View
2
Download
0
Category
Preview:
Citation preview
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, BonnGESENT, BonnGESENT, BonnGESENT, Bonn
December 2, 2011December 2, 2011December 2, 2011December 2, 2011
Achim SchneebergerAchim SchneebergerAchim SchneebergerAchim SchneebergerCMO, AFFiRiSCMO, AFFiRiSCMO, AFFiRiSCMO, 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
2
3 Dr. Walter Schmidt
Alzheimer - Targets
secretase modulators
immunotherapy amyloid binders
anti-inflammatories Antioxidants neuroprotectants
β-secretaseinflammation oxidative stress
γ-secretase excitotoxicity direct toxicity
Neuron deathAβAPP pTau
Tau-inhibition
PlaquesOligomersProtofibrils
Aβ1-40/1-42N-term. mod. species
XXX------------------------------Aβ monomers
Synapses Neurons
4 Dr. Walter Schmidt
Tau Immunotherapy
Sigurdsson, NY USM:
Active Tau Immunization; Target: P-Ser 396, 404
Passive Tau Immunization; Target: P-Ser 396, 404 with Ab
PHF1 from P. Davies (Albert Einstein)
• IT reduces the accumulation of tau aggregates in 2 tangle models
• IT prevents and reverses cognitive decline (htau/PS1) and attenuates motor impairments (P301L)
• Both active and passive immunizations are effective
Citron, Indianapolis, Eli Lilly&Company:
Passive Tau Immunization in 2 models (JNPL3, P301S) using
various antibodies: PHF1, MC1 (Davies), CP13, CP17, PG5
• Treatment was well tolerated
• Biochemical evidence (reduction of AT8 tau in P1 fraction without changing total tau
• Functional benefit (delay in weight loss & motor function decline)
Conference on Neurodegenerative Disorders, Uppsala 2011
3
5 Dr. Walter Schmidt
AN1792 – the first AD vaccine
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIADAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIADAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIADAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
1 42
AAAAβ 1111----42424242+ Adjuvant QS21+ Adjuvant QS21+ Adjuvant QS21+ Adjuvant QS21
+ PS+ PS+ PS+ PS----80808080
Model systems:- Immunogenic- neuropathol. improved- cognition improved
Humans- Immunogenic- Biologically active- cognition?- side effect:
meningoenceph.
6 Dr. Walter Schmidt
AN1792: Meningoencephalitis
Frequency: 18/298 = 6% of Vaccinees
Course: subacute (16-100 days after first immunisation)
Symptoms: progressive confusion, headache, lethargy, fever
Prognosis: Restitutio ad integrum 12/18, Sequelae 6/18
Cause: Aβ-specific, CD4+ TH1-Type T cells
Leptomeningeal CD3Leptomeningeal CD3Leptomeningeal CD3Leptomeningeal CD3++++TTTT----Cell infiltrateCell infiltrateCell infiltrateCell infiltrate
Orgogozo et al 2003; Nicoll et al. 2003
4
7 Dr. Walter Schmidt
Passive Immunotherapy
Biological Comany A Epitope Stage
Bapineuzumab® Elan/Wyeth N-Term Phase III
Solanezumab® Eli Lilly central domain Phase III
Gammaguard® Baxter/Cornell IVIG Phase III
Octagam® Octapharma IVIG Phase II
PF04360365 Pfizer/Rinat C-Term Phase II
R1450 Roche N-Term + central Phase I
GSK933776A GlaxoSmithKline Phase I
Bapineuzumab s.c.® Elan/Wyeth N-Term Phase I
MABT5102 Roche/Genentech conformational Phase I
Abbott conformational preclinic
AAB-002 Elan/Wyeth conformational preclinic
Biogenidec/Neurimmune preclinic
Eisai/BioArctic protofibrils preclinic
8 Dr. Walter Schmidt
Bapineuzumab Phase II Trial
Gilman et al., ICAD 2008
5
9 Dr. Walter Schmidt
Bapineuzumab – human POC
Rinne et al. 2010
10 Dr. Walter Schmidt
Bapineuzumab Phase II: Vasogenic Edema
Solloway et al. Neurology 2009
Vasogenic edema
- temporary deterioration of blood vessel permeability?:
=> 12 out of 124 Bapineuzumab-treated pats.
=> 10 APO E4 pos.
=> 8/12 within the high dose group (including 2 APO E4 neg. pats)
=> Radiology > clinical symptoms: 6/12 asymptomatic
=> redosing in 6/12 wo additional VE (lower dose level)
6
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
APO E4 neg: 0.5; 1.0 (and 2.0) mg/Kg, x13 weeks; internat.; each1250 (1000) pats.
vasogenic edema – high dose group was canceled
Bapineuzumab®
12 Dr. Walter Schmidt
Solanezumab®
Solanezumab®
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
7
13 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
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
≠
8
15 Dr. Walter Schmidt
IVIG – Passive Immunization?
AAAAβ40404040 AAAAβ42424242
Octagam (phase II): negative
Gammagard (NIH and Baxter) Phase III: -360 patients
16 Dr. Walter Schmidt
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
9
17 Dr. Walter Schmidt
Reverse Translational MedicineProtective Factor ?
Comparing antibody responses
Human Ab,protective properties?
18 Dr. Walter Schmidt
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
10
19 Dr. Walter Schmidt
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
Starting point: m158
• POC studies
• Humanization of m158 ���� BAN2401
Start of clinical development program in 2010
Phase I studies in the USA
• Single ascending dose: 0.1; 0.3, 1.0; 3.0; 10; 15 mg/kg
• Multiple dose ascending: 0.3; 1.0; 3.0; 10 mg/kg
Phase II study planned for 2012
• 1 year trial in both prodromal and mild to moderate AD
Conference on Neurodegenerative Disorders, Uppsala 2011
11
21 Dr. Walter Schmidt
Nobel Prize Physiology / Medicine 1996
Discovery concerning the specifity of cell mediated immune defence
Peter Doherty Rolf M. Zinkernagl
22 Dr. Walter Schmidt
Second generation AD vaccines
vaccine company Antigen Adjuvant stage
ACC001 Elan/Wyeth Aβ 1-6 QS 21 II
V950 Merck/Acumen Aβ conformation ? I/II (?)
CAD106 Novartis/Cytos Aβ 1-6 VLP II
AD01 AFFiRiS/GSK Bio AFFITOPE, N-Term of Aβ, 6 AS Alum I
AD02 AFFiRiS/GSK Bio AFFITOPE, N-Term of Aβ, 6 AS Alum II
AD03 AFFiRiS/GSK Bio AFFITOPE, mod. N-Term of Aβ, 6 AS Alum I
12
23 Dr. Walter Schmidt
AFFITOME® technology is based on molecular mimicry
AAAAββββ
APP
AAAAββββ
YAAAAββββ
YPotential crossreaction with APP
AAAAββββ
Y
AAAAββββNo APP recognitionY
1 42
24 Dr. Walter Schmidt
AFFiRiS Alzheimer Vaccines Multicomponent Safety Concept
Affiris Vaccine Function
Short Peptide, single components a priori safe and/orCarrier, excellent safety profileAdjuvant
Short precludes activation of Aββββ-specific T-cellsAntigenic ���� no cellular autoimmunity / MEPeptide
AFFITOME® precludes crossreaction with APPTechnology ���� no humoral autoimmunity
13
25 Dr. Walter Schmidt
AFFIRIS USP
AFFITOME® platform technology
Antigen technology:
• Generates a pool of antigens
• Immunologically foreign – no need to break tolerance
• Targeting neoepitopes
• Fixed backbone
• Quick generation/selection of new antigens
• IP
26 Dr. Walter Schmidt
AD01 & AD02:Summary Preclinical Studies
Induction of specific antibodies
Reduction of cerebral Aβ load
Improved cognition in APP transgenic mice
No activation of Aβ-specific T cells
No APP-specific antibodies
No increase in microhemorrhaging
Well safety/efficacy balance to be expected
There is no simple correlation between antibody titers and clinico-pathological vaccine activity!• Surrogates
- fine specificity (e.g., APP, monomers, oligomers) - antibody trapping- IgG subtypes- other yet unknown factors
14
27 Dr. Walter Schmidt
Design Phase I FIH Studies
study population: patients, mild to moderate AD (MMSE 16-26)
randomized, single-center, patient-blinded, parallel groups (+/- Adjuvant)
primary EP: safety/tolerability; secondary EP: immunol./clin. activity
Add-on setting
Data Safety Monitoring Board, IC capability, Caregiver
screening treatment observation
Prim. EP
- clin. safety
- MRI
Sec. EP
- immunol.
- clin. activity
12
vaccination
0-2
EP = endpoint
20Time [weeks]
28 Dr. Walter Schmidt
In- and Exclusion Criteria (AFFiRiS 001)
Probable Alzheimer‘s disease (NINCDS/ADRA); MMSE 16-26
Hachinski Ischemia Score ≤ 4
Informed consent capability
Written informed consent
Age ≥ 50 years.
Availability of the partner/caregiver
Stable „conventional“ AD therapy(≥ 3 months)
Allergy to vaccine*
Contraindication for MRI
Experimental AD immunotherapeutics including IVIG or vaccines for AD
Immunosuppressive drugs, β-blockers
Autoimmune disease*
Cancer(Exceptions: basal cell carcinoma, intraepithal cervical neoplasia)
Major psychiatric disorder(e.g. schizophrenia)*
Active infectious disease(e.g. Hepatitis B, C)
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
15
29 Dr. Walter Schmidt
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
16
31 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
Both candidates met the primary phase I endpoints!
32 Dr. Walter Schmidt
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
17
33 Dr. Walter Schmidt
Why wait?
Pederson, Lancet Neurology 2010
Presymptomatic Prodromal Dementia
>Neurodeg.
34 Dr. Walter Schmidt
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:
18
35 Dr. Walter Schmidt
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
36 Dr. Walter Schmidt
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%
19
37 Dr. Walter Schmidt
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%
20
39 Dr. Walter Schmidt
Verständnisprobleme
40 Dr. Walter Schmidt
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
21
41 Dr. Walter Schmidt
MimoVax Phase I Study (AFF005A)
Parallel to AD01- and AD02 Phase I Studies (AFF001/AFF002)
• Alzheimer’s patients NINCDS-ADRDA-Criteria; MMSE 16-26• Informed consent capability!• Age: 50-80; caregiver• Endpoints:
– SAFETY/TOLERABILITY
– CLINICAL
– MMSE – CERAD – Cogstate Test Battery
– CIBIC – ADL
– ADAScog – NP
– IMMUNOLOGY; NEUROIMAGING: Volumetry
Differences to AD01- and AD02 Phase I Studies (AFF001/AFF002)
• 3 immunizations• Alum dose (1/2)• MRI (quality controlled � volumetry, safety: microhemorrhages)• Cogstate computerized test battery („objective“ measure)
42 Dr. Walter Schmidt
Summary / Conclusions
AD Immunotherapy: Aβ>> tau
Disease modifying potential, biological activity.
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,…
22
43 Dr. Walter Schmidt
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
F. Mattner W. Schmidt
AFFiRiSPreclinical Unit
Clinical Department
GSK BiologicalsRemi PalmantierCécile NeytDaniel LarocqueDavid Burk
Patrick TherasseVincent Brichard
44 Dr. Walter Schmidt
AFFiRiS Pipeline (clinical)(as of Nov 2011)
Target Preclinical Clin. Devel. I II III
N-term Aβ
N-term Aβ
t/m-term Aβ
CETP
α-synuclein
AD01
AD02
AD03 (MimoVax)
AT03
PD01
Atherosclerosis
Parkinson
Recommended