1. 1 BENTAIEB Fathi FETRO Christine LINDNER Lucie MAAMAR Suina RAME Blandine Feb. 18 th, 2014 - M2 AREIPS

2.  September 17,2013 the European Commission has granted marketing authorization for Lemtrada for patients with relapsing remitting MS  December 13, 2013 Health Canada has approved Lemtrada for the management of adult patients with relapsing remitting multiple sclerosis.  December 19, 2013 the Australian Therapeutic Goods Administration has approved Lemtrada for the treatment of relapsing forms of multiple sclerosis.  December 30, 2013 the FDA has rejected approval of the investigational drug Lemtrada. 2

3.  Approved in the US (Campath®) and the EU (MabCampath®)in May 2001 and July 2001 respectively  Withdrawn from all markets in 2012  ATU in France  Compassionate use in Europe  Campath access program in the US 3

4. Alemtuzumab 2001 Alemtuzumab 2013 LEMTRADAMSCAMPATHB-CLL 4

5. 5

6. I.Scientific Overview II.Economic Strategy III.Regulatory Overview IV.Conclusion SUMMARY 6

7. 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS I.SCIENTIFIC OVERVIEW 7

8. A LONG AND WINDING HISTORY… A Long and Winding History ： Campath(Alemtuzumab) の数奇な運命 1983 Originally synthesized by Herman Waldmann at the Department of Pathology in Cambridge University (hence Cam-Path) 2011 8

9. A LONG AND WINDING HISTORY… http://www.whatisbiotechnology.org/exhibitions/campath/change 1997 Joint-venture LeukoSite/Ilex Onco In 1999 Millennium purchased Leukosite /Ilex Joint clinical trials in B-CLL 9

10. A LONG AND WINDING HISTORY… http://www.whatisbiotechnology.org/exhibitions/campath/change Merger in 2004 Genzyme had to continue working with Bayer. Joint venture started by Ilex with Schering AG for the development of Campath-1H in MS 10

11. ALEMTUZUMAB  CAMPATH-1M rat IgM  CAMPATH-1G rat IgG2b  CAMPATH-1H humanized IgG1 http://www.path.cam.ac.uk/~mrc7/campath/campath.html 11

12. ALEMTUZUMAB PROFILE  Humanized monoclonal antibody  Targets CD52 antigen abundant on the surface of B and T lymphocytes  Apoptosis Murine CDR’s 12

13. 13 Alemtuzumab MoA - One target : CD52 Expert Opin. Biol. Ther. (2010) 10(3):421-429

14. FROM B-CLL TO MS B-CLL MS B-CLL Cross AH et al. (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 112: 1–14 Nature Clinical Practice Neurology (2006) 2, 201-211 Immunopathogenesis and immunotherapy of multiple sclerosis Bernhard Hemmer 14

15. 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS I.SCIENTIFIC OVERVIEW 15

16. CHRONIC LYMPHOCYTIC LEUKEMIA Decreased hemoglobin: Anemia Infections decreased platelets: bleeding Lymphocytes B, produced by the bone marrow, never die again. Accumulation in the blood, spleen, lymph and bone marrow. Disease the most common leukemia occurring in adults approximately 3,000 new cases per year in France. It affects twice as many men than women, >50 years Epidemiology no sign of disease, unnoticed. CBC: too many B cell + immunophenotyping 3 stages: A, B, C 2/3 only treat Diagnostic Complications 16

17. CLL - TREATMENT No treatment Monitoring First line: Rituximab (Mabthera®, Rituxan®) + Fludarabine + Cyclophosphamide (Endoxan®) 2nd line: -Campath® +/-corticotherapy ou -Campath® +/- fluda+/ cyclophosphamide 2nd line :Rituximab + pentostatine + cyclophosphamide AB,C FDA – 2007  First line 17

18. 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS I.SCIENTIFIC OVERVIEW 18

19. © Inserm 19

20. EPIDEMIOLOGY 2 million patients 80 000 in France starts between 20 and 40 years and affects women more than men (ratio 3:2) 20

21. DIAGNOSTIC Visual disorders Loss of motricity Sensitivity disorders Balance disorders Functional disorders Clinical Diagnostic Mcdonald’s criterias Number of relapses Number of lesions Existence of an inflammation  Complications Biologic and Radiologic diagnostic Lumbar puncture MRI 21

22. EDSS SCORE 22

23. 3 DIFFERENT FORMS 85% 15% 50% 23

24. TREATMENT (1/2) The treatment of MS generally falls into two categories symptomatic treatments + Kinesitherapy Treatments that change the course of the disease Flares: Methilprednisolone IV MS Relapsing- Remitting 24

25. TREATMENT (2/2) Betaferon®, Avonex®, Rebif®, Copaxone® Elsep®, Tysabri®, Gilenya® Aubagio® LEMTRADA® Reco HAS 25

26. 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS 1.ALEMTUZUMAB 2.LLC 3.MS 4.CLINICAL TRIALS I.SCIENTIFIC OVERVIEW 26

27. A prospective, noncomparative phase II trial called CAM211 EVALUATION IN B-CLL Primary objective: evaluate Overall Response rate (OR) Secondary objectives: safety profile and clinical benefit April-October 1998 93 patients (73 male, 20 female) 27

28. Accelerated approval in US (final study report in Nov 2006) For the treatment of B-cell CLL in patients who have been treated with alkylating agents and who have failed fludarabine therapy EVALUATION IN B-CLL: SURVIVAL CURVE CAM211 (n=93) Response rate (95% IC)33.3 % (23-43%) n=31 Complete response (CR)2.2% n=2 Partial response31.1% n=29 FDA 7 May 2001 28 March 2001 EMA Treatment of patients with chronic lymphocytic leukaemia (CLL) who have been treated with alkylating agents and who have failed to achieve a complete or partial response or achieved only a short remission (less than 6 months) following fludarabine phosphate therapy 28

29. EVALUATION IN B-CLL: CAM307 An international, multi-center, randomized, open-label trial One observation :the worst disease progression and survival outcomes correlate with deletions of 17p (the location of the p53 gene) and 11q => resistance to purine analogs =>identify treatments for CLL that work through p53-independent 29 JCO-2007-Hillmen 5616-23 A phase III study Primary end point: progression free- survival (PFS) Secondary end points: overall response rate (ORR), and overall survival

30. EVALUATION IN B-CLL: CAM307 297 patients 149 patients received Alemtuzumab (IV) Dose escalation and 30mg/weeks for no more than 12 weeks 148 patients received Chlorambucil (PO) 40mg/m² 30 From December 2001 to July 2004

31. CAM307 : CHANGE IN LABELLING 31 07 July 2001 The treatment of patients with B-CCL for whom fludarabine combination chemotherapy are not appropriate 19 September 2007 expanded the labelling: indicated as a single agent for the treatment of B-CLL

32. EVALUATION IN MS: CARE-MS STUDIES PHASE III COMPARISON OF ALEMTUZUMAB AND REBIF EFFICACY IN MULTIPLE SCLEROSIS CARE-MS 1 (S323)CARE-MS 2 (S324) 32 Same design: A 2-year rater-masked, randomised, controlled phase 3 trial Same Coprimary endpoints: relapse rate time to 6 month sustained accumulation of disability defined as an increase from baseline of at least one EDSS point confirmed over 6 months

33. with previously untreated relapsing-remitting MS (between Sept 7,2007 and April 17,2009) EVALUATION IN MS : CARE-MS 1 187 patients received interferon beta 1a 376 patients received alemtuzumab 12 mg Baseline 12 months Alemtuzumab ORInterferon 33

34. RESULTS Lancet 2012; 380: 1819–28 34

35. for patients after disease-modifying therapy Between Oct 20,2007 and Sept 18,2009 Same schedule of administration CAMMS324 OR CARE-MS 2 202 patients received interferon beta 1a 426 patients received alemtuzumab 12 mg 170 patients received alemtuzumab 24 mg decision to close recruitment into the arm was made by the Neurology Steering Committee and Genzyme management without review of safety or efficacy data from this study 35

36. RESULTS Lancet 2012; 380: 1829–39 36

37. A SIMILAR SAFETY 37 CARE-MS 1

38. A SIMILAR SAFETY 38 « The substantial efficacy of alemtuzumab in needs to be balanced against potentially serious but treatable adverse effects » CARE-MS 1

39. TO SUMMARISE 39 2013:Lemtrada® ALEMTUZUMAB CARE MS 1CARE MS 2 Study designRandomized, rater- masked phase 3 DateSept 7,2007-April 17,2009 Oct 20, 2007- Sept 18, 2009 Coprimary endpoint: -relapse rate -SAD 6 months -ok -no -ok Safety-infusion associated reactions -infections -IS -infusion associated reactions -infections -IS 2 pivotal studies 2 different decisions

40. II.Economic Strategy 1.SANOFI 2.GENZYME 3.COSTS CONSIDERATIONS 1.SANOFI 2.GENZYME 3.COSTS CONSIDERATIONS 40

41. SANOFI RANK - 2005 2004 – Merge Sanofi- Synthelabo & Aventis 41 2005 – Sanofi reachs the 3 rd rank of Pharma companies worldwide under J-F Dehecq

42. MAIN REVENUES & PATENTS PERSPECTIVES – 2005 42 TAXOTERE ® (docetaxel) ELOXATINE ® (oxaliplatine) STILNOX ® (zolpidem) PLAVIX ® (clopidogrel) APROVEL ® (irbésartan) COPAXONE ® (glatiramère) LANTUS ® (insuline glargine) LOVENOX ® (enoxaparine) Revenues – 2005 (M€) PROTECTION END US EU 20122011 2013 2010 20082006 20072004 2014 2015 20112012

43. NEW DIRECTION In 2008 : Christopher Viehbacher takes the Lead of Sanofi-Aventis (  Sanofi in 2011) while 6/7 main products lose protection within next 2-4 years He wants to direct the Groupe to : OTC medicines R&D reinforcement Biotechnologies 43

44. THE POTENTIAL BIOTECHS 44 MedImmune  AZ - 2007 Genetech  Roche – 2009

45. GENZYME - ID Genzyme : Biotechnology Compagny specialized in rare diseases founded in 1981 at Boston (headquarter) by Henry Termeer Presence in 40 countries12 production sites : US (8) ; Australia (1) and Europe (3)Products distributed in 100 countries 45

46. GENZYME – PORTFOLIO 46 ProductPathologyIncidence Revenues 2010 (M€) End of Protection Cerezyme™/Cer edase™ Gaucher disease1/ 57 000719.62001 www.genzyme.fr

47. GENZYME - PORTFOLIO 47 ProductPathologyIncidence Revenues 2010 (M€) End of Protection Cerezyme™/Cer edase™ Gaucher disease1/ 57 000719.62001 Renagel™Hyperphosphoremia 10% world population 697.7 2014 (US) 2015 (EU) The Lancet – 2013 www.genzyme.fr

48. GENZYME - PORTFOLIO 48 ProductPathologyIncidence Revenues 2010 (M€) End of Protection Cerezyme™/Cer edase™ Gaucher disease1/ 57 000719.62001 Renagel™Hyperphosphoremia 10% world population 697.7 2014 (US) 2015 (EU) Fabrazyme™ Fabry disease (a-galactosidase deficit) 1/50 000188.22010 The Lancet – 2013 www.genzyme.fr

49. GENZYME - PORTFOLIO 49 ProductPathologyIncidence Revenues 2010 (M€) End of Protection Cerezyme™/Cer edase™ Gaucher disease1/ 57 000719.62001 Renagel™Hyperphosphoremia 10% world population 697.7 2014 (US) 2015 (EU) Fabrazyme™ Fabry disease (a-galactosidase deficit) 1/50 000188.22010 Myozyme™ Pompe disease (a-glucosidase deficit) 1/40 000≈315 2013 (US) 2016 (EU) The Lancet – 2013 www.genzyme.fr

50. GENZYME - PORTFOLIO 50 ProductPathologyIncidence Revenues 2010 (M€) End of Protection Cerezyme™/Cer edase™ Gaucher disease1/ 57 000719.62001 Renagel™Hyperphosphoremia 10% world population 697.7 2014 (US) 2015 (EU) Fabrazyme™ Fabry disease (a-galactosidase deficit) 1/50 000188.22010 Myozyme™ Pompe disease (a-glucosidase deficit) 1/40 000 ≈ 315 2013 (US) 2016 (EU) Aldurazyme™ Mucopolyscharidosis (type 1) 1/100 000≈150 2010 (US) 2013 (EU) The Lancet – 2013 www.genzyme.fr

51. CAMPATH ® 51 End of Protection : 2014 (EU) & 2015 (US) 2009 Genzyme obtains the rights of Campath® for $1.25B (over next 10 years) + royalties upon worldwide sales (buy-out option = $900 M) Why did Bayer sell Campath ? 2010 Campath ® revenues is only less than $150M (max revenues since its MA in 2001 in the US)

52. SANOFI RANK - 2010 52  2010 – Sanofi is at the 6 th rank of Pharma companies worldwide

53. GENZYME ACQUISITION 20,1 billion $ en 2011 (74$ per share) + Contingent Value Right (CVR – Certificat de valeur conditionnelle) based on Lemtrada ® sales (max 14$ per share) : $2.8B by 2020. A long deal : 9-month ! A great deal : Genzyme is stucked with a contamination issue for months in 2009 (impact on Cerezyme™/Fabrazyme™ production) … but Sanofi can help with its vaccine knowledge … 2013 : Sanofi reachs the 4 th rank of pharmaceutical companies worldwide 53

54. 54 Why does Sanofi prefer Lemtrada ® ?

55. COSTS CONSIDERATIONS 55 Campath ® Indication LLC Dose 30mg/ml Scheme W1 : 3 vials W2-4-6-8-10-12 : 3 vials/week Price 435 € (1 vial) Cost per mg 14.50 € Annual Costs 9 135 € SMR II (important) aSMR IV (mild – 1st line) CT opinion 2008

56. COSTS CONSIDERATIONS 56 Campath ® Indication LLCSEP-RR Dose 30mg/ml10mg/ml (12mg) Scheme W1 : 3 vials W2-4-6-8-10-12 : 3 vials/week Y1 : 5 vials Y2 : 3 vials Price 435 € (1 vial) 435 € (1 vial) Cost per mg 14.50 €36.25 € Annual Costs 9 135 €1 740 € SMR II (important)NA aSMR IV (mild – 1st line)NA CT opinion 2008NA

57. COSTS CONSIDERATIONS 57 Campath ® Lemtrada ® Indication LLCSEP-RR Dose 30mg/ml10mg/ml (12mg) Scheme W1 : 3 vials W2-4-6-8-10-12 : 3 vials/week Y1 : 5 vials Y2 : 3 vials Price 435 € (1 vial) 435 € (1 vial) 10 650 € (1 vial) Cost per mg 14.50 €36.25 €887.50 € Annual Costs 9 135 €1 740 €42 600 € SMR II (important)NApending aSMR IV (mild – 1st line)NApending CT opinion 2008NApending

58. COSTS CONSIDERATIONS 58 Campath ® Lemtrada ® Tysabri ® (natalisumab) Gilenya ® (fingolimod) Indication LLCSEP-RR Dose 30mg/ml10mg/ml (12mg) 20mg/ml (300mg)0.5 mg Scheme W1 : 3 vials W2-4-6-8-10-12 : 3 vials/week Y1 : 5 vials Y2 : 3 vials 300mg / month1cp / day Price 435 € (1 vial) 435 € (1 vial) 10 650 € (1 vial) 1 800 € (1 vial) 1 923 € (28 caps) Cost per mg 14.50 €36.25 €887.50 €6 €137 € Annual Costs 9 135 €1 740 €42 600 €21 600 €23 076 € SMR II (important)NApendingII (important) aSMR IV (mild – 1st line)NApendingIII (modéré)IV (mineur) CT opinion 2008NApending20072011

59. COSTS CONSIDERATIONS 59 Campath ® Lemtrada ® Tysabri ® (natalisumab) Gilenya ® (fingolimod) Aubagio ® (teriflunomide) Indication LLCSEP-RR Dose 30mg/ml10mg/ml (12mg) 20mg/ml (300mg)0.5 mg14 mg Scheme W1 : 3 vials W2-4-6-8-10-12 : 3 vials/week Y1 : 5 vials Y2 : 3 vials 300mg / month1cp / day Price 435 € (1 vial) 435 € (1 vial) 10 650 € (1 vial) 1 800 € (1 vial) 1 923 € (28 caps) 1 251 € (28 caps) Cost per mg 14.50 €36.25 €887.50 €6 €137 €3 € Annual Costs 9 135 € 1 740 € 42 600 € 21 600 €23 076 €15 012 € SMR II (important)NApendingII (important) pending aSMR IV (mild – 1st line)NApendingIII (modéré)IV (mineur)pending CT opinion 2008NApending200720112013

60. KEY POINTS Campath® : LLC (MA : 2001 – US)Genzyme gets Campath ® rights from Bayer (2009)Sanofi buys Genzyme (2011)Lemtrada® : MS (MA : 2013 – EU) ; co-development Genzyme/BayerAlemtuzumab end of protection : 2014 (EU) & 2015 (US)Lemtrada price may impact health insurance systemsLeukemia market < MS market 60

61. III.REGULATORY OVERVIEW 1.EMA 2.FDA 1.EMA 2.FDA 61

62. III.REGULATORY OVERVIEW 1.EMA 2.FDA 1.EMA 2.FDA 62

63. 63 Start Campath ® / MabCampath ®  B cells CLL (30 mg/ml) = ALEMTUZUMAB = Lemtrada ®  MS (10 mg/ml)

64. 64 Start MAH intends to take action to withdraw a product from the market At the request of Genzyme From 50 countries (including European market) in August 2012 To Prevent off-label use  risk for patients Commerical reasons : to launch Lemtrada in MS

65. 65 Start MAH intends to take action to withdraw a product from the market What is the MA procedure? MabCampath ® (alemtuzumab) Agency product number : EMEA/H/C/000353 Rap. Dr J. Ersboll (Denmark) / Co-Rap. Prof. S. Garattini (Italy)  Product authorised through the CENTRALISED PROCEDURE

66. 66 Start MAH intends to take action to withdraw a product from the market What is the MA procedure? Art. 116 & 117 of Dir. 2001/83/EC ? NO

67. IN THE EUROPEAN UNION European legal basis for the withdrawal: Regulation (EC) No 726/2004 Article 13(4) : The MHA is required to “notify the Agency if the product ceases to be placed on the market of a Member State, either temporarily or permanently”. “Such notification shall, otherwise than in exceptional circumstances, be made no less than two months before the interruption in the placing on the market of the product”. Regulation (EU) 1027/2012 Article 14b : The notification must include the reasons for such action. 67

68. 68

69. ANY OTHER POSSIBILITIES ? 2 ≠ MA ? Indication’s extension ? RTU ? 69

70. THE MA IS NO LONGER VALID IN B-CELL CLL BUT … As NO standard alternative therapies are available !!! & PATIENT FIRST !!!  Discussion between the EMA & Genzyme  PATIENT ACCESS PROGRAM in 50 countries: “Compassionate Use” 70

71. COMPASSIONATE USE IN THE EU To cover the supply of an unlicensed medicinal product to patients for whom no standard alternative therapies are available Usually reserved for the treatment of serious, often fatal diseases Definition Directive 2001/83/EC Regulation (EC) No 726/2004 Legal basis The EMA manages a procedure for providing recommendations to Member States Compassionate use programmes remain coordinated and implemented by Member States Condition 71

72. IN FRANCE Named ATU PTU Campath ® access 72

73. IN FRANCE Named ATU PTU Campath ® access  Derogation  Permitted for medicinal products intended to treat severe or rare diseases, in the absence of appropriate alternative treatment  Named patient ATU applications are made by the prescribing doctor for a specific patient and transmitted to the ANSM by the hospital pharmacist 73

74. IN FRANCE Named ATU PTU Campath ® access The authorisation implies the implementation of a “Protocol for Therapeutic Use & Collection of Information”. It should be signed between agency and industrial. It describes practical information about prescription, delivery and monitoring associated with treatment and collection of data on conditions of use.  Genzyme is required to transmit to ANSM every 6 months a report 74

75. IN FRANCE Named ATU PTU Campath ® access  How long ?  How much ? 75

76. IN FRANCE : HOW LONG ? In theory The duration of a named ATU must be specified on the authorisation This corresponds to the treatment duration & cannot exceed 1 year If it is necessary to prolong treatment, an application for an ATU renewal is submitted to the ANSM In practice No end date published !!! Interim solution Until an alternative is found … 76

77. IN FRANCE : HOW MUCH ? Fees ATU applications are free of charge Cost Laboratory’s decision Free of Charge (for current & futur users) … 77

78. 78 Genzyme started informing US & European doctors of the upcoming withdrawal of campath & the patient access plan in July 2012 CLL comunity:  Disapointment  Group favoring All leukeamia patients will benefit from free of charge programs that make sure that all patients receive their much needed medicine MS comunity:  serious implications for vulnerable UK patients with MS  Patients already taking the drug off- label could see their condition deteriorate as they wait for the drug to be re-launched as Lemtrada Campath withdrawal in August 2012 in the EU & Sept. 2012 in the US «Lemtrada remains available to patients who are taking part in clinical tests.»  safety monitoring Restores access to MS drug after pressure from Neurologists Focus on obtaining regulatory approval as a ttt for MS  the best way to ensure access for the greatest number of patients. EACH OBJECTION HAS ITS ANSWER

79.  TIME CONSUMING !!! 79

80. THE MOST IMPORTANT… : PATIENTS 80 « Programme run so far quite smoothly » (the German society for haematology & oncoloogy) “The companies had done a strong job of laying the groundwork for a transition from commercial product to one available for free under a compassionate-use protocol” “They’ve actually been quite supportive by telling us what the distribution is & how they have communicated their plans to health care providers who treat our patients” (Leukemia & Lymphoma Society)  An efficient communication’s strategy

81. LEMTRADA Approved in the EU (Sept. 2013) RMP Price & reimb. (NICE & HAS) 81

82. III.REGULATORY OVERVIEW 1.EMA 2.FDA 1.EMA 2.FDA 82

83. US BACKGROUND Submission (MS) Withdrawal (B-CLL) - patient-access program 1 same active ingredient (alemtuzumab) 2 different diseases (B-CLL & MS) 1 initial MA (B-CLL) NO Marketing Authorization ► Withdrawn (B-CLL) September 4, 2012 ► Rejected (MS) December 27, 2013 NO Marketing Authorization 1. FDA Regulatory Process 2. Consequences of rejection 83

84. US BACKGROUND NO Marketing Authorization 1. FDA Regulatory Process 2. Consequences of rejection 84

85. FDA REGULATORY PROCESS 85

86. FDA REGULATORY PROCESS 86

87. Code of Federal Regulations - Title 21 Sec. 314.110 Complete response letter to the applicant  Drug will not be approved in its present form  Changes must be made before an application can be approved.  The FDA does not divulge the contents of a CRL  Press release from the company COMPLETE RESPONSE LETTER Potayto—Potahto? The Meaning of the FDA's "Complete Response" Letters September 2008, Vol 1, No 7September 2008, Vol 1, No 7 - FDA Watch Mark Senak, JD American Health & Drug BenefitsFDA WatchMark Senak, JD 87

88. FDA REGULATORY PROCESS 88

89.  Panels of independent experts  Renewal at two-year intervals  Recommendations (not legally binding) According to the FDA Amendment Act of 2007 (FDAAA), the FDA should refer new drugs to an advisory committee meeting, or alternatively justify why an advisory committee meeting was not requested FDA ADVISORY COMMITTEE FDA Consumer Health Information www.fda.gov/consumer 89

90. 27/11/2012 NDA Alemtuzumab applications Reviewing process 3 FDA reviewers 16/10/2013 Alemtuzumab Background Package 13/11/2013 Peripheral and NCS Drugs Advisory Committee Meeting THE KEY DATES 90

91. Prepared by the FDA Division of Neurology Clinical safety, efficacy and statistics reviews To members of the Advisory Committee In preparation for the meeting to discuss BLA for alemtuzumab in MS ALEMTUZUMAB BACKGROUND PACKAGE 91

92. ADVISORY COMMITTEE MEETING 92

93. 11-6- (1 abstention) that Sanofi's clinical trials were inadequate 12-6 that Lemtrada provided substantial evidence of effectiveness in relapsing MS. The ADVISORY COMMITTEE voted 93

94. 14-2- (2 abstentions) against its benefits on disability. The ADVISORY COMMITTEE voted 94

95. 17 to 0 (1 abstention) that, safety results would not preclude approval. The ADVISORY COMMITTEE voted 95

96. 16-0 with two abstentions that Lemtrada should not be indicated as a first-line MS therapy. The ADVISORY COMMITTEE voted 96

97. ADVISORY COMMITTEE RECOS □ METHODOLOGY Potential Bias (unblinding of patients and physicians) Double dummy design +++ □ EFFECTIVENESS / FLARES □ DISABILITY □ SAFETY □ FIRST LINE 97 X X X

98. FDA REGULATORY PROCESS 98

99. OPEN PUBLIC HEARING 99

100. OPEN PUBLIC HEARING “ Lemtrada has the potential to be a highly effective treatment for MS. The determination of risk versus benefit is best to be considered between the treating physician and the informed patient.” Doug Franklin, CEO “ Other approved medicines also carry safety risks ” http://www.mymsaa.org/news-msaa/ CODE OF FEDERAL REGULATIONS (21 CFR PART 14) “If one of your family members had MS, wouldn’t you want them to have a choice? We, as patients, deserve the right to have a choice of therapy” Melissa Burdick 100

101. US BACKGROUND NO Marketing Authorization 1. FDA Regulatory Process 2. Consequences of rejection 101

102. CONSEQUENCES  Return of alemtuzumab to the US market for treatment of B-CLL  Off-label use of alemtuzumab for MS  using a formulation intended for B-CLL  from other countries (registered product) 102

103. 103

104. CONSEQUENCES  Return of alemtuzumab to the US market for treatment of B-CLL  Off-label use of alemtuzumab for MS  using a formulation intended for B-CLL  from other countries (registered product)  Appeal …. 104

105. SANOFI CEO CHRISTOPHER VIEHBACHER GENZYME CEO DAVID MEEKER January 23, 2014, Bloomberg TV  (…) this is a drug that has been approved by thirty countries around the world. We are seeing patients that have gone five years without a relapse so Sanofi believes that the drug actually is working and it's important for patients and that's why for the first time in my twenty-five years in the industry we're thinking about doing an appeal with the FDA.  (…) We can't possibly go do the new trial so the product comes to the market or it doesn't come to the market. In the rest of the world though the market is a little different. There are more MS patients in Europe than in the US so Lemtrada can still be a big success. February 6, 2014, Annual report  We did receive a complete response letter from the FDA in late December. As you know, we are in the process of appealing that decision. (…)  I think it's important to put this in a bit of context. As we look at the overall franchise and the unmet medical need in the multiple sclerosis market, U.S. patients represent about 400,000 out of the 2.1 million patients affected with MS (…) we'll continue to work with the FDA to find hopefully a path forward. http://seekingalpha.com/article/2000831-sanofi-management-discusses-q4-2013-results-earnings-call-transcript Feb 6, 2014 105

106. FDA is committed to the principle that regulated industry has a right to disagree with an agency decision, action, or operation, and that full and open discussion of issues in controversy produces a better decision in the end. Moreover, regulated industry is entitled to receive high quality administrative practices and procedures from all parts of FDA.” (FDA Ombudsman’s website) FDA APPEAL PROCESS Guidance for Industry – Formal Dispute Resolution: Appeals Above the Division Level 106

107. APPEAL PROCESS FDA Ombudsman CDER/CBER Ombudsman Division Director 107

108. Regulatory Sclerosis Time is short The FDA Nixes a Pathbreaking Drug for MS The Wall Street Journal Friday, January 17, 2014 1,000 Neurologists Were Asked About Lemtrada; This Is What They Said http://seekingalpha.com/author/chris-demuth-jr/instablog/4 108

109. 109

110. IV.CONCLUSION To date : European MA Price & reimbursement pending But FDA : Doesn’t seem to be willing to approve Patient First  FDA required Campath ® re-introduction To be continued… 110

111. 111 d ’ u n m é d i c a m e n t n ’ e s t p a s

112. Bibliography www.sanofi.fr www.genzyme.fr www.ansm.sante.fr www.ema.europa.eu www.fda.gov www.thelancet.com www.nature.com www.nejm.org 112

113. BACK UP 113

114. STATISTICS 114 CDER Formal Appeals by FY & Acceptability CDER Formal Appeals Accepted by FY & Granted/ Denied DIA 2013 – 49 th annual meeting Amy Bertha CDER/CBER Formal Dispute Resolution: Appeals Above the Division Level

115. 115

116. Hybridoma cell secreting monoclonal antibodies with bottle of Campath-1H. Image compiled from photos kindly supplied by Geoff Hale. 116

117. ALEMTUZUMAB ONE TARGET : CD52 Expert Opin. Biol. Ther. (2010) 10(3):421-429 117

118. NDA ALEMTUZUMAB APPLICATIONS ► 118

119. FDA 119

120. DISPUTE RESOLUTION 1. first discuss with the review team and Division Director 2. CDER/CBER Ombudsman 3. FDA Ombudsman (Agency level) «3. alternatively, you may raise the matter up the management chain by either contacting the director of the Office to which the Division/Office reports or invoking the formal dispute resolution process The request for formal dispute resolution should be submitted to the appropriate review division as an amendment to the application BLA 120

121. A SIMILAR SAFETY Interferon beta 1a (n=187) Alemtuzumab (n=376) Infusion-associated reactions (any event) NA338 (90%) Infections (any event)85 (45%)253 (67%) Malignant disease : thyroid cancer 02 (1%) Blood and lymphatic system disorders (any event) 36 (19%)66 (18%) Of which 3(1%) : immune thrombocytopenic purpura 121

122. OVERALL RESPONSE RATE (CR+PR) CR= freedom from clinical disease for at least 2 months with normal blood count (Hb> 11g/L, neutro>1.5 G/L, Lc 100G/L), no lymphadenopathy, no hepatosplenomegaly, less than 30% small Lc in the bone marrow without nodules PR= at least 50% reduction in lymphadenopathy or hepatosplenomegaly for at least 2 months for one. 122

123. EVALUATION IN B-CELL : SAFETY CAM211 -Infusion related toxicity -Infections complications -Cytopenias and immunosuppression CAM307 -Infusion related -CMV events 123