Summary of results. Name of the sponsor. Name of the finished product Name of active ingredient Title of the study

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1 Summary of results Name of the sponsor Name of the finished product Name of active ingredient Title of the study Study centers: Related publications Study period (Date of obtaining first subject s informed consent - Date of completing the study treatment in the last subject) Phase of development: Objective of the study Method of the study Number of subjects (planned and analyzed) Main entrance criteria Ajinomoto Pharmaceutical Co., Ltd. Takeda Pharmaceutical Company Limited. NE mg tablet Sodium risedronate hydrate (JAN) Phase 3, double-blind comparative study of NE (once-monthly formulation) comparison of once monthly (75 mg) and once daily (2.5 mg) administration 60 centers Bone February 8, 2010 to August 25, 2011 Phase III The purpose of this study is to evaluate the efficacy and safety of NE mg tablets administered orally once monthly for 12 months compared to NE mg tablets administered orally once daily for 12 months as the control, in patients with involutional osteoporosis. Using mean lumbar BMD (L 2-4 BMD) determined by dual energy X-ray absorptiometry (DXA) as the primary endpoint, the study will confirm that a 75-mg once-monthly treatment regimen is not clinically inferior to a 2.5-mg once-daily treatment regimen. Multi-Center, Randomized, Double-Blind study <At the time of planning> Number of enrolled subjects: 800 (400 subjects/group) Number of evaluable subjects: 646 (323 subjects/group) <At the time of analysis> Number of Randomaized subjects: 852 subjects Full analysis set (FAS) : 850 subjects Per protocol set (PPS) : 711 subjects Safety analysis set: 850 subjects <Subjects> Patients with involutional osteoporosis <Main inclusion criteria> 1

2 Test product, dose and mode of administration, and batch number 1) Aged 50 yrs at the time of informed consent 2) In the case of female patients, women who are at least 2 years postmenopausal ( 2 yrs since last period) 3) Ambulatory patients <Main exclusion criteria> 1) Patients with secondary osteoporosis 2) Patients with diseases other than secondary osteoporosis who present with decreased bone mass 3) Patients with any of the ovserbation which may affect the evaluation of mean lumbar bone mineral density by DXA 4) Patients who are unable to maintain an upright position (standing or sitting) for at least 30 min after taking the study drug 5) Patients with a history of lumbar or pelvic radiotherapy 6) Patients with a drug allergy to bisphosphonate or calcium preparations 7) Patients who plan to undergo surgical dental treatment (including implants) such as tooth extraction during the treatment period 8) Patients with a history of bisphosphonate use within 24 weeks prior to commencement of the treatment period 9) Patients who have received treatment with any of the drugs which may affect bone metabolism within 8 weeks prior to commencement of the treatment period 10) Patients with hypocalcemia 11) Patients with hypercalcemia 12) Patients with serious renal disease, hepatic disease, or cardiac disease [Test product] NE mg tablets and placebo tablets, which were indistinguishable in appearance from each other, were administered on the day after the initial prescription, and once monthly thereafter on the anniversary date of the first administered dose (same date each month). [Contrast product] NE mg tablets and placebo tablets, which were indistinguishable in appearance from each other, were 2

3 Duration of Treatment Endpoint Statistical Methods administered once daily from the day after the initial prescription. <Lot No.>DB months <Primary endpoint> Mean percent change from baseline in lumbar vertebrae L 2-4 BMD measured using DXA at the end of the study (Month 12 with the last observation carried forward, hereafter referred to as M12, LOCF) <Secondary endpoints> Biochemical markers of bone metabolism Evaluation index:mean percent change from baseline at each evaluation point and the end of the study Frequency of vertebral fractures Evaluation index: Frequency of non-traumatic vertebral fractures in treatment period <Safety endpoints> Adverse events <Primary endpoint> Mean percent change from baseline in L 2-4 BMD at the end of the study (M12, LOCF) A non-inferiority t-test (non-inferiority margin Δ= 1.5%) was performed as the primary analysis, to compare the primary endpoint between the 75 mg once-monthly group and the 2.5 mg once-daily group in FAS. <Secondary endpoints> The following analyses were performed using the FAS. 1) Biochemical markers of bone metabolism: Bone formation markers(serum BAP), Bone resorption markers (serum TRACP-5b, urinary DPD/CRN, urinary NTX/CRN, urinary CTX/CRN) Summary statistics for the percent change from baseline at each evaluation point was calculated and 95% confidence intervals (2-sided) of the mean values were calculated by treatment group. The time course of changes in the means and standard deviations was displayed as a graph. 3

4 Summary of Results 2) Frequency of vertebral fractures Based on results of the central commitee, vertebral fractures (including/excluding worsening of existing fractures) were also examined at the end of the study (M12, LOCF) by calculating the frequency. The 95% confidence intervals (2-sided) for the freaquency of the new vertebral fractures were calculated by treatment group and for the differences between treatment groups. <Safety endpoints> 1) Adverse events A treatment emergent AE (TEAE) was defined as any event not present prior to the initiation of treatment or any symptom or pretreatment event that worsens following exposure to the treatment. The incidence of the TEAEs were tabulated for each treatment group. <Summary of efficacy> (1) Primary endpoints Mean percent change from baseline in L 2 -L 4 BMD at the end of the study (M12, LOCF) About the mean percent change from baseline in L 2 -L 4 BMD at the end of the study (M12, LOCF), the 75 mg once-monthly group proved to be non-inferior to the 2.5 mg once-daily group in the non-inferiority t-test. (2) Secondary endpoints 1) Biochemical markers of bone metabolism Both groups showed a similar profile of change over time. Decreases in bone resorption markers and bone formation markers were seen after 1 and 3 months, respectively, with both markers continuing to show low levels until 12 months. 2) Frequency of new vertebral fractures The frequency of new vertebral fractures were similiar in both treatment groups. <Summary of safety> The frequency of AEs were similiar in both treatment groups. 4

5 <Conclusion> It was confirmed that the efficacy of the NE mg tablet once-monthly treatment regimen is not inferior to that of the NE mg tablet once-daily treatment regimen. In terms of safety, the tolerability is acceptable compared the once-monthly formulation to the once-daily formulation. Therefore, it was concluded that the NE mg tablet formulation is a very useful treatment for osteoporosis. Date of Report Dec 20,