Presentation of Highlight Results from recent Phase 3 Trials of Vonoprazan Fumarate for the Treatment of Acid-related Diseases at the DDW 2014 Meeting

May 7, 2014

Osaka, Japan, May 7, 2014 --- Takeda Pharmaceutical Company Limited (“Takeda”) announced today that the results of five Phase 3 trials for Vonoprazan Fumarate (development code:TAK-438) were presented at the poster session of Digestive Disease Week (DDW) being held May 3-6, 2014 in Chicago, Illinois.

Vonoprazan Fumarate, discovered by Takeda, belongs to a new class of acid secretion inhibitors called potassium-competitive acid blockers (P-CAB). It competitively inhibits the binding of potassium ion to H+, K+-ATPase (proton pump) in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan Fumarate has strong and sustained acid secretion inhibitory effects and shows efficacy from the early stages of dosing. Takeda submitted a New Drug Application in Japan in February 2014. These highlight results presented at DDW include the Phase 3 results that were submitted with the New Drug Application.

Takeda aims to achieve better treatment outcomes in the field of gastrointestinal diseases and is striving to meet the medical needs of more patients.

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＜A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of TAK-438 (20 mg Once-Daily) Compared to AG-1749 (Lansoprazole; LPZ) (30 mg Once-Daily) in Patients With Erosive Esophagitis (EE) (Abstract #Tu1059)＞

Objective	To evaluate the efficacy and safety of TAK-438 (20 mg Once-Daily) compared to LPZ (30 mg Once-Daily) in Japanese patients with EE
Study Design	Multicenter, randomized, double-blind, active-controlled, Phase 3 trial
Population	Patients with EE of Los Angeles Classification Grade (LA Grade) A to D
Patients	409
Description	This study consisted of 2 periods; an observation period of 3 to 7 days and a double-blind treatment period of 8 weeks. The subjects were stratified by the baseline LA Grades (A/B or C/D) and randomized in a ratio of 1:1 to receive TAK-438 20 mg or LPZ 30 mg, once daily. The subjects with endoscopically confirmed healing of EE at Week 2, 4, or 8 were regarded as having completed the study.
Primary endpoint	Proportion of healed patients at Week 8 * EE healing was defined as endoscopically confirmed Grade O (i.e. no mucosal breaks) by investigators.
Results	Efficacy ・ For the primary endpoint, the proportion of healed patients at Week 8, the non-inferiority of TAK-438 to LPZ was verified (99.0% vs. 95.5%, p＜0.0001). ・ The superiority of TAK-438 to LPZ was also verified for the proportion of healed patients at Week 8 based on the post-hoc analysis results (p=0.0337). ・ The difference in the proportion of healed patients between the 4-week treatment of TAK-438 and the 8-week treatment of LPZ (TAK-438 group – LPZ group) was 1.1% (96.6% vs. 95.5%). The lower limit of the 95% CI of the difference was above -10% (=the lower limit of the non-inferiority margin for the primary analysis), which indicated the non-inferiority of TAK-438 4W to LPZ 8W. ・ Notably, the differences in the proportion of healed patients between TAK-438 group and LPZ group were large in the subgroups of CYP2C19-EM (98.9% vs. 94.5%) and LA Grade C/D (98.7% vs. 87.5%) . Safety ・ The incidences of AEs, drug-related AEs, AEs leading to study drug discontinuation, and serious AEs were comparable between the groups. ・ Nasopharyngitis was most commonly reported TEAE in both groups (TAK-438, LPZ: 3.4%, 4.0%). The incidences of other TEAEs by PT were ≦ 2%.

＜A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of TAK-438 (10 mg or 20 mg Once-Daily) Compared to AG-1749 (Lansoprazole; LPZ) (15 mg Once-Daily) in a 24-week Maintenance Treatment in Patients With Healed Erosive Esophagitis (EE) (Abstract #Tu1052)＞

Objective	To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to LPZ (15 mg Once-Daily) in a 24-week maintenance treatment for healed EE
Study Design	Multicenter, randomized, double-blind, active-controlled, phase 3 trial
Population	Patients with EE of Los Angeles Classification Grade (LA Grade) A to D
Patients	607
Description	Subjects with EE of LA Grade A to D received TAK-438 20 mg once daily for 2, 4, or 8 weeks during the treatment period. If EE healing was confirmed, the subject was stratified by the baseline LA grade (A/B or C/D) and randomized in a ratio of 1:1:1 to receive TAK-438 in doses of 10 mg, 20 mg, or LPZ 15mg, once daily, in a 24-week maintenance period. Once EE recurrence was endoscopically confirmed, the subject discontinued the study.
Primary endpoint	Proportion with recurrence at Week 24 *EE recurrence was defined as endoscopically confirmed LA Grade A to D by investigators.
Results	Efficacy ・ For the primary endpoint, the proportion with recurrence at Week 24, the non-inferiority to LPZ was verified for both TAK-438 groups. The proportion was 16.8%, 5.1%, 2.0% in the LPZ 15 mg, TAK-438 10 mg and TAK-438 20 mg, respectively (p＜0.0001). ・ The superiority to LPZ was also verified for both TAK-438 groups for the proportion with recurrence at Week 24 based on the post-hoc analysis results. (LPZ 15 mg vs. TAK-438 10 mg: p=0.0002, LPZ 15 mg vs. TAK-438 20 mg: p＜0.0001). ・ Notably, the differences in the proportion with recurrence between each TAK-438 group and LPZ group were large in the subgroups of CYP2C19-EM (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 19.6%, 5.4%, 1.8%) and LA Grade C/D (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 39.0%, 13.2%, 4.7%). Safety ・ The incidences of AEs, drug-related AEs, AEs leading to study drug discontinuation, and serious AEs in the maintenance period were comparable among the groups. ・ Nasopharyngitis was the most commonly reported TEAE in all groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 13.9%, 16.8%, 13.2%). ・ Serum gastrin increased to the greatest degree in TAK-438 20 mg group, followed by TAK-438 10 mg group, and LPZ group. On the other hand, no obvious difference among the groups in gastric mucosa histopathologic tests were observed during the study. The increase in serum gastrin observed during the study did not cause any adverse effects on the gastric mucosa as evidenced by histopathological testing.

＜A Phase 3, Multicenter, Randomized, Double-blind, AG-1749 (Lansoprazole; LPZ) -controlled, Parallel-group, Comparison Study to Evaluate the Efficacy and Safety of TAK-438 (10 mg or 20 mg, Orally, Once Daily) for the Prevention of Recurrent Gastric or Duodenal Ulcers During Long-term Therapy of Non-steroidal Anti-inflammatory Drug (NSAID) (Abstract #Tu1054)＞

Objective	To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to LPZ (15 mg Once-Daily) for secondary prevention of peptic ulcers associated with NSAID therapy
Study Design	Multicenter, randomized, double-blind, double-dummy, non-inferiority, active-controlled Phase 3 trial
Population	Patients with a history of gastric ulcers (GU) or duodenal ulcers (DU) who require long-term NSAID therapy
Patients	642
Description	Patients receive NSAID with TAK-438 in doses of 10 mg, 20 mg, or LPZ 15 mg, once daily.
Primary Endpoint	The proportion of patients with recurrent GU or DU confirmed with endoscopy at Week 24.
Secondary Endpoints	The proportion of patients with the development of hemorrhagic lesion confirmed with endoscopy in stomach or duodenum
Exploratory Analysis	Time to event of ulcer recurrence or hemorrhagic lesion occurrence in stomach or duodenum
Results	Efficacy ・ At Week 24, non-inferiority of TAK-438 10 mg and 20 mg to LPZ 15 mg was verified for the proportion of patients with recurrent peptic ulcers (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 5.5%, 3.3%, 3.4% : p＜0.0001 vs. LPZ 15 mg). The proportion of patients with recurrent peptic ulcers in the TAK-438 10 mg and 20 mg through week 24 was slightly lower than in the LPZ 15 mg, although no statistically significant differences were observed. ・ The proportion of patients with the development of hemorrhagic lesion in stomach or duodenum was slightly lower in each TAK-438 group than in LPZ 15 mg through 24 weeks, but no statistically significant differences were observed (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg at Week 24 : 2.0%, 1.4%, 1.0%). The proportion of cumulative incidences of GU/DU or hemorrhagic lesion was lower in each TAK-438 group than in LPZ 15 mg group. Safety ・ The incidence of treatment emergent adverse events (TEAEs) was almost similar across the treatment groups. ・ The most commonly reported TEAE was nasopharyngitis in all the treatment groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 18.6%, 22.9%, 18.4%). ・ Serum gastrin of patients in each TAK-438 group was higher compared to that in LPZ 15 mg group, and degree of increase was dose-dependent. Serum gastrin increased at Week 4 in all treatment groups, no obvious increasing tendency was observed thereafter, and it was almost stable until Week 24.

Objective	To evaluate the efficacy and safety of TAK-438 (10 mg or 20 mg Once-Daily) compared to Lansoprazole (LPZ) (15 mg Once-Daily) for secondary prevention of peptic ulcers associated with LDA therapy
Study Design	Multicenter, randomized, double-blind, double-dummy, non-inferiority, active-controlled phase 3 trial
Population	Patients with a history of gastric ulcers (GU) or duodenal ulcers (DU) who require long-term LDA therapy
Patients	621
Description	Patients receive LDA with TAK-438 in doses of 10 mg, 20 mg, or Lansoprazol (LPZ) 15 mg, once daily.
Primary Endpoint	The proportion of patients with recurrent GU or DU confirmed with endoscopy at Week 24
Secondary Endpoints	The proportion of patients with the development of hemorrhagic lesion confirmed with endoscopy in stomach or duodenum
Exploratory Analysis	Time to event of ulcer recurrence or hemorrhagic lesion occurrence in stomach or duodenum
Results	Efficacy ・ At Week 24, non-inferiority of TAK-438 10 mg and 20 mg to LPZ 15 mg was verified for the proportion of patients with recurrent peptic ulcers (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 2.8%, 0.5%, 1.5% : p＜0.0001 vs. LPZ 15 mg). The proportion of patients with recurrent peptic ulcers in the TAK-438 10 mg and 20 mg through 24 weeks was slightly lower than in the LPZ 15 mg, although no statistically significant differences were observed. ・ The proportion of patients with the development of hemorrhagic lesion in stomach or duodenum was significantly lower in each TAK-438 groups than in LPZ 15 mg through 24 weeks, and higher prevention effect on hemorrhagic lesion was observed (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg at Week 24 : 2.9%, 0.0%, 0.0% : p=0.0129 vs. LPZ 15 mg). ・ The proportion of cumulative incidences of GU/DU or hemorrhagic lesion at Week 24 was lower in each TAK-438 group than in LPZ 15 mg group, and statistically significant differences were observed (p=0.0066: TAK-438 10 mg vs. LPZ 15 mg, p=0.0471: TAK-438 20 mg vs. LPZ 15 mg). Safety ・ The incidence of treatment emergent adverse events (TEAEs) was almost similar across the treatment groups. ・ The mostly commonly reported TEAE was nasopharyngitis in all the treatment groups (LPZ 15 mg, TAK-438 10 mg, TAK-438 20 mg: 17.1%, 14.9%, 20.3%). ・ Serum gastrin of patients in each TAK-438 group was higher compared to that in LPZ 15 mg group, and degree of increase was dose-dependent. Serum gastrin increased at Week 4 in all treatment groups, no obvious increasing tendency was observed thereafter, and it was almost stable until Week 24.

＜A Phase 3, Randomized, Double-Blind, Double Dummy, Multicenter, Parallel Group Comparison Study to Evaluate Efficacy and Safety of a Triple Therapy With TAK-438, Amoxicillin (AMPC) and Clarithromycin (CAM) by Comparison With a Triple Therapy With AG-1749 (Lansoprazole; LPZ), AMPC and CAM for the First Line Eradication of H.Pylori (Abstract#Tu1056)＞

Objective	To evaluate the efficacy and safety of a Triple Therapy with TAK-438, AMPC, and CAM as First Line Eradication of H. pylori and a Triple Therapy with TAK-438, AMPC, and Metronidazole (MNDZ) as Second Line Eradication of H. pylori
Study Design	Multicenter, randomized, double-blind, active-controlled, phase 3 trial
Population	H. pylori-positive patients with cicatrized gastric or duodenal ulcer
Patients	650
Description	650 eligible subjects were randomly allocated at a 1:1:1:1 ratio to receive one of four 7-day courses as the first line therapy; TAK-438 (20 mg b.i.d.), AMPC (750 mg b.i.d.) and CAM (200 mg b.i.d. or 400 mg b.i.d.), or LPZ (30 mg b.i.d.), AMPC (750 mg b.i.d.) and CAM (200 mg b.i.d. or 400 mg b.i.d.). 50 of 101 subjects for whom the first line eradication had failed in this study received additional 7-day course of TAK-438 (20 mg b.i.d.), AMPC (750 mg b.i.d.) and MNDZ (250 mg b.i.d.) as the second line therapy. More than 4 weeks after the treatment, eradication was evaluated by using ¹³C urea breath test.
Primary Endpoint	H. pylori eradication rate with the first line therapy
Secondary Endpoint	H. pylori eradication rate with the second line therapy
Results	Efficacy ・ In the analysis of primary endpoint, H. pylori eradication rate, the non-inferiority of the first line therapy with TAK-438 to that with LPZ was verified using the Farrington and Manning test with a non-inferiority margin of 10% (Eradication rate: with TAK-438: 92.6% [300/324], with LPZ: 75.9% [243/320], p < 0.0001). Based on the additional analysis, the superiority of the first line therapy with TAK-438 to that with LPZ was confirmed (p < 0.0001). In the subjects who were treated by the second line therapy with TAK-438, the H. pylori eradication rate was also high (98.0% [49/50]). ・ The H. pylori eradication rates were significantly higher in the first line therapy with TAK-438 than that with LPZ in the subjects with EMs for CYP2C19 (with TAK-438: 92.9% [250/269], with LPZ: 75.0% [204/272]) and the subjects with a CAM MIC of ≥ 1 μg/mL, CAM resistance (with TAK-438: 82.0% [82/100], with LPZ: 40.0% [46/115]). The doses of CAM did not affect the H. pylori eradication rate with the first line therapy (200 mg b.i.d: with TAK-438: 93.3% [152/163], with LPZ: 78.7% [129/164], 400 mg b.i.d : with TAK-438: 91.9% [148/161], with LPZ: 73.1% [114/156]). Safety ・ In the first line therapies, the overall incidences of Treatment-Emergent Adverse Events (TEAEs), drug-related TEAEs, TEAEs leading to study drug discontinuation and serious TEAEs were comparable between both therapies. In the second line therapy, those were similar to those of the first line therapies. ・ The TEAEs with ≥ 2% incidence were diarrhoea, nasopharyngitis, and dysgeusia in both of the first line therapies (LPZ 15 mg,: 15.3%, 4.7%, 3.1%, TAK-438: 12.5%, 5.5%, 4.0%). No remarkable differences between both therapies were observed in the incidences of TEAEs by Preferred Term. The incidence of dysgeusia seemed to be related to daily CAM dose. The TEAEs reported in 2 subjects treated by the second line therapy with TAK-438 were diarrhoea (4.0%), flatulence (4.0%), nasopharyngitis (4.0%), ALT increased (4.0%), and AST increased (4.0%) ・ Serious TEAEs were reported from 6 subjects in the first line therapies and 1 subject in the second line therapy. In the first line therapy with TAK-438, 1 serious TEAE, acute myocardial infarction, was assessed as related to the study drug. All the other serious TEAEs in the first line therapies and all the serious TEAEs in the second line therapy were assessed as not related to the study drug by the investigators.