Dev evel elopm pment nt of of Nov ovel el B Biothe otherap - - PowerPoint PPT Presentation

Innov novat ative NeuroTec echno hnologi

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es, I , Inc.

Panor anoram ama Res esea earch, h, I Inc nc.

Dev evel elopm pment nt of

• f Nov
• vel

el B Biothe

• therap

apeu eutics for for the the Treatm eatmen ent of

• f Tauopat

auopathies

Innovative NeuroTechnologies, Inc.

430 Goddard Irvine, CA 92618-4610 USA

June 2016 - Non-confidential www.innovneurotech.com

Inno novat ative e Neur uroT

• Tec

echno nologi

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Neur eurode

• dege

gener erat ative T e Tauopat auopathi hies

Tauopathies are age-related neurodegenerative diseases characterized by the presence of aggregates of abnormally phosphorylated Tau. They are clinically characterized by dementia and include:

• Alzheimer’s disease (AD)
• Frontotemporal dementia (FTD) or Pick’s disease

– Mutations in the Tau gene microtubule associated protein Tau (MAPT) cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) – Aβ plaques are not found in patients with FTDP-17

• Chronic traumatic encephalopathy (CTE) or dementia pugilistica (DP)
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)
• Parkinson’s disease dementia (PDD)
• Posttraumatic stress disorder (PTSD)

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Hyper erpho phosphor phorylat ation o

• n of Tau Destabi

abilizes es Microt

• tub

ubul ules es Leadi Leading ng to Neurodegener

• degenerat

ation a

• n and C

Cell Death

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Pathol

• log
• gies

es of Dem ementias as

• All dem

demen entias ar are e char haracter erized by by two or

• or mor
• re hal

e hallmar arks

• All dem

demen entias ar are e char haracter erized by by loc

• cal

alized ed neur neurona nal l los

• ss (

(cel ell deat death)

Neurodegener

• degenerat

ative D e Dis isorder der Pathologi hological H al Hallm llmarks* Alzheimer’s Disease NFTs, Aβ plaques, and cell death Frontotemporal Dementia NFTs and cell death Chronic traumatic encephalopathy NFTs and cell death Corticobasal degeneration NFTs and cell death Progressive supranuclear palsy NFTs and cell death

All of

• f t

the hese cond

• nditions ar

are e rel elated t to T

• Tau

au

*NFTs are neurofibrillary tangles of Tau protein. Aβ plaques are largely composed of beta-amyloid protein.

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Mul ultiple Epi Epitopes of

• f Tau

au as as Pot Potential Ther herapeu eutic Tar arge gets for

• r Tauop

auopathies

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Impor portanc nce e of the e Tau au N-Ter ermin inus

• In its native shape, Tau maintains a “paperclip” conformation

shielding the N-terminus

• The phosphatase activating domain (PAD) sequence is 100%

identical between 6 isoforms (amino acids 2-18): AEPR AEPRQEF EFEV EVMEDHAG AGTY

• Exposure of the N-terminus is a necessary first step in conversion of

normal physiological Tau to pathological Tau (amongst the earliest alterations in the development of AD and other tauopathies)

• Aberrant exposure of N-terminus leads to inhibition of fast axonal

transport (FAT) through a signaling cascade involving PP1 and GSK3

• Immunization against this PAD sequence should have no effect on

native Tau and should only bind to pathological Tau preventing adverse downstream pathology1,2,3,4

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Exper eriment ntal Confor

• rmat

ation

• n of Tau

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In solution, Tau normally adopts a closed “paperclip-like” conformation

N-terminus C-terminus

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Fas ast Ax Axon

• nal Tran

ansport (FAT AT) and and Tau au

*FAT is critical to neuron function and viability

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INT NT-1 & INT-2: PAD PAD-derived mAbs

• Both recognize discrete regions within the N-terminus
• Display strong, conformation-dependent reactivity with pathological forms of

Tau, but not normal Tau in non-denaturing assays

• Label diffuse, pre-tangle pathology in hippocampal tissue sections from Braak

stages I-VI cases

• Co-localize with pathology identified by very early, conformation-specific Alz50

antibody

• Do not co-label in thiazine red-positive late-stage neurofibrillary tangles (NFTs)
• r ghost tangles
• Thus, INT-1 and INT-2 mAbs are central in differentiating between normal and

pathological Tau; PAD exposure is a very early conformational change in Tau that occurs as pathology begins to accumulate in neurons1

• Patent

ent No. U US 2012/ 12/014 014602 602 A A1

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INT INT-1 1 mAb Ab Detec Detects ts Ear Early y Tau Tau Patho Patholog

• gy in

n Di Diseas sease

• Multi-label fluorescent stain reveals that INT-1 (TNT1) mAb detects early

Tau pathology in the hippocampus and the extend of pathology increases with Braak stage

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INT INT-2 2 mAb Ab Detec Detects ts Ear Early y Tau Tau Patho Patholog

• gy in

n Di Diseas sease

• Multi-label fluorescent stain reveals that INT-2 (TNT2) mAb detects early

Tau pathology in the hippocampus and the extend of pathology increases with Braak stage

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INT NT-3: Phospho ho-Ty Tyr18-tau (PY18) mA mAb

• Tau is phosphorylated on Tyrosine-18 at its amino terminus by Fyn, Src and LcK, and

members of the Src family non-receptor tyrosine kinase family (SFK)5

• Immunohistochemical studies have indicated that tyrosine phosphorylation of Tau at

Tyrosine-18 is present in paired helical filaments (PHFs) and NFTs of AD brain6

• Fyn has been proposed to have a key role in disease pathogenesis based on data
• btained from AD patients
• Fyn depletion confers protection against neurotoxicity induced by Aβ and reduces the

synaptotoxicity and neurotoxicity in human amyloid precursor protein (hAPP) trangenic mice over-expressing Aβ7,8

• Fyn over-expression in this same mouse model potentiates behavioral deficits9
• Fyn and Tau interact genetically to modulate synapse loss, behavioral deficits, and

electroencephalographic abnormalities in APP transgenic mice10

• This suggests an important role for Fyn-Tau interaction in the neurodegenerative

process for AD and other related tauopathies

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INT NT-3: Phospho ho-Ty Tyr18-tau (PY18) mA mAb

• Net result of aberrant cellular prion protein (PrPc)-mGluR5-Fyn signaling is synaptic

malfunction and loss

• Tau also appears to play a dendritic function at the postsynaptic density (PSD) and can

mediate Aβ toxicity when AD is initiated

• This suggests a putative model for the Fyn-Tau-Amyloid “Toxic Triad” in the pathogenesis
• f AD, in which Tau and Aβ pathologies are directly linked through the actions of Fyn
• Patent

ent N

• No. US 7

7,238, 38,788 B 788 B2

• Schematic illustrating the central role of Fyn in amyloid-beta oligomer (Aβo) signaling

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Adeno-Associated Viral (AAV) Vectors for Gene Therapy

• Over the last decade, AAV has emerged as a highly promising and attractive approach to

gene therapy with proven safety in clinical trials

• AAV is a common, naturally occurring virus that is not currently known to cause disease
• Advances in AAV vector design and related dosing techniques have made AAV particularly

well-suited for the treatment of CNS disorders (e.g., AD, FTD, and PD)

• Since the targeted cells in the CNS are long-lived, non dividing neurons, therapy can

potentially be delivered via a single dose and be a long-lasting (or even a lifelong) treatment

• It is possible that more than 8 years of durable expression be observed in the brain

following AAV treatment

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Tau-bas ased ed B Biother erape peut utics in D Development

Toxicology (N=2) Genentech NeurImmune Dis iscov

• ver

ery Bio iologic logics N=19 19

Phase I (N=3) Eli Lilly BMS Abbvie

AAV Discovery Biologics (N=2) Voyager Therapeutics and INT NT Antisense (N=1)

09/ 09/2015 2015 BMS ini nitiat ated d a a Phas hase e I clinica cal trial for

• r

PSP with h thei heir N-ter ermina nal mAb Ab. 06/ 06/2016 2016 Abbv bbvie e was as gr grant anted ed or

• rphan

phan dr drug ug des designa nation

• n for
• r trea

eatmen ent

• f
• f PSP with

h thei heir N- ter erminal al mAb. b. 06/ 06/2016 2016 Eli Li Lilly y announced announced that hat they hey had had ent enter ered ed a a mAb Ab in n Phas hase e I.

N=number of companies

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• The total U.S. costs of AD and other dementias were over $214 billion in

2013

• Alzheimer's will cost an estimated $1.2 trillion (in today's dollars) in 2050.
• An estimated 5.5 million Americans are currently diagnosed with AD, and AD

is the 6th leading cause of death in the U.S.

• In t

n the he U U.S. al alone, int ntroduction of

• f a

a dr drug t tha hat del delayed t the he ons

• nset of
• f A

AD by by 5 5 yea ears w woul

• uld r

res esult i in n savings of

• f $15

$150 bi billion ov

• ver t

the he f first 20 y 20 yea ears of

• f us

use

200 400 600 800 1000 1200 1400 2015 2020 2025 2030 2035 2040 2045 2050

Impac pact of a a 5-year Del elay on C

• n Cos
• sts (

(in n bi billions), Amer ericans A Age ge 65 and 65 and Older with A AD 201 2015-2050 2050

• In 2013, 44.4 million people

globally suffered from dementia and a new case is diagnosed every 7 seconds

• The total estimated worldwide

costs of AD and other dementia were over $604 billion in 2010

Inno novat ative e Neur uroT

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Gl Global Cos

• sts of
• f Dem

emen entia by by Regi egion (in n 2013 2013 millions of

• f USD

SD)

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50 100 150 200 250 300

2050 2030 2013

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Referenc ences es

1 Combs, B., et al. 2016. Neurobiol Dis. 94(18-31). 2 LaPointe, N.E., et al. 2009. J Neurosci Res. 87:440-451. 3 Kanaan, N.M., et al. 2011. J Neurosci. 31(27):9858-9868. 4 Kanaan, N.M., et al. 2012. Neurobiol Aging. 826.e15-826.e30. 5 Lee, G., et al. 2004. J Neurosci. 24:2304-2312. 6 Bhaskar, K., et al. 2005. J Biol Chem. 280:35119-35125. 7 Ho, G.J., et al. 2005. Neurobiol Aging. 26:625-635. 8 Lambart, M.P., et al. 1998. Proc Natl Acad Sci USA. 95:6448-6453. 9 Chin, J., et al. 2005. J Neurosci. 25:9694-9703. 10 Roberson, E.D., et al. 2011. J Neurosci. 31:700-711.