed by the Dysphagia Symptom Questionnaire (DSQ), a patient-reported outcome measurement tool. The key secondary efficacy endpoint included change in DSQ score from baseline to final treatment. Additionally, the change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period was evaluated as a secondary endpoint. The clinical trial also evaluated the safety of BOS, including measuring the number and types of adverse events. The majority of treatment-emergent adverse events (TEAEs) were mild to moderate in severity and similar between the BOS- and placebo-treated groups. This is the first of two pivotal Phase 3 studies; the findings presented during ACG reflect aggregate data only because the second Phase 3 double-blind, placebo-controlled maintenance study is ongoing.¹ 

The BOS clinical development program is the first U.S. pivotal Phase 3 program investigating a treatment for EOE based on U.S. Food and Drug Administration (FDA) guidance. The program assesses safety and efficacy in patients with EoE during both an initial 12 weeks of treatment and for a longer duration in the ongoing extension study.^2,10,11,12 In parallel with the BOS Phase 2 clinical studies, the DSQ was developed and validated as part of the BOS program. The DSQ met FDA guidelines for use in the registration trials in EoE, and the DSQ is now an established tool in this field of clinical study.^13,14,15,16

"We are deeply committed to bringing EoE-specific clinical evidence to patients and providers, and driving further awareness to the needs of this community. We consider the results of this scientifically rigorous study an important step toward a more data-driven treatment approach for patients with EoE," said Debra Silberg, MD, PhD, FACG, Vice President, Clinical Science Head GI, Takeda. "We are focused on the continued investigation of BOS as a potential treatment option for this community and look forward to sharing further study data."

Study results found significantly more histologic responders and dysphagia symptom responders in the BOS-treated group versus the placebo-treated group (53.1% vs 1.0%, P< .001; 52.6% vs 39.1%, P=.024, respectively). Improvements in mean DSQ score from baseline to week 12 were also significantly greater in the BOS group (n=197) than the placebo group (n=89) (−13.0 vs −9.1; P=.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n=202) than placebo (n=93) (−4.0 vs −2.2; P< .001).¹ 

In total, 61.0 percent (194/318) of patients reported a TEAE [BOS, 61.0% (130/213); placebo, 61.0% (64/105)], with 2.5 percent of patients experiencing a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). TEAEs that affected 2 percent or more of the patients in either the placebo or BOS arm of the study included nasopharyngitis, sinusitis, esophageal candidiasis, oral candidiasis and upper respiratory tract infection. TEAEs of candidiasis such as oral or esophageal candidiasis were seen in fewer than 5 percent of patients overall and in either treatment group. Rates of individual TEAEs such as oral candidiasis cannot yet be disclosed by treatment group until the maintenance study completes. There were no life-threatening TEAEs or deaths reported.¹

The complete abstract, as well as three additional Takeda-sponsored EoE-related abstracts being presented during ACG, can be accessed via: https://www.eventscribe.com/2019/ACG/agenda.asp?pfp=full.

Presentations include:

• "Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results from a Phase 3, Randomized, Placebo-Controlled Trial": Oral presentation, Presidential Plenary Session 1, Monday, October 28, 8:00-8:12am¹
• "Healthcare Resource Utilization in the 12 Months After Diagnosis in Patients with Eosinophilic Esophagitis Compared with a Matched Cohort" (P1176): Poster presentation, Monday, October 28, 1:00-2:15pm¹⁷
• "Baseline Characterization of Patients with Eosinophilic Esophagitis (EoE) using the EoE Histology Scoring System and Correlations With Endoscopic and Symptom Outcomes: Analyses From a Randomized, Placebo-Controlled Trial" (P1161): Poster presentation, Monday, October 28, 1:00–2:15pm¹⁸
• "A pharmacokinetic bridging study to compare the bioavailability of budesonide between budesonide oral suspension and ENTOCORT EC in healthy subjects" (P2107): Poster presentation, Tuesday, October 29, 1:00–2:15pm¹⁹

About TAK-721 (formerly SHP621) Budesonide Oral Suspension (or BOS)  
Budesonide Oral Suspension (BOS) is a topically active, oral viscous formulation of budesonide, formulated specifically as an investigational treatment for Eosinophilic Esophagitis (EoE).²⁰ In May of 2016, the U.S. FDA granted Breakthrough Therapy Designation for BOS for the treatment of EoE following results from a Phase 2 trial in adolescents and adults (aged 11 to 40) with EoE. The co-primary endpoints of the Phase 2 trial were met and, compared with placebo, 12 weeks of BOS treatment significantly achieved higher proportion of subjects with histologic response (less than or equal to 6 eos/hpf) and reduced dysphagia symptoms as measured by the DSQ. In the Phase 2 trial, a similar percentage of subjects across the treatment groups experienced at least 1 TEAE. One subject on BOS developed oral candidiasis and 1 developed esophageal candidiasis.²¹

The Phase 3 clinical trial program investigating BOS in adolescents and adults with EoE (aged 11 to 55 years) was initiated in 2015.¹¹ BOS received Orphan Drug Designation from the FDA in December, 2006.

TAK-721 is an investigational treatment and has not been approved for use by the U.S. Food and Drug Administration or other regulatory authorities. Neither Breakthrough Therapy Designation nor Orphan Drug Designation guarantee approval or commercial availability.

About Eosinophilic Esophagitis (EoE)
Eosinophilic Esophagitis (EoE) is a chronic, rare disease that has been increasingly recognized over the past decade. Although the exact cause of EoE is unknown, it is believed to be triggered by a variety of stimuli including certain foods and environmental allergens. In severe cases, it can lead to strictures causing food impaction (food getting stuck in the esophagus). Currently, there are no FDA approved therapeutic options specifically indicated for the treatment of EoE. Current guidelines for EoE recommend the elimination of targeted food from patient diets, the use of proton pump inhibitors and/or treatment with topical corticosteroid formulations.⁸ 

Takeda's Commitment to Gastroenterology
Gastrointestinal (GI) diseases can be complex, debilitating and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for more than 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies.

About Takeda in the United States
Takeda has maintained a strong and growing commitment to the United States for more than 50 years. On January 8, 2019, Takeda completed its acquisition of Shire, PLC, becoming a global, values-based, R&D-driven biopharmaceutical leader. In the U.S., Takeda employs more than 18,000 employees across multiple business units, and as of August 2019, is headquartered out of the greater Boston area. Additionally, Takeda also has a research facility in San Diego, California, specialty products manufacturing facilities in Brooklyn Park, Minnesota and plasma fractionation manufacturing facilities in Covington, Georgia.

As one of the world's leading biopharmaceutical companies, Takeda is committed to bringing Better Health and a Brighter Future to people worldwide. We aspire to bring our leadership in translating science into life-changing medicines to the next level, in our core focus areas; oncology, gastroenterology, neuroscience, rare diseases, plasma-derived therapies, and vaccines.

Important Notice
For the purposes of this notice, "press release" means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited ("Takeda") regarding this press release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.

The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, "Takeda" is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words "we", "us" and "our" are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.

Forward-Looking Statements
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda's future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as "targets", "plans", "believes", "hopes", "continues", "expects", "aims", "intends", "ensures", "will", "may", "should", "would", "could" "anticipates", "estimates", "projects" or similar expressions or the negative thereof. Forward-looking statements in this document are based on Takeda's estimates and assumptions only as of the date hereof. Such forward-looking statements do not represent any guarantee by Takeda or its management of future performance and involve known and unknown risks, uncertainties and other factors, including but not limited to: the economic circumstances surrounding Takeda's global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the timing and impact of post-merger integration efforts with acquired companies; and the ability to divest assets that are not core to Takeda's operations and the timing of any such divestment(s), any of which may cause Takeda's actual results, performance, achievements or financial position to be materially different from any future results, performance, achievements or financial position expressed or implied by such forward-looking statements. For more information on these and other factors which may affect Takeda's results, performance, achievements, or financial position, see "Item 3. Key Information—D. Risk Factors" in Takeda's most recent Annual Report on Form 20-F and Takeda's other reports filed with the U.S. Securities and Exchange Commission, available on Takeda's website at: https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov. Future results, performance, achievements or financial position of Takeda could differ materially from those expressed in or implied by the forward-looking statements. Persons receiving this press release should not rely unduly on any forward-looking statements. Takeda undertakes no obligation to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results of Takeda in this press release may not be indicative of, and are not an estimate, forecast or projection of Takeda's future results.

Media contacts:                                                       
For U.S. media
Amy McCarthy
[email protected]
+1 781.496.7761  

References

¹ Hirano et al. Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results from a Phase 3, Randomized, Placebo-Controlled Trial. Presented during American College of Gastroenterology Annual Meeting, October 28, 2019.

² U.S. National Library of Medicine. Phase 3 Eosinophilic Esophagitis Clinical Studies in United States. Available at: https://clinicaltrials.gov/ct2/results?cond=Eosinophilic+Esophagitis&Search=Apply&recrs=a&recrs=e&recrs=m&age_v=&gndr=&type=Intr&rslt=&phase=2&fund=2. Accessed September 23, 2019.

³ U.S. National Library of Medicine. Eosinophilic Esophagitis Clinical Studies. Available at: https://clinicaltrials.gov/ct2/results?cond=Eosinophilic+Esophagitis&flds=aby&recrs=a&recrs=e&recrs=m&age_v=&gndr=&type=Intr&rslt=&fund=2&Search=Apply. Accessed September 23, 2019.

⁴ EU Clinical Trials Register. Eosinophilic Esophagitis Clinical Studies. Available at: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eosinophilic+esophagitis. Accessed September 23, 2019.

⁵ NIH FAQs about Rare Diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed September 23, 2019.

⁶ Dellon ES. Eosinophilic Esophagitis. Gastroenterol Clin North Am. 2013;42(1):133-153.

⁷ Dellon ES, et al. Prevalence of Eosinophilic Esophagitis in the United States. Clin Gastroenterol Hepatol. 2014;12(4):589-596.

⁸ American Partnership for Eosinophilic Disorders. EoE. 2006-2019. Available at: https://apfed.org/about-ead/egids/eoe/. Accessed September 11, 2019.

⁹ O'Shea et al. Pathophysiology of eosinophilic esophagitis. Gastroenterology. 2018 January; 154(2): 333–345.

¹⁰ U.S. Food and Drug Administration Center for Drug Evaluation and Research. Eosinophilic Esophagitis: Developing Drugs for Treatment Guidance for Industry. February 2019. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=2ahUKEwjL_aDqhovlAhVjmuAKHVNZAhcQFjAAegQIBBAB&url=https%3A%2F%2Fwww.fda.gov%2Fregulatory-information%2Fsearch-fda-guidance-documents%2Feosinophilic-esophagitis-developing-drugs-treatment-guidance-industry&usg=AOvVaw0LJ7v5xgu_4wbmhamMOWXr. Accessed October 7, 2019.

¹¹ U.S. National Library of Medicine. A Study in Adolescents and Adults with Eosinophilic Esophagitis (EoE) Measuring Histologic Response and Determine if Reduction in Dysphagia is Achieved. Available at: https://clinicaltrials.gov/ct2/show/NCT02605837?cond=budesonide+oral+suspension&phase=2&rank=3. Accessed September 23, 2019.

¹² U.S. National Library of Medicine. An Extension Study to Evaluate Maintenance of Efficacy and Long-term Treatment Effect of Oral Budesonide Suspension (BOS) in Adults and Adolescents With Eosinophilic Esophagitis (EoE). Available at: https://clinicaltrials.gov/ct2/show/NCT02736409?cond=budesonide+oral+suspension&rank=2. Accessed October 7, 2019.

¹³ Shah et al. Managing eosinophilic esophagitis: challenges and solutions. Clinical and Experimental Gastroenterology 2016:9 281–290.

¹⁴ Hudgens et al. Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension. Journal of Patient-Reported Outcomes. 2017. 1:3.

¹⁵ U.S. National Library of Medicine. Study to Determine the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE). Available at: https://clinicaltrials.gov/ct2/show/NCT03633617?cond=dupilumab+eosinophilic+esophagitis&rank=2. Accessed October 7, 2019.

¹⁶ U.S. National Library of Medicine. Budesonide Versus Fluticasone for Treatment of Eosinophilic Esophagitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02019758?cond=budesonide+fluticasone+eosinophilic+esophagitis&rank=1. Accessed October 7, 2019.

¹⁷ Goodwin B. Healthcare Resource Utilization in the 12 Months After Diagnosis in Patients with Eosinophilic Esophagitis Compared with a Matched Cohort. Presented during American College of Gastroenterology Annual Meeting, October 28, 2019.               

¹⁸ Collins MH et al. Baseline Characterization of Patients with Eosinophilic Esophagitis (EoE) using the EoE Histology Scoring System and Correlations With Endoscopic and Symptom Outcomes: Analyses From a Randomized, Placebo-Controlled Trial. Presented during American College of Gastroenterology Annual Meeting, October 28, 2019.

¹⁹ Song, Ivy. A pharmacokinetic bridging study to compare the bioavailability of budesonide between budesonide oral suspension and ENTOCORT EC in healthy subjects. Presented during American College of Gastroenterology Annual Meeting, October 29, 2019.

²⁰ Dellon ES, et al. Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2019;17:666–673.

²¹ Shire Press Release. Shire Receives FDA Breakthrough Therapy Designation for SHP621 and SHP625, Investigational Products for Rare Gastrointestinal Conditions. June 13, 2016. Available at: https://www.shire.com/en/newsroom/2016/june/13-06-2016-shire-receives-fda-breakthrough-therapy-designation. Accessed September 23, 2019.

SOURCE Takeda Pharmaceuticals U.S.A., Inc.

Related Links

https://www.takeda.com