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Campath® Withdrawal Anatomy of a Brainstorming Coralie Duriez, Philippine Guillier, Valentine Ripert, Pierre Titeca August 2012 « Arrêter la commercialisation de la spécialité ISSUES : Scientific « décision n’est pas prise pour des motifs de tolérance ni d’efficacité, ni d’approvisionnement Strategic » « se consacrer au développement Ethic dans le traitement de la MabCampath » sclérose en plaque » 2 -1- Alemtuzumab, Scientific aspect 3 Introducing Campath = Alemtuzumab, AcM • 3 generations, 3 isotypes 1980 Campath-1M IgM (rat) 1986 Campath-1G IgG (rat) 1987 Campath-1H IgG1 (human) • First humanized antibody • Ac => Ag 4 Targeting CD52 CD52 Glycosylphosphatidylinositol (GPI) anchored protein 12 amino-acids, negative charged Expressed on B-cells, T-cells, Monocytes Fonction anti-adhesion • Monoclonal Ab humanisé recombinant de type IgG1 kappa • CDR-L3 : Dominant role in Antigen Binding • Ionic interactions • An optimized Paratop 5 Alemtuzumab 6 General mecanism of Mab 7 8 Prospects • Immunosuppression potentiel known since 90’s • Kill lymphocytes by – Complemet-mediated lysis – Cell-mediated lysis • Extensive research : – – – – Leukemia Vascularitis (1990) Marrow and organ transplantation (1991) Treatment of various autoimmune diseases • Rhematoid arthritis(1992) • Multiple sclerosis (1994) 9 B-CLL 10 Several targeted treatments options of B-CLL 11 Chronic Lymphocytic Leukemia • Accumulation in the blood, bone marrow and secondary lymphoid organs of small B-cell monoclonal mature morphology but immunophenotype characteristic. – B lymphocytosis > 5000/mm3 – Surface markers characteristic : IgM, IgD, CD19, CD20, CD23, CD5+ • Incurable disease 12 Figures • Incidence : 4,1 pour 100 000 (Australia, USA, Ireland, Italy) • Elderly (60 years old) • Male predominance (2/3 of cases). • The 5-year relative survival is about 80%. 13 Symptoms • • • • • • • Fever, fatigue Weight loss shortness of breath Night sweats Lymphadenopathy Thrombocytopenia Anemia, splenomagalie. • Asymptomatic 25% of cases not treated Complications • Infections • Auto immune: hemolitique Anémia, Thrombopenia • Lymphoma 14 Main Treatments –Fludarabine –Chlorambucil Deletion 17p resistance –Cyclophosphamide –Allogeneic hematopoietic stem cell 15 Development ? Strong need of New Chemicals for B-CLL Clinical development of Gets a TUA already used - 2001 16 CAM 307 To verify clinical benefit in an open-label, international, multicenter, randomized trial. J Clin Oncol 25:5616-5623. © 2007 by American Society of Clinical Oncology 17 CAM 307 : Phase III study From 2001 to 2004 Annual Cycle CAM 307 297 naive patients RAI I to IV Alemtuzumab® 3mg ; 10mg ; 30 mg i.v Chlorambucil ® 40 mg/m² oraly - 3 times/week 12 weeks - Once every 28 days maximum of 12 month 18 Procedure Primary Endpoint Secondary Endpoint Progression- free survival (PFS) Duration. Overall and Complete response rates OR and CR > 2 months 19 Kaplan-Meier estimates of progression-free survival (PFS) based on Independent Response Review Panel. 20 21 22 Other treatements depends on "suicide gene" 17p53 Deletion resistance Campath independent from gene TP 53 17th chromosome locus P53 23 Alemtuzumab as First line therapy for B-CLL ? - 2007 - « Alemtuzumab has been shown to be an effective monotherapy in both firstline and refractory chronic lymphocytic leukaemia. » « Notably, in patients who had the cytogenetic deletion of 17p (p53), there was a three-fold increase in OR with alemtuzumab (64%) compared with chlorambucil (26%) » 24 In practice • The therapeutic strategy depends on the existence of comorbidity(s), the presence of 17p deletion and the nature of prior treatments • 17p deletion: 10% of patients 25 Marketing authorization approval • FDA : September 2007 • EMA : July 2001 • « MabCampath is used to treat patients with B-cell chronic lymphocytic leukaemia [...] MabCampath is used in patients for whom treatment combinations including fludarabine (another medicine used in leukaemia) are not appropriate. » RCP 26 Multiple sclerosis 27 MS & autoimmunity Molecular mimicry Hypothesis • High involvment of Lymphocytes (CD52) 28 Autoimmunity & Pathogenicity Inflamation reaction In the MS, the cells of the immune system cross the hémato-meningeal barrier and affect the girdle of myélin surrounding nerves. Démyélinisation Myelin: Protect these fibers and accelerate the transmission of the nervous messages Change of the impulse transmission 29 Multiple Sclerosis Worldwide • + 2,5 millions people diagnosed • 2000 per year in France • Affects 20 to 40 years old people • Incapacitating disease ++ 1st cause of neurological disability Environmental Factors? Hygien, UV-, Tobacco 30 Clinical signs Motor disorders muscle weakness, motor control, loss of balance Sensory disorders numbness, tingling, loss of sensitivity of certain parts of the body Visual disorders decrease of sight, mouth, optic neuritis Cognitive disorders memory loss, decrease in attention Urinary and sexual problems incontinence, impotence, dysuries 31 3 upgradable forms • Relapsing-remitting stage RRMS (70%) • Relapsing-persistant deficits SPMS (20%) • Progressive persistant stage PPMS (10%) RRMS SPMS PPMS 32 How to score MS • Score of quality of life • EDSS Scale Quantifiing Disability 33 Background treatments Main treatments Relapses treatments Corticoïdes IV méthylprednisolone Background treatments ( RR forms ) Immunomodulators IM or SC Interféron Béta : Rebif, Betaferon, Avonex prevent cells of immunity to cross this BHE Acétate de glatiramère : COPAXONE Protein which looks like the protein of the myéline plays the role of delusion 34 1991-2002: Cambridge Experience Firsts trials for « Campath-IH » in MS 7 patients with MS, 10-day intravenous course • Central nervous system lesions of MS detected by MRI with gadolinium M-3 +51 active lesions Treatment M+3 +15 active lesions M+6 +2 active lesions BUT : – Rate Ratio significantly reduced in only 3 patients – First infusion : exacerbation or re-awakening of preexisting symptoms, TNF, IFN (H+2), IL-6 (delayed H+4) 35 Early MS only ? Results of a first open label Study of Alemtuzumab in MS patients limits the applications RRMS patients SPMS patients Study fomat Open label Open label Number of patients 36 22 Reduction in ARR 94 % 97% Mean evolution of EDSS score after 2 years ( per patient per year) -1,2 + 0,2 A.J.Coles, et Al J.Neurol.253 (2006) 98-108 • BUT infusion causes : • acute cytokine-release syndrome consisting of pyrexia, headache, malaise and an urticarial rash • exacerbation of neurological symptoms => Substancially ameliorated by pre-treatment with corticosteroids36 CAMMS 223 : Phase II Study blind, randomized, 2002-2007 (2 years follow-up) Annual Cycle 111 - IFN B 1a Rebif ® 44μg, SC 3 times a week 113 - Alemtuzumab 12mg, IV - Month 1 : 1/d for 5 days CAMM 223 334 naive treatments patients MSRR EDSS ≤ 3.0 - Month 12 : 1/d for 3 days 110 - Alemtuzumab 24mg, IV - Month 24 : 1/d for 3 days 37 Procedure Primary Endpoint Secondary Endpoint -Annualized relapse rate -Time to sustained accumulation of disability -Lesion load on T2-weighted MRI at 12/24/36 month -Brain volume on T1 weighted MRI EDSS reevaluated every 3 months MRI every years 38 Outstanding results - Reduction in relapse rate and sustained disability - Could even be better than approved therapies 39 ECTRIMS Investor Presentation October,14,2010 Persistance of effect in Time – 5years 5years follow up of CAMM 223 40 “ It is the first time when by treating early sick young people, we observe a decrease of the handicap. The images by MRI of the brain of the patients taking the experimental medicine, show an increase of the cerebral volume, so the brain repairs ”. Dr Alasdair Coles Clinical trials : until 2010 41 Alemtuzumab : neuroprotective effects ? • Increased concentration of : – Brain Derived Neurotrophic Factor related to nerve growth factor • Increased axonal lengh : myelinisation – Ciliary Neurotrophic factor • survival factor for neurones and oligodendrocytes Brain 2010/ 133;2232-2247 Neuroprotective Action strongly suspected 42 Studies of phase III Same Endpoints 43 Etude CARE MS I ( 2007-2011) Résults : After two years of alemtuzumab with regard to IFB beta 1a : Rate of relapse reduces of 55 % Etude CARE MS II : Rate of relapse reduces of 49% 44 Alemtuzumab : Side effects Much more effective than INF in terms of results BUT many questions concerning its tolerance !! • DEATH due to immune thrombocytopenic purpura • Infections • Events affecting thyroid ( hypertyroidism, hypotyroidism ) 45 A step forward? Current competitors used in RRMS: • Natalizumab Tysabri (Biogen Idec et Elan ) IV : approved in 2007 • Fingolimod Gilenya (Novartis ) : approved end 2011 46 New Therapeutics marketed in Active MS Natalizumab TYSABRI Fingolimod GILENYA Biogen (FTY720, Novartis) Mechanism Monoclonal antibody anti-A4 integrin Modulator of the sphingosine-1-phosphate receivers Route of administration Intravenous way Oral route Efficacity Side Effects WARNING FDA Decrease of 70% of pushes number Decrease of 90 % of new inflammations Reduction of 70 % of pushes frequency Stabilization of the brain damages • Hypersensitivity reactions • Bradycardia after first dose • Risk of Progressive Multifocal • Infections Leukoencephalopathy • Eye Macular oedema • Basal-cell carcinomas 2005 : 2 PML Suspension, then Black Box warning 2011 : reported death after administration 47 Comparision of both indications Alemtuzumab for Disease CLL RRMS + 60 years 25 -35 years Prevalence + +++ Incidence 4 per 100.000 80 per 100.000 + ++ CAM 307 Care-MS 1 et 2 Age Position on Market Clinical Trials Adverse Events Lymphopenia, neutropenia, Infections Thrombocytopenia Anemia An obvious lucrative 2nd indication Thrombocytopenic purpura Infections Hypotyroidism Hypertyroidism GO FOR MS ? 48 Context • The biotechnology pharmaceutical companie Genzyme : the manufacturer of alemtuzumab • In August 2010, Sanofi makes a friendly takeover bid for Genzyme 49 Acquisition of Genzyme by Sanofi-aventis • The acquisition was delayed by a dispute between the two companies regarding the value of alemtuzumab. Business Unit Therapeutic Area Products Research Pipeline Rare diseases Genetic diseases Cerezyme, Fabrazyme, Aldurazyme, Myozyme, Lumizyme, Elaprase Eliglustat Mipomersen Endocrine Thyrogen Cardiovascular Cholestage Multiple Sclerosis Aubagio Alemtuzumab 50 Genzyme and Sanofi agree on deal outline • February 16, 2011: definitive agreement : Sanofi-aventis bought Genzyme for $20.1 billion in cash ($74 per share), plus payments contingent on the success of some of Genzyme's drugs • => Sanofi acquires a molecule with dual indication, how will be use its potential ? 51 - 2 – Strategic aspects How to market alemtuzumab for MS ? 52 Extending the indication? Y1 - No Y2 First infusion Campath 30 mg/injection / 36 injections Alemtuzumab in MS 12mg/injection / 5+3 injections Different dosage = Different M.A. 53 Marketing Authorization • Requires – Registration dossier : Clinical studies • drug safe and effective in its proposed use(s) benefits of the drug outweigh the risks – Appendixes : labelling, SPC, drug instruction – Drug Monitoring and Risk Management Plan – Price – A Trademark name No Restraint ! 54 55 Drug Value What’s the acceptable cost of an effective medicine ? • Drug value evaluated by: – QALY =Quality Adjusted Life Year – ICER = incremental cost-effectiveness ratio • a measure that assesses the additional cost for a new treatment • ∆Cost / ∆Efficacy • In UK ICER per QALY >30.000 Not Cost-Effective <30.000 Cost-Effective 56 Informal Care 12% Adaptations 5% Services 2% Other Drug 6% DMTs 22% Global Costs of MS Sick Leave / Reduced Work 10 % Early Retirement 34 % Hospital Inpatient Care 3% Ambulatory Care 4% Tests 2% 57 ICER of Tysabri Tysabri Compared with IFN Copaxone RES-RRMS 32.000 £ 34.600 £ Suboptimal therapy group 43.400 £ 44.300 £ Natalizumab for the treatment of adults with highly active relapsing– remitting multiple sclerosis, NHS, June 2010 Course of 20 years 30 years ICER Natalizumab vs B-INF 32.000 £ 24.600 £ COST-EFFECTIVENESS FOR ACTIVE MS RES-RRMS : Rapidly Evolving and Severe RRMS 58 Cost of a 1 year treatment Natalizumab (Tysabri®) Fingolimod (Gylenia®) Dose per pack 1/4w, injection 1/d, oral route WAC per package $ 3.076 $ 3.688 WAC per Year $ 39.985 $ 47.951 Ken O’Day and al. Cost-effectiveness of natalizumab versus fingolimod for the treatment of relapsing multiple sclerosis. Journal of Medical Economics Vol. 14, No. 5, 2011, 617–627. What to expect for Lemtrada? 59 What to expect for Alemtuzumab in MS? If QALY >>>, then the Cost-effectiveness rises Price ↗↗ 60 When 1mg of powder is worth gold… Campath® - BCLL Lemtrada® - MS Tysabri® - MS Weight per vial 30 mg 12 300mg Number of vials 36 8 13 Per mg $55 $55 $416 $15 WAC per package $1.666 $660 $4.998 $4.576 WAC per year $60.000 $5.280 $39.985 $39.985 • If we assess that Lemtrada will cost at least what costs Tysabri : – Then price per mg for the same chemical would increase by $55 to $416 : x8 – Price of APIs are only connected with pathologies 61 Same chemical + $/mg (Lemtrada) = 8 times $/mg (Campath) + Clinical Studies for both indications = Off-Label Risk OR : A pharmaceutical industry is liable for the off-label uses of its products, and is to manage or prevent them Avastin / Lucentis “Given the known safety profile of alemtuzumab, I think MS doctors will be reluctant to use it off label.” Til Menge, University Hospital Dusseldorf 62 Off-label-use : hefty bill • Avoid the use of Alemtuzumab before & after the MS-indication approval ? Total dose 60mg (Y1) + 36mg (Y2) Number of Campath® 30mg vials Total Cost ($1.666) 4 $6.666 • Estimated Losses : from $30.000 to $35.000 per patient (compared to Tysabri®) • Potential market : 700.000 patients 63 Campath®-Alemtuzumab Patent Expires in 2014 64 Biosimilars • Estimated price for biosimilar products will be 65%-85% of their originators. • FDA : Patient Protection and Affordable Care Act (2010) – Abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. • Pending arrival of Biosimilars – A Campath’s biosimilar could cause off-label uses for MS 65 Avoiding off-label use Reglementary concerns ? or Financial protection ? 66 • A different Market Authorization for Lemtrada®: – A different Trademark name – A price legitimataly corresponding to MS-market But • 2 indications requiring different doses : – A previous indication ruining the price/mg – A high-risk of off-label use of Campath® for MS 67 Decision Sanofi withdraws Campath 68 Financial report, August 2012 • « Campath est actuellement approuvé aux États-Unis, en Europe et dans quelques autres juridictions dans certaines indications oncologiques. Genzyme mettra fin à la commercialisation de Campath. Cette décision n'a pas été prise pour des raisons liées à la qualité du produit, sa sécurité, son efficacité ou son approvisionnement dans les indications actuellement approuvées, mais parce que Sanofi et Genzyme ont décidé de se concentrer sur Lemtrada™ pour la sclérose en plaques, et il existe des différences dans le dosage et le profil d’innocuité entre Campath et Lemtrada. Compte tenu de l’arrêt de la commercialisation de Campath, Sanofi travaille avec les autorités de santé pour mettre en place des programmes d’accès au médicament par le biais desquels Sanofi fournira Campath gratuitement pour les indications dans lesquelles le produit est actuellement approuvé. Dans le 69 cadre de ce processus, les autorisations de commercialisation - 3 – Regulation, ethical approach and risk management 70 Regulation • « Should a marketing authorisation holder decide withdraw it from the market before the expiry of its marketing authorisation, he shall accordingly inform the Agency six months in advance. » • Will prevent the off-label use (laboratory is responsible for offlabel uses of their products) • Additional security against the potential future generic 71 Patients First 72 Consequences for patients • Patient without treatment • Ethically, it is unthinkable for Leukemia Patients to deny the access to their treatment. • First line in 17p deletion 73 Incredible patient access program • Patient access program : for all patients who need it ( current users and future users) • Free of charge : $0 • For oncologists for CLL and malignancies 74 Incredible patient access program • Nominative TUA – Second TUA – TUP • monitoring and surveillance of patients • terms of drug dispensing and monitoring of patients • Product request form (basic patient information, the intended use, the number of vials requested and agree to the terms and conditions of the program) 75 76 Incredible patient access program • Nominative TUA • Product request form (basic patient information, the intended use, the number of vials requested and agree to the terms and conditions of the program) • Genzyme is required to transmit to ANSM every 6 months a report • How long time ? No end date published 77 Patient associations and prescriber reactions CLL MS -Hildy Dillon, vice president of patient services for the Leukemia & Lymphoma : «They’ve actually been quite supportive to us and our constituents » -Three British Neurologists have written to the Health Minister, Jeremy Hunt, to protest against Genzyme - Prescriber : addition of more paperwork, Loss of time -Multiple sclerosis research blogspot : a blog for people with MS ans their families => + FAVORABLE => +++ UNFAVORABLE 78 Therapeutic alternative ARZERRA (ofatumumab) IV monoclonal antibody (CD20) • Treatment of patients with CLL who have not responded to fludarabine and alemtuzumab. • Side effects : Infection ++, Infusion reactions, Low blood cell counts, Bowel problems 79 Work in MS 80 Alemtuzumab, MS • This stoppage shows Sanofi's confidence in the approval of Alemtuzumab in multiple sclerosis 81 Focus in preparation for global launch Japan Spain four key countries Italy France 7% UK 9% 57% 660,000 diagnosed patients 16% USA Positive initial conservations with stakeholders Germany MS prevalent populations across 7 majors pharmaceutical markets 100% = 740 000 patients in 7 major markets 82 Alemtuzumab, MS • FDA : action expected on the application in the second half of 2013 (in August 2012, the FDA asked Sanofi to resubmit its application) • Genzyme has already submitted its marketing authorization application for Lemtrada to the EMA and the review process is underway. • Expected price after negociation : – 45 000 to 50 000/year 83 Risk management • Estimated sales Campath® 2011 $76.000.000 Lemtrada® 2018 $500.000.000 • Return on investisment – Purchase price of Genzyme : $20.1 billion – + CVR 84 Objectives of Sanofi • The withdraw of Campath was already programmed by Genzyme. While negociating, Genzyme required their prerogatives. • Terms of the CVR agreement call for additional cash payments under certain circumstances : • The CVR terminates on December 31, 2020 • $14 per CVR : $3,8 billion $1.00 per CVR if specified Cerezyme®/Fabrazyme® production levels are met in 2011 $1.00 per CVR upon final FDA approval of LemtradaTM for multiple sclerosis indication $2.00 per CVR if net sales post launch exceed an aggregate of $400 million within specified periods per territory $3.00 per CVR if global net sales exceed $1.8 billion $4.00 per CVR if global net sales exceed $2.3 billion $3.00 per CVR if global net sales exceed $2.8 billion 85 Prospect in MS Molecules in MS : • Natalizymab (Tysabri*) • Fingolimod (Gilenya*) MARKET IN MS DRUGS in 2013 in 2022 (estimation) $13,8 billion $19,6 billion Pipeline in MS : • • • • Ocrelizumab (OPERA and ORATORIO Phase 3 : ORCHESTRA) Daclizumab (SELECT Phase 2b and DECIDE Phase 3) Fampyra (MS-F203 and MS-F204 Phase 3) BG-12 (Fumarate de diméthyl) : Currently under regulatory review (DEFINE and CONFIRM Phase 3) 86 Sanofi in MS • Teriflunomide (Aubagio*) • once-daily pill • Sept, 2012 : Market authorization in US and Australia • Alemtuzumab (Lemtrada*) • « When you walk in the display area, we are as prominent as any other company. We are a player now ». Bill Sibold, Genzyme head of MS 87 MERCI DE VOTRE ATTENTION 88