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R&D strategy Director & Corporate Officer Development Headquarters Ken-ichi Yanagisawa November 7, 2006 0 Development Pipeline Status 1 1 Development status of new products - NDA filed Product (Generic name) Remicade (Infliximab) Maintate (Bisoprolol) Anti-TNFα monoclonal antibody (Behcet’s disease) Selective β1 antagonist (Chronic heart failure) In-house Origin: Centocor In-house Origin: E.Merck Modiodal (Modafinil) Psychoneurotic agent (Narcolepsy) Alfresa Pharma Talion (Bepotastine) Anti-allergic agent (Orally disintegrating tablet) Category (Indications) Development In-house 2 In most advanced stage, we have 4 products NDA filed. Remicade for behcet’s disease, Modiodal for narcolepsy, and Talion for orally disintegrating tablet are expected to obtain approval within the current fiscal year. 2 Development status of new products – Phase III Product (Generic name) Gastrom (Ecabet) Remicade (Infliximab) Remicade (Infliximab) Remicade (Infliximab) Remicade (Infliximab) Category (Indications) Stage Japan EU/US Gastrointestinal mucus protecting agent (Ulcerative colitis) Anti-TNFα monoclonal antibody (Crohn’s disease, maintenance) Anti-TNFα monoclonal antibody (RA, dose escalation) Anti-TNFα monoclonal antibody (Ulcerative Colitis) Anti-TNFα monoclonal antibody (Psoriasis) III II (US) III III III III Development JP:In-house US: Tanabe AAI LLC In-house Origin: Centocor In-house Origin: Centocor In-house Origin: Centocor In-house Origin: Centocor Blue: Stage changed since FY2005 3 Blue letter expresses having changed since FY2005. In Phase III clinical trial stage, Remicade/ crohn’s disease, maintenance therapy, phase III clinical trial was completed and being under preparation for NDA filing. Remicade/ RA for dose escalation, phase III is in progress aiming NDA filing in the next year. Remicade/ ulcerative colitis and psoriasis, phase III has started. Remicade/ ankylosing spondyltis, being prepared phase III and waiting for starting 3 Development status of new products– Phase III Product (Generic name) TA-8317 APTA-2217 (Roflumilast) Category (Indications) Stage Japan EU/US Narcotic analgesic (breakthrough cancer pain) PDEIV inhibitor (asthma) II/III PDEIV inhibitor (COPD) II/III III Development In-house Origin: Cephalon Co-development with Altana Pharma Blue: Stage changed since FY2005 4 TA-8317, narcotic analgesic for breakthrough cancer pain, phase II ended and phase III has started. APTA-2217, phase II/III is ongoing for both asthma and COPD. 4 Development status of new products– Phase II Product Category (Indications) (Generic name) TA-6666 TA-5538 TA-1790 (Avanafil) TA-2005 (Carmoterol) T-0047 DPP-IV inhibitor (type II diabetes) NK-1 receptor antagonist (overactive bladder) PDEV inhibitor (erectile dysfunction) Long-acting β2 agonist (asthma, COPD) Cell adhesion inhibitor (MS, IBD etc.) Stage Japan EU/US I Development II (US) In-house II (EU) In-house II (US) Licensed to Vivus II (EU) Licensed to Chiesi II Licensed to GSK (EU/US)* Blue: Stage changed since FY2005 * Clinical Hold by the FDA 5 In Phase II clinical trial stage, TA-6666, DPPIV inhibitor for diabetes, is in phase II in the US, and phase I has started in Japan. TA-5538, NK-1 antagonist for overactive bladder has entered phase II in EU. T-0047 has been precautionary taken a clinical hold by the FDA because of Tysabri which is an MS biologic agent. Since Tysabri has resumed on the market, GSK is communicating with the authorities about T0047 resuming as well, expecting a conclusion within this year. 5 Development status of new products– Phase I Product Category (Indications) Stage Japan EU/US Development T-0128 DNA topoisomerase I inhibitor (cancer) I (EU) Licensed to Menarini TA-1702 BK channel opener (overactive bladder) I (US) Licensed to GSK TA-5493 p38 mapkinase inhibitor (RA, Psoriasis) I (EU) In-house Blue: Stage changed since FY2005 6 We have a new compound started phase I. The compound, TA-5493, a p38 mapkinase inhibitor, we began phase I in EU for the targeting indication of RA and Psoriasis, by ourselves, in-house development. 6 Priority Disease Areas 1. 2. 3. Cardiovascular and Metabolism Urology Immunology and Inflammation 7 In Tanabe’s Medium-Term Management plan announced in May, we focused our R&D on three disease areas. Cardiovascular and Metabolism Urology Immunology and Inflammation I explain the development status of each area. 7 Priority Therapeutic Area (CV, Metabolism) Diabetes In-house New Chemical Entities - TA-6666 (DPPIV inhibitor) Phase II is ongoing in the US Phase I start in Japan - Other NCEs (Pre-clinical) 8 In this priority area, CV and Metabolism, we facilitate producing in-house new chemical entities especially in Diabetes. TA-6666, DPPIV inhibitor is in phase II in the US and phase I started in Japan. Furthermore two development candidates with other different mechanism are now preparing for entering clinical phase. We accelerate much more prioritizing diabetes area with these compounds. 8 Priority Therapeutic Area (Urology) Overactive Bladder In-house New Chemical Entities - TA-5538 ・NK-1 receptor antagonist ・Phase II start in EU TA-1702 ・BK channel opener) ・Phase I is ongoing in the US (GSK) - 9 In urology area, In-house two NCEs with different mechanism of action are being developed targeting overactive bladder. TA-5538, NK-1 receptor antagonist, phase II started in EU. TA-1702, BK channel opener is under phase I in the US by GSK. These two compounds have different mechanisms of action from M3 antagonists which are popularly prescribed on current market. The compounds are expected to be unique compounds in efficacy and safety. 9 Priority Therapeutic Area (Immunology, Inflammation) Rheumatoid Arthritis Maximizing Remicade, In-Licensing product and In-house New chemical entity. - Remicade i.v. : Dose-escalation clinical trial CNTO 148 s.c. : In-License Methotrexate TANABE: Launch TA-5493 p.o. : Phase I start Others - Remicade: Clinical trials for other indications 10 In Immunology and Inflammation area, we focus on maximizing Remicade targeting RA and also focus on in-licensing and in-house development. In RA, Remicade dose-escalation study is cunducted in phase III. We have licensed-in CNTO148, anti-hTNFα monoclonal antibody as a s.c. injection. Newly marketed methotrexate by Tanabe is expected to produce synergistic effect on Remicade marketing promotion. Additionally orally active RA agent, TA-5493, in-house NCE, phase I has started in EU. As shown above Tanabe is working for full-line strategy in RA area. Furthermore, Remicade’s clinical trials for other indications are ongoing. 10 CNTO 148 (Golimumab) - Licensed-in from Centocor in Aug. 2006 - Humanized anti-TNFα monoclonal antibody 9 Development Status ••Co-development Co-developmentwith withJANSSEN JANSSENPharmaceutical PharmaceuticalK.K. K.K. ••Phase PhaseII ••Rheumatoid Rheumatoidarthritis arthritis ••Every Every4weeks 4weeks s.c. s.c. 11 CNTO148 (Golimumab), anti-hTNFα monoclonal antibody, was licensed-in from Centocor in Aug 2006. In Japan, Janssen pharmaceutical is implementing phase I trial and clinical trials from phase II are scheduled to be conducted jointly by Tanabe and Janssen pharmaceuticals. The products, targeting RA and other related diseases, is scheduled to be administered every 4 weeks by s.c. injection. We expect CNTO148 has a better characteristics in terms of compliance for the patient. 11 TA-5493: Phase I start in EU 9 Strength ・・Strong Strong& &selective selectivep38 p38mapkinase mapkinaseinhibitor inhibitor ・・Suppress Suppressthe thecytokine cytokineproduction production in invitro: vitro:TNFα, TNFα,IL-1β, IL-1β,IL-6 IL-6and andIL-8 IL-8 in invivo vivo(oral (oralefficacy): efficacy):TNF TNFα α ・・Express Expressanti-inflammatory anti-inflammatoryeffects effects)) 9 Development Status ・・Expected Expectedindication: indication:Rheumatoid Rheumatoidarthritis, arthritis,Psoriasis Psoriasis ・・Phase I Phase I No Nosignificant significantadverse adverseevent eventwas wasobserved observed Dose dependant inhibition for TNFα, Dose dependant inhibition for TNFα,IL-6, IL-6,IL-8 IL-8(ex-vivo) (ex-vivo) 12 TA-5493, started phase I in EU, is a p38 mapkinase inhibitor. Some compounds of this class are reported their efficacy for RA. TA-5493 selectively inhibits p38α mapkinase and suppresses the cytokine production (TNFα, IL-1β, IL-6, IL-8) in vitro. In animal models, inhibitory effects on TNFαproduction are exhibited. In addition, p38α is known to relate differentiation of osteoclasts responsible for born resorption. The compound exhibit inhibitory effects on both differentiation of ostelclasts and born resorption. Accordingly, TA-5493, in combination with TNFα inhibition is expected to have born resorption inhibition. through ostelclast system and is expected to prevent joint destruction more prominently than methotrexate. No significant adverse event was observed in non-clinical safety studies and phase I. Expected indications are RA, and Psoriasis. 12 Remicade (Behcet’s disease) : NDA filed Phase II and Long-term study N=13 N=12 Long-term study Phase II Retrospective period Additional study Observation period Additional clinical study Retrospective period Evaluation period 0 2 6 10W 5mg/kg、10mg/kg Evaluation period Observation period 0 2 6W 0 2 6 14 22 30 38 46W 5mg/kg 、10mg/kg 5mg/kg 単位期間(14週間)あたりの眼発作回数の推移 25.00 20.00 15.00 10.00 5.00 0.00 Pre Post 13 Regarding behcet’s disease, we filed NDA in 2003 after phase II and long-term studies. Left figure shows the number of optical events per 14 wks period in phase II and long-term studies. During the period when Remicade is not administered, optical events occur, but number of events decreases by Remicade administration. In long-term study, yearlong efficacy and safety are confirmed. Right figure shows the result of the additional clinical study. The result shows the same effectiveness as the previous phase II study. We have submitted those data to authority and expect an approval within FY2006. 13 Remicade (Crohn’s disease, maintenance): Phase III completed - Well controlled with every 8 weeks for one year Well maintenance result with every 4 weeks for patients who respond and then lose their response with every 8 weeks. - As good as ACCENT 1 study (EU/US pivotal study) NDA is scheduled to be filed by the end of 2006 14 Remicade for Crohn’s disease, maintenance therapy, phase III trial has been completed, and is now under preparing for NDA filing by the end of this year . The results suggested that the symptoms were well controlled with every 8 weeks injection for one year. Well maintenance result was also observed for patients with every 4 weeks injection whose responses were partially insufficient with every 8 weeks injection. Those satisfactory results are consistent with that of EU/US pivotal study (ACCENT1). NDA is scheduled to be filed by the end of this year. 14 Remicade (Ulcerative Colitis) : Phase III Moderately to severely active Ulcerative Colitis Efficacy evaluation: Mayo score Placebo-controlled double-blind design Patient population: Have failed to successfully taper, tolerate or respond to existence therapy Endpoint: Efficacy (clinical response), safety and pharmacokinetics 15 Remicade for ulcerative colitis, phase III study has been started in July. Patients with active ulcerative colitis, who have failed to response, have failed to successfully taper or have medical complications to other existing medications are included. Efficacy will be assessed by Mayo score, clinical index. The double-blinded, parallel-group comparative clinical study will be conducted to show the superiority of Remicade comparing with placebo. 15 EU/US study results (Ulcerative colitis) Mucosal healing (%) Clinical response (%) Clinical remission (%) ACT(Active Ulcerative Colitis Trials)1,ACT2(n=364 each) Clinical response: Decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding Of at least 1 point or an absolute subscore for rectal bleeding of 0 or1. Clinical remission: Total Mayo score of 2 points or lower, with no individual subscore Exceeding 1 point. Mucosal healing: Absolute subscore for endoscopy of 0 or 1 Mayo score at 8 weeks N Engl J Med 2005; 353: 2462-76 16 EU/US study results(Ulcerative colitis) CENTCOR completed two pivotal phase III studies (ACT1, ACT2) including patients with active ulcerative colitis having failed to successfully taper, tolerate or respond to existing therapy such as steroid and azathioprine. Three dosage groups (placebo, 5, 10mg/kg) were compared. As a primary endpoint, Mayo score (clinical response) at 8 wks was evaluated. Figure shows the positive data for clinical response of Mayo score, clinical remission and muscosal healing. Using these data, Remicade was approved for ulcerative colitis in EU in Feb 2006 and in the US in Sep 2005. We will file an NDA by bridging these data in Japan. Mayo score (0-12) consists of 4 subscores (0-3 each) such as frequency of fecal evacuation, rectal bleeding, endoscope observation, physician’s general evaluation. 16 Remicade (Psoriasis): Phase III Psoriasis Primary Endpoint: PASI score Aim: Confirm the superiority of TA-650 to placebo Placebo-controlled double-blind design Patient population: Who are candidates for systemic therapy or phototherapy and have a psoriasis area, and have certain number of total body surface area involved. Endpoint: Efficacy (clinical response), safety and pharmacokinetics 17 Remicade for psoriasis, phase III started in October. The study includes psoriasis patients who are candidates for systemic therapy or phototherapy. As a primary endpoint, PASI score is evaluated to confirm the superiority of Remicade by placebo controlled, double-blinded, parallel-group comparative clinical study. 17 EU/US study result (Psoriasis) Phase III:Randomized placebo-controlled 75% improvement in PASI at 10 weeks 100 80* 80 60 40 20 3 0 Placebo n=77 PASI(Psoriasis area and severity index) Lancet 2005: 366:1367-74 infliximab 5 mg/kg n=301 *p<0.001 vs. placebo 18 CENTCOR completed two pivotal phase III studies (EXPRESS, EXPRESS II) including patients who were candidates for phototherapy or systemic therapy. Remicade exhibited high effectiveness in PASI score in 75% improvement. Using these data, indication for psoriasis vulgaris was approved in EU in Sep 2005 and in the US in Sep 2006. In Japan we will file an NDA by bridging these data. 18 PLCM strategy for Remicade Ankylosing spondylitis preparing Psoriasis Ph3 Ulcerative colitis Ph3 Rheumatoid arthritis/dose escalation Ph3 Crohn’s disease/maintenance therapy Ph3 Behcet’s disease Rheumatoid arthritis sNDA Launched Getting approval in series to 2010 Crohn’s disease /induction therapy Launched 2006 2007 2008 2009 2010 19 Tanabe is strictly focusing PLCM (Product Life Cycle Management) strategy of Remicade. In addition to Crohn’s disease (induction of remission) and rheumatoid arthritis both approved, indications for Behcet’s disease as third indication, Crohn’s disease (maintenance) and RA for dose escalation are well progressing. Further, phase III studies for ulcerative colitis and psoriasis, have started and phase III study for ankylosing spondlitis will begin soon. We will obtain the approval for all above indications one by one from 2006 to 2010 and maximize the potential of Remicade. 19 Forward-Looking Statements ¾The statements contained in this presentation is forward-looking statements based on a number of assumptions and belief in light of the information currently available to management and is subject to risks and uncertainties. ¾Actual results or performance may differ materially from those anticipated in these statements depending on a number of factors. 20 20