1. 1 MEP141 May 2011 Mepact ®  (Mifamurtide) Fulfilling an unmet need in osteosarcoma treatment Prescribing information can be found at end of presentation

2. 2 MEP141 May 2011 Bone cancer incidence ●Incidence (annual) of bone cancer in EU –~1,225 newly diagnosed cases/year –Incidence Rate: 3 per 100,000 population ●Incidence (annual) of bone/connective tissue cancer in UK –2,025 annual cases ●1,091 deaths from bone/connective tissue cancer annually –Incidence Rate: 3.3 per 100,000 Bielack S. et al. Annals of Oncology, 2009;20 (Suppl 4):iv137–iv139 Cancer Research UK. 2006

3. 3 MEP141 May 2011 Osteosarcoma is a disease of children and young adults ●Most common type of primary bone cancer –Approximately half of all bone cancers ●Most occur between ages of 10 and 30 –Median age at diagnosis = 15 years ●50% more common in males than females ●Most common sites are ends of long bones –80% around knee joint Mascarenhas L. et al. SEER AYA Monograph. 2002;8:97-109 Meyers P A. Pediatric Clinics of North America. August 1997;44(4):973-90 Meyers PA. et al. J Clin Oncol. 2008;26:633-638 Chou A. et al. Pediatr Drugs. 2008; 10 (5): 315-327 Bielack S. et al. Annals of Oncology. 2009; 20 (Supplement 4):iv137–iv139, 2009

4. 4 MEP141 May 2011 Minimal improvement in osteosarcoma survival since 1980s Historical: Surgery alone Historical: Surgery alone Introduction of chemotherapy Attempted refinement of chemotherapy Lewis IJ. et al. J Nat L Cancer Inst. 2007;99:112-28

5. 5 MEP141 May 2011 Significant unmet need in osteosarcoma treatment ●Long-term survival is 60-65% –No improvement in past 20 years despite the introduction of multi-agent chemotherapy ●Relapse rate in newly diagnosed patients approximately one third –Most recurrences occur as lung metastases ●20% of newly diagnosed patients have detectable lung metastases –Worst prognosis –Almost all patients have subclinical microscopic metastases –Death from osteosarcoma is almost always the result of progressive pulmonary metastases NIH National Cancer Institute http://www.cancer.gov/cancertopics/pdq/treatment/osteosarcoma/HealthProfessional/page8 Cancer Backup American Cancer Society Grimer RJ. et al. Eur J Cancer. 2005;41(18):2806-11 Lewis IJ. et al. J Nat L Cancer Inst. 2007;99:112-28 Meyers PA. et al. Ped Clin N Am. 1997;44:973-989

6. 6 MEP141 May 2011 Introduction - What is Mepact? ●Mepact (mifamurtide) is L-MTP-PE, a liposomal formulation of Muramyl Tripeptide Phosphatidyl Ethanolamine (MTP-PE) –Liposomal formulation facilitates uptake by tissue macrophages after iv infusion –A potent activator of macrophages ●L-MTP-PE was initially developed as an immunostimulant with significant anti- tumour effects in preclinical models ●MTP-PE is a synthetic analog of muramyl dipeptide (MDP) –The smallest natural immuno-adjuvant from Mycobacterium cell wall Nardin A. et al. Current Cancer Drug Targets. 2006;6:123-133 Fidler IJ. et al. Proc. Natl Acad. Sci. USA. 1981;78:1680-1684

7. 7 MEP141 May 2011 Mepact is well studied and characterised ●Administered to more than 700 patients in clinical trials –One of most studied paediatric oncology drugs ●More than 100 pre-clinical studies –86 pharmacology studies, 12 pharmacokinetic studies and 20 toxicology studies were submitted as part of the EMA dossier ●Extensive clinical development program –18 Phase 1 and 2 studies were submitted as part of EMA dossier ●Robust phase III clinical data –Leading paediatric cooperative study group clinical trial is largest completed to date –Consistent, significant and long-term survival benefit ●Almost one third reduction in relative risk of death with an absolute risk reduction of 8% p=0.03 –Favourable benefit/risk profile Takeda Data on file 2008 EMA (Assessment report for Mepact EMEA/H/C/000802) Meyers PA. et al. J Clin Oncol. 2008;26:633-638

8. 8 MEP141 May 2011 Clinical trial exposure – all patients StudiesEnrolledReceived one dose or more of Mepact ControlRandomised to Mepact but never received treatment Total assigned to Mepact No information on patient EU14213560 1 Phase I/II248 00 0 Phase III793332398633950 Total1183715404637781 Takeda data on file 2008

9. 9 MEP141 May 2011 Mepact development pathway ●In pre-clinical models, Mepact was proven to be an immunostimulant with significant anti-tumour effects –Anti-tumour effects are macrophage mediated ●Direct (activated macrophage tumour killing) ●Indirect (cytokine mediated, activation of immune cells) ●Liposomal formulation facilitates uptake by tissue macrophages after iv injection –Particularly in lungs, nasopharynx, spleen, liver ●Lungs are primary site of metastatic disease in osteosarcoma so trials initiated in this tumour type Nardin A. et al. Current Cancer Drug Targets. 2006;6:123-133 Anderson A. Future Oncol. 2006;2:333-334

10. 10 MEP141 May 2011 Mepact was shown to be most effective immediately post-surgery in mouse model Time (days) Percent Mice Surviving Without Detectable Tumour p=0.001 p=0.01 p=0.2 Fidler IJ. Cancer Immun Immunother. 1986;21:169-173 Day 3 Day 7 Day 10 Day 3 post-surgery Initiation of Mepact Therapy Day 7 post-surgery Day 10 post-surgery

11. 11 MEP141 May 2011 MacEwen EG. et al. J Natl Cancer Inst. 1989; 81: 935-938 Mepact also showed improved survival in canine osteosarcoma which has similar biology to humans p < 0.002 vs placebo liposomes Mepact 2mg/m 2 twice weekly x 8 weeks, n=14 Placebo liposomes (same schedule), n=13 Cumulative Propprtion Surviving (%) 0 20 40 60 80 100 Days Post Surgery 02004006008001000

12. 12 MEP141 May 2011 Mepact shown to be taken up by macrophages in lungs, nasopharynx, spleen and liver spleen lungs* nasopharynx liver Murray et al. J Clin Oncol. 1989;7:1915-1925 Biodistribution study of a patient receiving 1 mg of Mepact in radio-labelled liposomes *principal site of metastatic disease in osteosarcoma

13. 13 MEP141 May 2011 Mepact monotherapy induces infiltration of inflammatory macrophages into lung metastases Kleinerman et al. Cancer Immunol Immunother. 1992;34:211-220 Pre-Mepact Post-Mepact

14. 14 MEP141 May 2011 Measured clinical effects ●Induction of tumouricidal monocytes ●Elevated levels of IL-1, IL-6, IL-8, IL-12 ●Elevated levels of TNF-  ●Increased levels of C-reactive protein (CRP), neopterin and β2-microglobulin ●Leukocytosis Takeda Data on file 2008 Kleinerman ES. et al. Cancer Research. 1989;49:4665-4670 Kleinerman ES. et al. J Clin Onco. 1992;10:1310-1316 Frost H. et al. J Biol Response Modifiers. 1990;9:160-166 Landmann R. et al. Biotherapy. 1994;7:1-12 Sculier JP. et al. Drug Invest. 1993;6:276-284 Creaven PJ. et al. J Biol Response Modifiers. 1990;9:492-498 Liebes L. et al. J Natl Cancer Inst. 1992;84:694-699 Asano T. Kleinerman ES. J Immunother. 1993;14:286-292

15. 15 MEP141 May 2011 Potential multiple pathways for Mepact Nardin A. et al. Current Cancer Drug Targets. 2006;6:123-133 L-MTP-PE iv Monocytes in lung vessels Activated AM Liver & Spleen Mφ Cytotoxicity TNF-α, IL-6, IL- 8, neopterin Inhibition of metastasis PMN, DC activation? Secondary effects? DC maturation NK activation PMN recruitment Secondary effects? DC maturation NK activation PMN recruitment Mφ : Macrophages TNF: Tumour Necrosis Factor IL6: Interleukin 6 IL8: Interleukin 8 PMN : Polymorphonucleocytes DC : Dendritic cells NK : Natural Killer cells AM : Alveolar macrophages

16. 16 MEP141 May 2011 Anti-tumour activity of Mepact is mediated by activation of the host immune system Adapted from; Strober W. et al. Nature Rev Immunol. 2006;6:9-20Fidler IJ. et al. Proc. Natl Acad. Sci. USA. 1981;78:1680-1684 Nardin A. et al. Current Cancer Drug Targets. 2006;6:123-133Anderson A. Future Oncol. 2006;2:333-334 Kleinerman ES. et al. Cancer Res. 1989;49:4665-4670Kleinerman ES. et al. J Clin Oncol. 1991;9:259-267 Kleinerman ES. et al. J Immunotherapy. 1995;17:181-193

17. 17 MEP141 May 2011 Mepact works in conjunction with chemotherapy Mori K. et al. Expert Rev Anticancer Ther. 2008;8(2):151-159 Fidler IJ. et al. Proc. Natl Acad. Sci. USA. 1981;78:1680-1684

18. 18 MEP141 May 2011 Mepact formulation ●Supplied as lyophilised cake –Liposome suspensions are formed after hydration of lyophilisate ●48 Doses over 36 Weeks –Weeks 1-12: ●One hour iv infusion 2x/week –Weeks 13-36: ●One hour iv infusion 1x/week Mepact SmPC, January 2011

19. 19 MEP141 May 2011 Overview of the administration process of Mepact ●Reconstitution –50ml 0.9% sodium chloride solution is added to the Mepact vial ●Filtering –Using the filter provided, the desired dose is withdrawn from the reconstituted solution (each ml of reconstituted suspension contains 0.08mg mifamurtide) ●Dilution –The desired dose of mifamurtide is added to 50ml 0.9% sodium chloride solution, and this solution is infused over 1 hour DETAILED INFORMATION ON THE ADMINISTRATION OF MEPACT CAN BE OBTAINED FROM THE SmPC

20. 20 MEP141 May 2011 Phase I studies determined maximum tolerated dose and optimal biological dose ●Maximum Tolerated Dose (4-6 mg/m 2 ) –Dose below level at which grade 3 adverse events occurred –Defined in Phase 1 studies (n>100 patients) of doses from 0.01-12 mg/m 2 ●Biological Dose (2 mg/m 2 ) –Induction of cytokines and inflammatory molecules ●Within hours of administration ●Observed at intermediate dose ranges –Induction of monocyte mediated tumouricidal activity ●Wide range of doses assessed ●Optimal range between 0.5-2.0 mg/m 2 –Doses above 2 mg/m 2 provide little increased effect –Similarity to other biologicals (IFN  ) that activate monocytes/ macrophages Kleinerman et al. Cancer Res. 1989;49:4665-4670

21. 21 MEP141 May 2011 Demonstrated efficacy of Mepact The Children’s Oncology Group phase III study ●National Cancer Institute sponsored, COG Cooperative Group study –Designed and conducted independently of corporate sponsor –1993-1997 enrollment –1993-2007 follow-up ●Largest study completed in osteosarcoma –178 sites – 1/3 of eligible paediatric cases in US ●Newly diagnosed patients(n=793; age <31) –678 non-metastatic resectable disease –115 with more advanced disease ●Study tracked by data monitoring committee and all survival events reviewed by Study Principal Investigator and Group Statistician ●Independently analysed and published survival benefit vs. chemotherapy alone –Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J Clin Oncol 2008; 26:633-638 Meyers PA. et al. J Clin Oncol. 2008;26:633-638 Meyers PA. et al. J Clin Oncol. 2005;23:2004-2011 Chou AJ. et al. Cancer. 2009. 115(22):5339-48 Takeda Data on File 2006

22. 22 MEP141 May 2011 Study objectives (Protocol 1993, Revision 2006) ●To determine if the addition of L-MTP-PE to cisplatin, doxorubicin and methotrexate, with or without ifosfamide will enhance overall survival –To determine if the addition of L-MTP-PE to cisplatin, doxorubicin and methotrexate, with or without ifosfamide will enhance disease free survival (DFS) as a surrogate endpoint ●To determine if the addition of ifosfamide to a control arm including doxorubicin, cisplatin and high dose methotrexate will increase disease free survival (DFS) for newly diagnosed patients ●To determine if the addition of ifosfamide to the control arm will increase overall survival of newly diagnosed patients ●To determine if the use of ifosfamide in the pre operative phase of chemotherapy will result in a higher rate of good histologic response, and whether histologic response predicts disease free survival ●To determine if multiple drug resistance encoded p-glycoprotein expression is useful to determine prognosis or assign therapy Takeda data on file 2006/008 (Study protocol 1993, Clinical study reports 2006/8)

23. 23 MEP141 May 2011 Mepact – phase III clinical study: factorial design InductionMaintenance 3 drugs 3 drugs +/- Mepact 3 drugs 4 drugs +/- Mepact

24. 24 MEP141 May 2011 Phase III study dose schedule CDDP: Cisplatin; DOXO: doxorubicin; HDMTX: high dose methotrexate; IFOS: ifosfamide Drug doses: cisplatin: 120 mg/m 2 four hours infusion; doxorubicin: 75 mg/m 2 72 hour continuous infusion; high dose methotrexate: 12 g/m 2 (max 20 g) four hour infusion followed by leucovorin 10 mg (fixed dose) 24 hours after start high dose methotrexate continuing until serum high dose methotrexate < 1 x 10-7 mol/L (100 nmol/L); ifosfamide: 1.8 g/m 2 for five days (total dose 9 g/m 2 (with mesna uroprotection); Mepact: 2 mg/m 2, with an additional 1 mg or 2 mg (maximum) at subsequent dosing according to patient biologic activity. Takeda data on file 2006 Meyers PA. et al. J Clin Oncol. 2008;26:633-638 Meyers PA. et al. J Clin Oncol. 2005;23:2004-2011 CDDP x 2 DOXO x 2

25. 25 MEP141 May 2011 Overall survival and event free survival for Mepact (2005 publication) Meyers PA. et al. J Clin Oncol. 2005;23:2004-2011

26. 26 MEP141 May 2011 Six year overall survival improved from 70 to 78% vs. chemotherapy alone According to Treatment Regimen Treatment RegimenEFS Probability (%)Survival Probability (%) 4 years6 years4 years6 years All patients66648174 Regimen A Without MTP With MTP 66 65 64 63 78 82 71 75 Regimen B Without MTP With MTP 60 74 58 71 77 86 70 81 Regimen A with or without MTP65638073 Regimen B with or without MTP67648275 Chemotherapy Without MTP With MTP 63 69 61 67 78 84 70 78 Abbreviations: EFS, event-free survival; MTP, muramyl tripeptide Meyers PA. et al. J Clin Oncol. 2008;26:633-638

27. 27 MEP141 May 2011 Overall Survival: HR = 0.71, which translates to an almost one third reduction in relative risk of death (absolute risk reduction 8%, p=0.03) vs. chemotherapy alone p=0.03, HR 0.71 (CI : 0.52, 0.96) Meyers PA. et al. J Clin Oncol. 2008;26:633-638

28. 28 MEP141 May 2011 Event free survival p=0.08, HR 0.8 (CI : 0.62, 1.00) Meyers PA. et al. J Clin Oncol. 2008;26:633-638

29. 29 MEP141 May 2011 Comparison between publications Meyers PA. et al. J Clin Oncol. 2008;26:633-638 Meyers PA. et al. J Clin Oncol. 2005;23:2004-2011 20052008 Reported endpointEFSOS and EFS 3 yr EFS (%)5yr EFS (%)4 yr EFS (%)6 yr EFS (%) Regimen A-71646664 Regimen A+68636563 Regimen B- (Ifos)61566058 Regimen B+78727471 6 yr OS*(%) Regimen A-71 Regimen A+75 Regimen B- (Ifos)70 Regimen B+81 Regimen A-A+73 Regimen B-B+75 Regimen A-B-70 Regimen A+B+p=0.0478 (p=0.03) Hazard ratio for overall survival 0.71 (95% CI 0.52-0.96) Impact of Ifosfamide irrespective of chemo regimen Impact of Mepact irrespective of chemo regimen *OS Overall survival

30. 30 MEP141 May 2011 Two clear results ●The addition of Mepact to chemotherapy: –Improved 6-year overall survival from 70% to 78% (p=0.03) –Reduced the risk of death by almost one third (Relative Risk = 0.71) ●Absolute risk reduction 8%, p=0.03 Meyers PA. et al. J Clin Oncol. 2008;26:633-638

31. 31 MEP141 May 2011 Adverse event profile Very Common Side Effects ●Anaemia ●Anorexia ●Headache, dizziness ●Tachycardia ●Hypertension, hypotension ●Dyspnoea, tachypnoea, cough ●Vomiting, diarrhoea, constipation, abdominal pain, nausea ●Hyperhidrosis ●Myalgia, arthralgia, back pain, pain in extremity ●Fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain Selected Common Side Effects ●Sepsis ●Leukopenia ●Thrombocytopenia ●Granulocytopenia ●Hypokalaemia Please refer to Summary of Product Characteristics (SmPC) for full list of adverse events Mepact SmPC, January 2011

32. 32 MEP141 May 2011 Phase III adverse events consistent with high dose chemotherapy Received at least one dose of any study drug Adverse Event No Mepact n=391Mepact n=390 n(%)n Stomatitis174(45)172(44) Infection92(24)84(22) Vomiting66(17)70(18) Hearing loss *within the range of Cisplatin reported effect23(6)47(12*) Ileus13(3)15(4) Diarrhoea7(2)16(4) Skin24(6)19(5) Abdominal Pain9(2)12(3) CNS19(5)21(5) Pyrexia8(2)10(3) Depression9(2)12(3) Takeda data on file 2006/2008 (EMA Oral explanation)

33. 33 MEP141 May 2011 CHMP positive opinion – 18 December 2008; EMEA approval – 6 March 2009 ●On 18 December 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending to grant a marketing authorisation for the medicinal product Mepact for the treatment of osteosarcoma. Mepact was designated as an orphan medicinal product on 21 June 2004. ●The benefits with Mepact when used in conjunction with combination chemotherapy are its effect in terms of overall survival, as observed in a randomised controlled trial when compared to chemotherapy alone. ●The approved indication is: “Mepact is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post- operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis ”. ●The CHMP, on the basis of quality, safety and efficacy data submitted, considers that there is a favourable benefit to risk balance for Mepact and therefore recommends the granting of the marketing authorisation. European Medicines Agency Evaluation of Medicines for Human Use European Medicines Agency EMEA/CHMP/635781/2008 Assessment report for Mepact

34. 34 MEP141 May 2011 Expert opinion “There has been a significant lack of progress during the last two decades in treating osteosarcoma,” said Ian Lewis, Professor of Cancer Studies at St. James University Hospital in Leeds, England. “The availability of Mepact brings hope to children and young adults in need of a more positive treatment option for the devastating disease.”

35. 35 MEP141 May 2011 ESMO clinical recommendations ●Doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue and ifosfamide are considered the most active agents against osteosarcoma recommendation [IB, A], but the ideal combination remains to be defined ●Addition of the immune modulator muramyl tripeptide (MTP) to postoperative chemotherapy correlated with a statistically significant advantage in overall survival and a non-significant trend in event-free survival in a recently published randomised trial European Society for Medical Oncology Bielack S et al. On behalf of the ESMO Guidelines Working Group. Annals of Oncology. 2009;20:iv137–iv139

36. 36 MEP141 May 2011 Mifamurtide 4mg vial. Presentation: 4 mg powder for suspension for infusion. Single vial in outer carton EU/1/08/502/001 £2375. Indication: Treatment of high-grade resectable nonmetastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults (2- 30 years) used in combination with post-operative multi-agent chemotherapy. Dosage & Administration: Should be initiated and supervised by specialist oncologists. Powder for suspension for infusion: Mepact ® should be reconstituted with 50mL sodium chloride 9mg/mL (0.9%) and the appropriate dose volume withdrawn and added to a sodium chloride 9mg/mL (0.9%) infusion bag for intravenous administration over 1 hour (see SmPC). Children, adolescents & young adults 2- 30 years: 2 mg/m2 body surface area. It should be administered as adjuvant therapy following resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks. Paediatric patients ( 65yrs): No data available. Patients with impaired renal or hepatic function: No data available regarding use in renal or hepatic failure. Contraindications, Warnings etc.: Contraindications: Hypersensitivity to mifamurtide or excipients. Concurrent administration with ciclosporin, other calcineurin inhibitors and high-dose non-steroidal anti-inflammatory agents (cyclooxygenase inhibitors). Precautions: In patients with asthma or other chronic obstructive pulmonary disease, consider administration of prophylactic bronchodilators. If a severe respiratory reaction occurs, administration should be discontinued and appropriate treatment initiated. Monitor and manage episodes of neutropenic fever. Fever or chills persisting more than 8 hours after administration of Mepact ® should be evaluated for possible sepsis. Use Mepact ® with caution in patients with a history of autoimmune, inflammatory or other collagen diseases. Monitor for signs or symptoms of arthritis or synovitis. If symptoms persist or worsen in patients with a history of thrombosis, vasculitis or unstable cardiovascular disorders, Mepact ® administration should be delayed or discontinued. Monitor for signs of allergic reactions. Gastrointestinal toxicity may be exacerbated when Mepact ® is used in combination with high dose, multi-agent chemotherapy and was associated with an increased use of parenteral nutrition. Interactions: There is no evidence of any interactions between Mepact ® and the anti-tumour effects of chemotherapy and vice versa. Mepact ® should be administered at a separate time to doxorubicin or other liposomal formulations. Chronic or routine use of corticosteroids should be avoided. Mifamurtide is not expected to interact with the metabolism of substances that are hepatic cytochrome P450 substrates. In a large controlled randomised study, Mepact ® used at the recommended dose and schedule did not exacerbate the renal toxicities of cisplatin and ifosfamide or the hepatic toxicities of methotrexate and ifosfamide. Pregnancy & lactation: No data available. Adverse Effects: Very common (>10%): Anaemia, anorexia, headache, dizziness, tachycardia, hypertension, hypotension, dyspnoea, tachypnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, hyperhidrosis, myalgia, arthralgia, back pain, pain in extremity, fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain. Pharmaceutical Precautions: Store in a refrigerator (2-8°C), protected from light. The reconstituted vial is stable for up to 6 hours at 25°C. PI Date: April 2011. PI Code: MEP131. Legal category: POM Name & Address of Marketing Authorisation Holder: IDM PHARMA SAS, 11-15 Quai De Dion Bouton, 92816 Puteaux Cedex, France Further information is available from: Takeda Pharmaceuticals Europe Ltd. Medical and Scientific Affairs. 61 Aldwych, London, WC2B 4AE, UK. +44 203 116 8879. Mepact ® is a registered trademark. Please refer to the summary of product characteristics for details on the full side-effects of Mepact ®. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Takeda. MEPACT ® Prescribing Information Please refer to Summary of Product Characteristics (SmPC) before prescribing