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ALZHEIMER IMMUNOTHERAPY Debarge Valentin Fontaine Quentin Olivier Jérôme $1,5 billion : a good investment? 02-2009.

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Presentation on theme: "ALZHEIMER IMMUNOTHERAPY Debarge Valentin Fontaine Quentin Olivier Jérôme $1,5 billion : a good investment? 02-2009."— Presentation transcript:

1 ALZHEIMER IMMUNOTHERAPY Debarge Valentin Fontaine Quentin Olivier Jérôme $1,5 billion : a good investment?

2 Summary I/ The deal II/ Mechanism of Alzheimers disease III/ Active immunisation V/ Our opinion IV/ Passive immunisation 1

3 I/ The Deal 2

4 JULY 2, 2009 I/ The Deal 3

5 Alzheimer Immunotherapy Program (AIP) : In 2008, Elan spent $113 million on AIP, partnered with Wyeth (now Pfizer), and estimated it would spend as much as $500 million on bapineuzumab and the rest of the portfolio over the next 3 or 4 years. Impossible for Elan NATURE BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009 I/ The Deal 4

6 Summer 2008 : two more patients taking the multiple sclerosis drug Tysabri (natalizumab) had contracted a potentially fatal brain disease : progressive multifocal leukoencephalopathy The J&J deal solves both problems These events combined to drive down Elans stock from more than 23 to less than 10 I/ The Deal 5

7 « As of April 2009, J&J did not list any neurodegenerative programs in its pipeline. We believe that AIP gives us a significant opportunity to build a position in Alzheimers disease by getting access to a late- stage molecule* that has potential in delaying progression of Alzheimers disease. J&J spokesman Srikant Ramaswami * bapineuzumab BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37 What did J&J want ? 6

8 BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37 Transaction I/ The Deal $885 M 18,4% Elan's capital IP Elan (AIP) Estimated at $500 M $ 500 M 49,9% Janssen AI's capital Royalties Under conditions

9 BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37 Transaction J&J purchased million Elan's shares at $8,241/share J&J also agreed not to acquire any more shares for the next five years The program will remain partnered with Wyeth, which was acquired by Pfizer Inc (01/2009, $68 billion) I/ The Deal Royalties : ONLY after J&J has earned profits from the AIP equal to its $500 M Janssen AI: all annual in-market sales Royalties for Elan $2 billion - $4 billion5 % $4 billion - $ 10 billion7 % > 10 billion9 %

10 Ian Sanderson, analyst at Cowen, New York, gives bapineuzumab a 50% likelihood of reaching the market, based on clinician surveys conducted by the investment bank. NATURE BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009 Bapineuzumab Whats the level risk for J&J ? 9

11 Bapineuzumab Probability of success estimated = 50 % < 80 % Why ? AN 1792 fail Disappointing phase II results « first in class » in CNS therapeutic area

12 NATURE BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009 Active immunotherapy Fail of AN 1792 Only in phase 2 today If immunotherapy fails … Empty pipeline ! No γ-secretase inhibitor No Abeta aggregation inhibitor Tau protein way non explorated Whats the level risk for J&J ? 11

13 Alzheimer's disease : background Leerink Swann analysis. Extrapolated from UN census and prevalence data from 2008 US Alzheimer's facts and figures 12

14 $ 6.0 billion in 2008 $ 7.8 billion expected in 2011 NATURE MEDECINE VOLUME 12NUMBER 7JULY 2006 Alzheimer's disease drugs market 13

15 Alzheimer's disease costs NATURE MEDECINE VOLUME 12NUMBER 7JULY 2006 The current direct and indirect cost of caring for the 4,5 million Americans with AD was at least $100 billion annually in 2006 and estimated at $160 billion in 2010 Medicare costs Medicaid costs 14

16 Solanezumab is the main competitor of bapineuzumab but the overall trial is anticipated to be completed in mid 2012 Are they alone on the target ? 15

17 II/ Mechanism of Alzheimers disease 16

18 La maladie dAlzheimer : aspects moléculaires, diagnostiques et thérapeutiques Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 Octobre 2009 Alzheimers disease Disease or neurodegenerative progressive appearance of mnemonic disorders evolving towards: a syndrome aphaso-apraxo-agnosic syndrome progressive loss of nerve cells in the brain death 17

19 La maladie dAlzheimer : aspects moléculaires, diagnostiques et thérapeutiques Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 Octobre 2009 Histological signs We observe two types of damage in the neocortex : Tau protein and neurofibrillary tangles=NFTs (intra-neuronal) Beta amyloid protein (Aß) and senile plaques (extra-cellular) 18

20 La maladie dAlzheimer : aspects moléculaires, diagnostiques et thérapeutiques Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 Octobre 2009 Senile plaques = insoluble substance (Aß) which settles slowly and gradually +++ in the grey matter of the cerebral cortex This substance seems to be neurotoxic in particular for neurones involved in the intellectual functions (memory, reading, writing, language, visual recognition …) Amyloid cascade hypothesis Synthesis of Aß peptide 19

21 Synthesis of Aß peptide From APP to Beta Amyloid (Aβ) 1 ) Amyloid precursor protein (APP) APP may help damaged neurons to repair themselves and may help parts of neurons to grow after brain injury APP sticks through the neuron's membrane Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA) Amyloid cascade hypothesis neurons grow neurons survive 20

22 Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA) 2 )Aβ is generated from APP : β-secretase cuts APP at an outside position of the cell γ-secretase cuts APP at an inside position of the cell membrane Synthesis of Aß peptide Amyloid cascade hypothesis 21

23 3 ) Fragments clump together and are mixed with other molecules,neurons and non-nerve cells Senile plaques Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA) Synthesis of Aß peptide Amyloid cascade hypothesis 22

24 Normal brain = Aβ 40 production > Aβ 42 production However, the amyloid plaque in Alzheimer's disease = Aβ 42 Aβ 42 aggregation faster than Aβ 40 Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA) Amyloid cascade hypothesis 23

25 The amyloid cascade theory JOURNAL OF NEUROCHEMISTRY|2009|110|1129–1134 Acknowledgments at the time of the deal

26 Genes involved in AD La maladie dAlzheimer : aspects moléculaires, diagnostiques et thérapeutiques Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 Octobre 2009

27 Can we unclutter plaques of Alzheimers Disease? 26

28 III/ Active Immunisation 27

29 Source:http://www.gensuisse.ch/gentech/mediz04_f.html ACTIVE: Injection of an antigen Production of antibodies PASSIVE: injection of antibodies directly Generalities of immunotherapy 28

30 Dale Schenk, Robin Barbour, Whitney Dunn, Grace Gordon,Henry Grajeda, Teresa Guido, Kang Hu, Jiping Huang,Kelly Johnson-Wood, Karen Khan, Dora Kholodenko,Mike Lee, Zhenmei Liao, Ivan Lieberburg, Ruth Motter,Linda Mutter, Ferdie Soriano, George Shopp, Nicki Vasquez,Christopher Vandevert, Shannan Walker, Mark Wogulis,Ted Yednock, Dora Games & Peter SeubertElan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, Amyloid-b peptide (Ab) seems to have a central role in theneuropathology of Alzheimers disease (AD). Familial forms ofthe disease have been linked to mutations in the amyloid precursorprotein (APP) and the presenilin genes. Disease-linkedmutations in these genes result inincreased production of the42-amino-acid form of the peptide (Ab42), which is the predominantform found in the amyloid plaques of Alzheimersdisease. The PDAPP transgenic mouse, which overexpressesmutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimers disease in an age- and brain- region-dependent manner. In the present study, transgenic animals were immunized with Ab42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-b déposition and several of the subsequent neuropathological changes were well established. We report that immunization of the Young animals essentially prevented the development of b-amyloidplaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD- like neuropathologies. Our results raise the possibility that immunization with amyloid-b may be effective in preventing and treating Alzheimer disease. Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse Source:Nature 1999 Beginning of Aβ42 immunisation 29

31 Human Mutation APP717 Source:http://www.gnis-pedagogie.org/pages/docbio/chap4/4.htm Production of Beta amyloid plaques Principle Beginning of Aβ42 immunisation 30

32 Transgenic Mouse with PBS Mouse immunised with Abeta 42 Human synthetic Results: Beginning of Aβ42 immunisation 31

33 PHASE I: patients: 64 treated+16 placebo 4 groups: 4 differentes formulations AN1792 (50 or 225 µg) with QS-21 adjuvant (50 or 100 µg) Or QS-21 only (control) in a 4:1 Source:http://www.ncbi.nlm.nih.gov/pubmed/ ?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&o rdinalpos=1 Elan pharmaceutical was the first in Active Immunotherapy on Alzheimer disease with AN1792 Results: - One meningoencephalitis - Good immune response First human trial: AN

34 Principal Objectif Patients Structure of immunisation Eligibility of inclusion Duration AN1792:phase IIa Randomized, multicenter, placebo controlled, double-blind IM Evaluation of safety and tolerance 300 patients : 225μg of AN μg of QS21 72 patients : NaCl Immunisation: 0, 1, 3, 6, 9 & 12 months Patients with Alzheimer Disease MMSE 16 to 26 Age: 50 – 85 years 12 months rather than 15 as originally planned First human trial: AN

35 Mini Mental State Examination Referential test for inclusions The lower the score, the more sever the disease Only If people have equal access to treatment Orientation to time Naming Registration Reading 30 : normal subject : mild AD : moderate AD Alzheimers tests on memory 34

36 Results of AN1792 IMMUNOGENIC RESULTS COGNITIVE EVALUATION OTHER EVALUATIONS Source:-www.ncbi.nlm.nih.gov:80/pmc/articles/PMC Neurology.2005 May 10;64(9): Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial 6% of meningoencephalitis 13/59 of responders 5/241 of low responders -No significant differences were found between antibody responder and placebo groups on battery of tests. -Only NTB test which revealed differences favoring antibody responders -CSF tau was decreased in antibody responders vs placebo subjects 35

37 Neuropsychological Test Battery Short-term & Long-term visual memory Short-term & Long-term auditive memory Verbal fluency language test Verbal learning test Long-term reminder memory test Memory span test Acquisition test 40 Alzheimers tests on memory 36

38 80 subjects enrolled into phase I study Phase I study completed 44 patients dead or refusing consent for clinical follow-up 12 patients treated 12 patients treated 12 patients with placebo 36 patients and/or carers agree to clinical follow-up and/or post mortem 10 patients died (10 treated) 10 patients died (10 treated) 26 patients alive (20 treated and 6 placebo) 26 patients alive (20 treated and 6 placebo) - Aβ42 immune response -degree of plaque removal -long-term clinical outcomes Follow of AN1792 AN1792 stops in 2002, 1 year later, start « follow-up study » for 3 years. Obj: assess 37

39 Persistent elevated Antibody titers No further cases of encephalitis Aβ load: -lower than in the unimmunised controls -was considerable variation both in the Aβ load and in the degree of plaque removal among the immunised participants No correlation : Between anti-Aβ antibody titres at long-term follow-up and rate of decline as measured by at 6-year follow-up (ADAS-Cog;MMSE, or DAD ) Follow of AN

40 39

41 There is no significant amelioration of survival or evolution to severe dementia between AN1792 and placebo groups. However, the small numbers of participants enrolled in the initial study greatly limit the power of this study and a larger trial might have shown some small benefits that could not be detected with the cohort size examined here. Follow of AN

42 Although immunisation with Aβ42 resulted in clearance of amyloid plaques in patients with Alzheimers disease, this clearance did not prevent progressive neurodegeneration. IMMUNOTHERAPY CAN BE ALWAYS A GOOD WAY FOR TREATMENT OF ALZHEIMER DISEASE? Conclusion for first immunotherapy tests 41

43 Principle Nature of Ag: injection 7 amino acid fragment Abeta N-terminal Supply:CRM197 (nontoxic variant diphteria toxin) Adjuvant:QS21 (to stimulate immune response) Story continues with ACC

44 First results In April 2008 the ACC 001 phase II study was suspended because one patient developed a vascularitis resulting in skin lesions. The cause is currently unknown Actually, this study is currently recruiting participants. Story continus with ACC

45 ArmAssigned Interventions 1: Active Comparator arm 1: ACC QS-21 2: Active Comparator arm 2: ACC-001 3: Placebo Comparator arm 3: QS-21 4: Placebo Comparator arm 4: Phosphate Buffered Saline Objectif Criteria of inclusion Scheme of phase II Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease Age: 50 – 85 years MMSE 16 to 26 ACC QS21 QS-21 is fixed at 50 micrograms. IM injection, dose 3-30micrograms, frequency: Day 1, month 1, 3, 6, &12. ACC-001 IM injection, dose 3-30micrograms frequency: Day 1, month 1, 3, 6, &12. QS-21: IM injection 50μg Drug: Phosphate buffered saline Story continus with ACC

46 Limits of Active immunisation approach: -The light immune response in older people -Trigger of chronic immune reaction and neurotoxic by T cell in the brain Also an other approach can be envisaged: PASSIVE IMMUNISATION 45

47 IV/ Passive Immunisation 46

48 1st humanized monoclonal candidate for AD Humanized version of the 3D6 murine monoclonal antibody Disulfide dimer between heavy and light chain of humanised mouses antibody AAB 001 IV phase III AAB 001 SC phase II Monoclonal Antibody Ig G1 Passive immunotherapie approach Target: the N-terminal 1-5 amino acids of Aβ peptides in amyloid plaques Goal: to bind to Aβ in the brain and facilitate its removal, yielding beneficial clinical effects What is Bapineuzumab ? 47

49 Three mechanisms postulated: Direct effect of antibody on amyloid β Dissolution Neutralization of Aβ oligomers Microglial cells with F c domain Plaques with Fab domain Phagocytosis Hypothesis on bapineuzumabs activity 48 The peripheral sink hypothesis : Administration of amyloid β specific antibodies Amyloid β specific antibodies lead to Efflux of Amyloid β from brain to blood Neurology december,2009

50 54 patients 50 to 85 years MMSE Diagnosis of AD The phase 1 study One single ascending dose placebo controlled double blind study Primary outcome measures: safety-tolerability Secondary outcome measure: to characterize the pharmacokinetic Studys design : 0,15 mg/kg or placebo 5,00 mg/kg or placebo Results Safety and Tolerance 1,5 mg/kg dose demonstrated a significant increase in MMSE score The dose of 5,00 mg/kg was associated with MRI abnormalities in 3 out of 10 patients Development of Bapineuzumab 49

51 The phase 2 study A randomized, multicenter, double blind, placebo-controlled study in patients with mild to moderate AD 0,15 mg/kg of bapineuzumab or placebo once every 13 weeks 0,50 mg/kg of bapineuzumab or placebo once every 13 weeks 1,00 mg/kg of bapineuzumab or placebo once every 13 weeks 2,00 mg/kg of bapineuzumab or placebo once every 13 weeks 234 patients 6 infusions of 1H Ratio 8B:7P Serum Cerebral Spinal Fluid Primary objectives: Safety & Tolerance Secondary objective: Efficacy Measurement PK/PD of Bapineuzumab Dosage of anti bapineuzumab antibodies 50 Development of Bapineuzumab

52 Inclusion Criteria Diagnosis of probable AD Age from 50 to 85 years 16

53 Hachinski Ischemic score Defines dementia nature The lower the score, the degenerative dementia Clinical criteria evaluated by doctor Depression ? Ischemia start Ischemia evolution Nocturnal confusion ? … Degenerative dementia: 0 4 Vascular dementia: 4 Alzheimers tests 52

54 Objectives: linear decline and compared treatment differences within dose cohorts 53 Neurology december,2009 Development of Bapineuzumab

55 Alzheimers tests on memory Alzheimers Disease Assessment Scale-Cognitive subscale Estimates severity and development of cognitive disorders Referential scale in all countries Unvarying method used at every visits Bad evaluation of attention fonctions & executive fonctions 11 advance sheets Scale fuller than MMSE No differences between kind of memory 54

56 Alzheimers tests Started action Carried out action Planned action Disability Assessment of Dementia Estimates 5 entry level activities and 5 instrumental activities in daily life For each activitythree answers 55

57 Started action Carried out action Planned action Disability Assessment of Dementia Estimates 5 entry level activities and 5 instrumental activities in daily life For each activity three answers 1 POINT Alzheimers tests 56

58 Neuropsychological Test Battery Short-term & Long-term visual memory Short-term & Long-term auditive memory Verbal fluency language test Verbal learning test Long-term reminder memory test Memory span test Acquisition test 40 Alzheimers tests on memory Sensibility NTB > Sensibility ADAS- Cog for dimly affected 57

59 Clinical Dementia Rating –Sum of Boxes A 5 points scale to characterize six domains Cognitive and functional performance 0=Normal 0,5=Very Mild Dementia 1=Mild Dementia 2=Moderate Dementia 3=Severe Dementia Memory Orientation Judgment and Problem Solving Community Affairs Home and Hobbies Personal Care Alzheimers tests evaluating daily life 58

60 59 Development of Bapineuzumab

61 Subject disposition Efficacy Results In the mITT population: Only trends on the ADAS –Cog the NTB In the Completer population: treatment differences were observed on the ADAS-Cog the DAD the NTB & only a trend on the MMSE 60 Neurology december,2009 Development of Bapineuzumab

62 One infusion every 13 weeks A dosage every 6 weeks One infusion every 13 weeks A dosage every 6 weeks No anti-bapineuzumab antibodies Bapineuzumabs activity blotter mecanism Bapineuzumabs activity blotter mecanism Bioavailability = 100 % 2 – 3 Bapineuzumab serum brain Pharmacokinetic Results Maximum concentrations 1 hour after each infusion Bapineuzumab dosage Small volume of distribution = ml/Kg Slow clearance 0,07-0,09 mL/h/Kg Long t ½ = days CSF Bapineuzumab 61 Neurology december,2009 Development of Bapineuzumab

63 Efficacy Results Exploratory analyses suggest to split population between ApoE4 Non ApoE4 62 Neurology december,2009 Development of Bapineuzumab

64 ApoE gene apolipoprotein E = component of VLDL lipoprotein responsible for removing excess cholesterol from the blood to the liver for processing Three alleles ε3: 65% ε2 :20% ε4 :15% = risk factor for AD Inherited from one parent: × 3 AD risk two parents: × 10 AD risk Carrier ApoE 4 allele AD AD Carrier ApoE 4 Why does ApoE4 gene influence study design? – 70 % patients with AD are ApoE4 carriers

65 Why does ApoE4 gene influence study design? 64

66 Deleterious action of ApoE4 in the brain Fixation ApoE4 + specific receptor link between receptor and APP Phagocytosis Proteases attack APP agregation of fragments cell death, memory loss and neurological dysfunction = Alzheimers disease Why does ApoE4 gene influence study design? 65

67 Efficacy Results For the 79 ApoE4 non carriers For the 146 ApoE4 carriers No treatment differences were observed on any endpoint including the ADAS-Cog the DAD 47 Bapineuzumab 32 Placebo Treatment differences were observed on the ADAS-Cog the NTB the MMSE the CDR-SB 72 Bapineuzumab 74 Placebo 66 Neurology december,2009 Development of Bapineuzumab

68 Efficacy Results ApoE 4 non carriers Mitt population The development of the Bapineuzumab 67

69 Efficacy Results The change in CSF biomarkers from baseline to Week 52 No differences in CSF Aβ or total τ Phospho-τ levels trend lower in Bapineuzumab-treated patients 68 Development of Bapineuzumab

70 Efficacy Results The change in CSF biomarkers from baseline to Week 52 No differences in CSF Aβ or total τ Phospho-τ levels trend lower in Bapineuzumab-treated patients 69 Development of Bapineuzumab

71 Efficacy Results MRI volumetric analyses through Week 71 (Mitt) Bapineuzumab patients In Total population no differences in brain volume & ventricular volume In ApoE4 carriers No significant change in brain volume Significant increase in ventricular volume Clinical relevance is unclear In ApoE4 non carriers Significant less brain volume decline than placebo 70 Neurology december,2009 Development of Bapineuzumab

72 Efficacy Results MRI volumetric analyses through Week 71 (Mitt) In Total population no differences in brain volume & ventricular volume In ApoE4 carriers No significant change in brain volume Significant increase in ventricular volume compared with placebo Clinical relevance is unclear In ApoE4 non carriers significant less brain volume decline than placebo ApoE4 Non carriers The development of the Bapineuzumab 71

73 Safety Results Most patients reported Adverse Effects 94 % Bapineuzumab 90 % Placebo 90 % mild to moderate in severity Back pain 12,1% vs 5,5%Weight loss 6,5% vs 1,8% Anxiety 11,3% vs 3,6%Paranoia 6,5% vs 0,9% Vomiting 9,7% vs 3,6%Skin laceration 5,6 % vs 2,7% Vasogenic Edema 9,7% vs 0%Gait disturbance 5,6% vs 1,8% Hypertension 8,1% vs 3,6%Muscle spasms 5,6 % vs 0,9% AEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients 72 Neurology december,2009 Development of Bapineuzumab

74 Safety Results Vasogenic Edema VE appeares with high signal intensity in the white matter 12/124 in Bapineuzumab group 0/110 in Placebo group after the 1 st or 2 nd infusion 12 VE detected by MRI In symptomatic patients, the most common AEs reported were 6 VE reported no clinical symptoms headache confusion vomiting gait disturbance One patient required dexamethasone treatment All these symptoms generally resolved over several weeks after cessation of dosing 73 Neurology december,2009 Development of Bapineuzumab

75 Safety Results VE increase with increase of bapineuzumab dose Bapineuzumab dose cohort VE rate 0,15 mg/kg3,2 % 0,50 mg/kg0 % 1,00 mg/kg10,0 % 2,00 mg/kg26,7 % ApoE statusVE rate ApoE4 carriers13,5 % (10/74) Non ApoE4 carriers4,3 % (2/47) 10 of 12 VE cases occured in ApoE4 carriers with a higher rate observed in ApoE4 VE rate increases with ApoE4 gene dose : 4,3% with 0 copy 33,3 % with 2 copies 74 Neurology december,2009 Development of Bapineuzumab

76 Apolipoprotein E4 enhances brain inflammation: better activation for NF-κB enriched in NF-κB response elements microglial and NF-κB activation more pronounced brain inflammation in apoE4 related to disregulation of NF-κB signaling pathway Growth of cerebral vasogenic edema ApoE 4 gene Vasogenic Edema 75

77 Positive benchmarksNegative Benchmarks Conlusion on Phase 2 study Safety Tolerability Greater efficacy in completer subjects (Non ApoE4) More advanced Aβ pathology in ApoE4 carriers may have affected the clinical response Efficacy not statistically demonstrated No segmentation on ApoE4 status Variable rate of decline in the treated & placebo groups Low-level statistical power for safety Inclusion of patients ever too ill Small dose cohorts 76 Neurology december,2009 Development of Bapineuzumab

78 The phase 3 study design: ApoE4 carrier ApoE4 non carrier ADAS-Cog DAD Avril 2009 Multiple dose, double-blind, placebo controlled, randomized, outpatient study Influenced by phase 2 results Endpoints : Efficacy & Safety on Treatment period : 18 mois Inclusion criteria Diagnosis of probable AD Age: years 16 < MMSE score < 26 MRI scan consistent with the diagnosis of AD Stable doses of medications (cholinesterase inhibitors and memantine allowed ) 2 cohorts well identified 77 Development of Bapineuzumab

79 The phase 3 stugy design: Multiple dose, double-blind, placebo controlled, randomized, outpatient stud y ApoE4 Non ApoE4 0,5 mg/kg of Bapineuzumab 1,0 mg/kg of Bapineuzumab 0,5 mg/kg of Bapineuzumab 1,0 mg/kg of Bapineuzumab 2,0 mg/kg of Bapineuzumab One infusion every 13 weeks A dosage every 6 weeks One infusion every 13 weeks A dosage every 6 weeks The development of the Bapineuzumab 78

80 The phase 3 stugy design: Multiple dose, double-blind, placebo controlled, randomized, outpatient stud y ApoE4 Non ApoE4 0,5 mg/kg of Bapineuzumab 1,0 mg/kg of Bapineuzumab 0,5 mg/kg of Bapineuzumab 1,0 mg/kg of Bapineuzumab 2,0 mg/kg of Bapineuzumab To decrease VE risk The development of the Bapineuzumab 79

81 Efficacy statistically showed in phase 3 Non ApoE4 0,5 mg/kg 1,0 mg/kg Marketing for Non ApoE4 carriers Non ApoE4 Marketing for Non ApoE4 carriers First-in-class diagnosis test Whats next for Bapineuzumab? 80

82 Efficacy statistically showed in phase 3 ApoE4 Marketing for ApoE4 carriers 0,5 mg/kg ApoE4 Non ApoE4 0,5 mg/kg Marketing for overall population First-in-class diagnosis test 81 Whats next for Bapineuzumab?

83 Critical reappraisal of amyloid hypothesis JOURNAL OF NEUROCHEMISTRY|2009|110|1129–1134 HypothesisStatusComments Other causes of AD would relate to Aβ production and clearance: PS I&II mutations γ secretase Aβ 42 ApoE4 Aβ deposition increased Validated By the cloning of PS I&II Aβ shoul be toxic +/- ValidatedAβ oligomers have a synaptic effect but << massive cell loose Aβ induces tangle disfunction ValidatedLink unknown Reducing Aβ & plaques would ameliorate AD symptoms Non validatedNot seen in clinical trials

84 SWOT StrengthsWeaknesses Proof of concept for immunotherapy Active immunotherapy: disappointing results/meningoencephalitis MAB most advanced Disappointing clinicals results of phase II for bapineuzumab Buyback of AIP: several products and experience phase III of Bapineuzumab not much conclusive currently If Abeta theory fails not γ secretase inhibitor, or products against Tau OpportunitiesThreats Before buyback nothing in pipeline Others companies on Alzheimers disease immunotherapy and others targets First in Alzheimers immunotherapy marketSolanezumab (Lilly) on phase III Market of $ 6 billion Early diagnostic is a problem BSP:forbetaben (phase III)

85 Our opinion about this deal !! 84

86 Thanks for your attention! 85

87 Any questions? 86

88 Special thanks Dr Mackowiak Marie-Anne (department of neurology CHRU Lille Mr Bertin Benjamin (laboratory of immunology) Mr Carnoy Christophe (laboratory of immunology) Mr Tartar André (organic laboratory chemistry) Mrs Gras Hélène (laboratory of therapeutic chemistry) 87


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