1 1 Dr. Walter Schmidt Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease GESENT, Bonn GESENT, Bonn GESENT, Bonn GESENT, Bonn December 2, 2011 December 2, 2011 December 2, 2011 December 2, 2011 Achim Schneeberger Achim Schneeberger Achim Schneeberger Achim Schneeberger CMO, AFFiRiS CMO, AFFiRiS CMO, AFFiRiS CMO, AFFiRiS 2 Dr. Walter Schmidt Agenda Facts + Rationale State of the Art: active & passive AD IT Focus on AFFiRiS vaccines (AD01, AD02, AD03) Challenges in AD drug development Summary & Conclusion
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1 Dr. Walter Schmidt
Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease Immunotherapy of Alzheimer‘s disease
GESENT, BonnGESENT, BonnGESENT, BonnGESENT, Bonn
December 2, 2011December 2, 2011December 2, 2011December 2, 2011
=> redosing in 6/12 wo additional VE (lower dose level)
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11 Dr. Walter Schmidt
Bapineuzumab®
humanized A Antibody 148.8 kDa
Phase II:Safety:- vasogenic edema (related to dose and APOE4 status)
Efficacy:- posthoc: cognition and global function – benefit in APO E4 neg. pats (no dose effect)- PK: t1/2: 20-33 days, no Bapineuzumab® neutralizing Abs
in Phase III:global Phase III program (ca. 4000 patients)
Stratification according to APO E genotype
APO E4 pos: 0.5 mg/Kg, x13 weeks; USA and international; 800 pat. each
humanisierter A Antikörper; LY2062430, IgG1κ ; 144,1 kDa
Phase II:
Sicherheit (kein vasogenes Ödem)Pharmakokinetik
in Phase III klinischer Entwicklung:
internationales (USA, Kanada, Argentinien, Japan) Phase III Programm, 1000 Patienten, Start Mai 2009, Ende Juli 2012Behandlung: 400 mg i.v. alle 4 Wo durch 80 Wochen
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Not all the same…
N-terminus Mid-domain C-terminus
Name Bapineuzumab Solaneuzumab Ponezumab
Target aa1-5 aa16-24 aa33-40
Isotype IgG1 IgG1 IgG2∆a
murine equiv. 3D6 m266 2H6
3D6 m266
14 Dr. Walter Schmidt
Not all the same…
N-terminus Mid-domain C-terminus
Name Bapineuzumab Solaneuzumab Ponezumab
Target aa1-5 aa16-24 aa33-40
Isotype IgG1 IgG1 IgG2∆a
murine equiv. 3D6 m266 2H6
3D6 m266
≠
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IVIG – Passive Immunization?
AAAAβ40404040 AAAAβ42424242
Octagam (phase II): negative
Gammagard (NIH and Baxter) Phase III: -360 patients
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Human blood contains Aβ aggregate-sp antibodies: protective autoantibodies?
Controls vs. AD
Marcello et al, JNT 2009
Aβ fibrils CAPS
Aβ monomers 95% of 260 screened
donor plasma samples
contain amyloid fibril
reactive IgGs
O‘Nuallain et al, JCI 2010
CAPS = „synthetic“ fibrils
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Reverse Translational MedicineProtective Factor ?
Comparing antibody responses
Human Ab,protective properties?
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RTM™ delivered BIIB037
RTM™ delivered high affinity human-derived monoclonal Abs
against Aβ aggregates
Donor cohorts included elderly subjects with excellent and
stable cognitive performance, remission from beginning
disease or unusual mild course of dementia
Promising candidate: BIIB037
• High affinity and selectivity for aggregated Aß
• Crosses BBB and accumulates on β-amyloid plaques
• Reduces soluble Aβ in transgenic mouse brain (dose dependent)
• Dose dependent reduction of 6E10 immunoreactive Aβ deposits
• No increase in CAA or frequency of microhemorrhages
• Increased neurogenesis and dendritic arborization
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Developing Antibodies with specific properties
Hypothesis: Aβ protofibrils are the most toxic /
relevant Aβ species in AD pathogenesis
mAb m158: selective recognition of Aβ protofibrilsInhibition assay
Lannfelt & colleagues, BioArctic/Eisai
20 Dr. Walter Schmidt
Aβ protofibril-specific Antibody
Collaboration between BioArctic and Eisai:
Development of an Aβ protofibril-specific Antibody
Presence and/or history of immunodeficiency (e.g. HIV)
Pregnancy
Significant neurological disease other than AD*.
Significant systemic illness*
Inclusion Criteria Exclusion Criteria
* if considered relevant by the investigator
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ResultsPhase I- and Follow-up Studies
Phase I – AFF001 Follow-up study AFF003
AFF004 / Boost AFF004A Phase I – AFF002
AFFITOPE® AD01
AFFITOPE® AD02
Screenings 28 (16/12)
Enrolled 24 (13/11) 22 (12/10)
Drop outs 0 0
Screenings 29 (14/15)
Enrolled 24 (13/11) 23 (12/11) 20
Drop outs 0 0 0
20+2 weeks 52 we
20+2 we - 52 we
30 Dr. Walter Schmidt
Results
AFF001 AFF002
Adverse Events 348 285
SAEs 3 2
(Hosp. AF, Hosp. back pain, Paraphrasia)
(Hosp. diabetes therapy, Hosp. common cold)
SUSARs 0 0
local reactions 219 (10% / 90%) 162 (17% / 83%)
systemic AEs 129 (46% / 64%) 123 (60% / 40%)
drop outs 0 0
vaccination reaction none none
Meningoencephalitis no case no case
APP-spec. Antibodies none none
DSC opinion safe safe
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Results
AFF001 AFF002
Adverse Events 348 285
SAEs 3 2
(Hosp. AF, Hosp. back pain, Paraphrasia)
(Hosp. diabetes therapy, Hosp. common cold)
SUSARs 0 0
local reactions 219 (10% / 90%) 162 (17% / 83%)
systemic AEs 129 (46% / 64%) 123 (60% / 40%)
drop outs 0 0
vaccination reaction none none
Meningoencephalitis no case no case
APP-spec. Antibodies none none
DSC opinion safe safe
Both candidates met the primary phase I endpoints!
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AD02 – mode of action? Facts II
Clinical benefit in AD02-treated patientscontrols: advantage of adjuvanted versus non-adjuvanted
formulation; no benefit in AD01
Benefit over all disease-affected domains
Benefit in patients with MMSE ≥20
Parallel effect on body weight
Parallel effect in brain MRI parameters (ventricle volume)
Correlation with AD02 IgG titers
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Why wait?
Pederson, Lancet Neurology 2010
Presymptomatic Prodromal Dementia
>Neurodeg.
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Note: old criteria have a lowspecificity in clinical trials
J. Nicoll: 4/16 AN1792 recipients were no AD patients; rate of misdiagnoses: 25%
E. Masliah: series of 12 AN1792 recipients: 6 did not have AD; rate of misdiagnoses: 50%
Based on the neuropathological analysis of patientstreated within immunotheraoy trials:
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Diagnostic Criteria:Earlier & Positive Prediction
A - Early / significant episodic memory impairment
Probable AD: A plus one or more supportive featuresProbable AD: A plus one or more supportive featuresProbable AD: A plus one or more supportive featuresProbable AD: A plus one or more supportive features
Supportive features:Supportive features:Supportive features:Supportive features:B B B B –––– Medial temporal lobe atrophyMedial temporal lobe atrophyMedial temporal lobe atrophyMedial temporal lobe atrophyC C C C ---- Abnormal cerebrospinal fluid markerAbnormal cerebrospinal fluid markerAbnormal cerebrospinal fluid markerAbnormal cerebrospinal fluid marker
AAAAβ1111----42: low, ptau: high42: low, ptau: high42: low, ptau: high42: low, ptau: highD D D D ---- Specific pattern on PETSpecific pattern on PETSpecific pattern on PETSpecific pattern on PET
FDGFDGFDGFDG----PET, PIBPET, PIBPET, PIBPET, PIB----PETPETPETPETE E E E ---- AD mutation within the immediate familyAD mutation within the immediate familyAD mutation within the immediate familyAD mutation within the immediate family
Dubois et al., Lancet Neurology 2007
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FCSRT +/- MRI: validation studies
memory Memory
+ CSF
Memory
+ MRI
Memory
+ MRI + CSF
Sarazin(251 pts)
85%
Ewers
(385 pts )
94% 95%
Bouwman(145 pts)
97% 98% 100%
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Phase II Study on AFFITOPE® AD02
Early AD (MMSE ≥ 20)
FCSRT+BM
6 countries involved (Austria, Germany, France, Slovakia, Croatia[Czech Republic])
420 patients to be recruited
Multiple immunizations, various
doses/formulations vs. placebo
PI: Dubois
Cogstate: J. Harrison
Statistics: S. Hendrix
Imaging: Bioscape
CRO: JSW Lifesciences
38 Dr. Walter Schmidt
cognitive alteration
dementia
Alzheimer’s disease
Exclude other reasons
(z.B. delir, depression,
etc.)
Exclude other
dementias
Alzheimer = Diagnosis by exclusion
> late> Specificity: ~80%
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Verständnisprobleme
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AD03 - targeting modified Aβ
pE3 Aβ is abundant in
plaques and CAA in human
AD, NHP and APP tg mice
Appears early in ADpathogenesis
Resists degradation
Is neurotoxic
Seed for Aβ aggregation
Phase I, Depart. Psychiatry and Psychotherapy, Prof. Kasper: just finished
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MimoVax Phase I Study (AFF005A)
Parallel to AD01- and AD02 Phase I Studies (AFF001/AFF002)
They are all different! Newer compounds address aggregated- or modified (pE) Aβ.
AD01, AD02 (and AD03) are safe and well tolerated (no ME, VE, expected rate of microbleeds).
AD02 promising clinical activity
Challenges: earlier diagnosis, diagnostic specificity, communication of „new diganostic criteria, endpoints,…
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Data Safety Committee G. Stingl P. Bauer C. Bancher
Dept. of Neurology Dept. of Clin. Pharm. E. Auff M. Müller P. Dal-Bianco M. Brunner E. Assem-Hilger M. Bauer J. Lerner M. Weber G. PusswaldE. Stögmann Dept. of Psychiatry
S. Kasper
A. Erfurt D. W inkler
A. Kutzelnigg
Medical University of Vienna - AFF001
Institute for Psychosom. Med. Neurology
M. Schmitz + Team D. Volc
D. Meshkat C. Thun-Hohenstein
R. Frey H. Pockberger
A. Kutzelnigg
N. Stadler P. Trauner
A. Laggner
H. Domanovits
AFF002
Dept. Of Emergency Medicine
MimoVax - AD03
MU ViennaDpt. of PsychiatryS. Kasper, A. Kutzelnigg, D.Meshkat
JSW
A. Achleitner M. Mandler J. StegerT. Bayer S. Meindl M. Trefil P. Gruber D. Pichler H. Weninger E. Kopinits B. Pilz C. Lahsnig R. Santic
B. Avanessian R. CursaruT. Böhm A. Karner J. ZimmermannV. Bürger V. Miciak