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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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Page 1: Schneeberger GESENT Bonn2011 released [Kompatibilitätsmodus]

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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

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

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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

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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

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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

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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)

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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

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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:

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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%

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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%

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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

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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,…

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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