a common treatment strategy alzheimer’s/parkinson’s, · ©asdera (2017) non-confidential...

1© ASDERA (2017) Non-confidential Information

Mission

A common treatment strategy for age-related diseases, incl.

• metastatic cancer,

• Alzheimer’s/Parkinson’s,

• atherosclerosis, and

• multiple sclerosis

Knut M. Wittkowski, PhD ScD,

[email protected]

http://www.asdera.com


ASDERA – Approach

Derisking

How: Finding targeted therapies from genetics

through a computational biostatistics platform,

Advantage: the first to identify genetic risk factors for complex diseases

DrugDiscoveryPlatform

(US 7,664,616)

The platform screens not only for individual genetic ‘letter’ positions (SNPs) but genetic ‘words’ (several neighboring SNPs).

It also accounts for genetic ‘grammar’ (neighborhood, compound hetero-zygosity, recombination hotspots, ...) within the statistical method.

Feasible only since 2001 (32-bit OS), it already yielded several hits.

Methodologybased on

Technology

1800 Gauss-Legendre 1948 Hoeffding� �

1965IBM256 kB

PCA

1985PC16 MB

Bayes

1900Ohdner9 Byte

ANOVA

2001GPU4 GB

u-Stat


ASDERA – Pipeline

Mission Goal: To bring novel drugs to market for high unmet needs.

Approach

How: Derisking and finding targeted therapies


Advantage: the first to identify genetic risk factors

for complex diseases (“missing heritability”)

Time-Pipeline

Validation: Confirmation of known drug targets in epilepsy

Out-licensed: ASD-002 pro-MFA against mutism in autism (ph 3 ready)

In-trial ASD-003 treating Crohn’s disease

Current lead ASD-004 treating breast cancer metastases (pat. pending)

family of ASD-005 treating Alzheimer’s / Parkinson’s / MS (pat. ... )

assets ASD-006 preventing BC, AD/PD, CAD, ... (pat. pending)

Service ASD-000 Explaining non-response in phase 2/3 trials



20,000/yr US children become non-verbal due to mutism in 2nd year of lifeUnmet Need

FDA 505(b)(2) path for pro-MFA, an NSAID ester prodrug (Ofirmev®)

single Phase 2b/3 outpatient trial (breakthrough drug)

2–3 years from market (Vyvanse®, pro-D-amphetamine)

https://medcitynews.com/2017/04/q-biomed-early-stage-autism-deal-asdera/

Plan forward

(Precedents)

Platform Results � Association: K+ ion channels associated with mutism

Public Results

(in vitro,animal,human)

Agency Findings

� Cellular defect: K+ outward loss-of-function causes mutism

Activity: MFA activates outward K+ channels.

Efficacy: MFA prevents induced seizures.

� Model system: Migraineurs

� Effectiveness: MFA is effective against migraines.

Age: 12 – 24 mo is the window of opportunity.

Safety/dose: 50+ years of chronic use from 6 months of age (UK)

ASDERA’s Drug Discovery Platform: First Asset outlicensed (QBIO)


ASDERA – Overview

Mission Goal: To bring novel drugs to market for high unmet needs.

Approach

How: Derisking and finding targeted therapies


Advantage: the first to identify genetic risk factors

for complex diseases (“missing heritability”)

Time-Pipeline

Validation: Confirmation of known drug targets in epilepsy


In-trial ASD-003 treating Crohn’s disease










ASDERA – Market Need / Opportunity (Metastatic Cancer)

Breastcancer

Breast cancer (BC) is the most common cancer in women worldwide.

US: ~5,000,000 prevalence (250,000/yr).

Triple-neg.BreastCancer

37,500/yr are triple negative (TNBC, 15% of breast cancer)

• high risk of metastases post surgery (20% at 2.5 yr) [Dent 2007]

• high risk of death (13% at 2.5 yr)

Unmet Need

BC

Most cancer death are caused by metastases

driven by β1 integrin, yet no targeted treatment exists

to prevent metastases to brain, lung, liver, and bone.

Unmet needTNBC withhigh risk

For TNBC, the only treatment options

after surgery have severe side effects:

• radiation

• chemotherapy


ASDERA – Market Need / Opportunity (Neurodegeneration)

Alzheimer’sParkinson’s

Alzheimer’s is the most common form of dementia worldwide (60–80%).

5,500,000 US people are affected with Alzheimer’s (AD).

1,000,000 US people are affected with Parkinson’s (PD).

Unmet Need

AD/PD

There is no effective treatment for AD.

PD Patients often respond initially to L-dopa,

but become refractory

Early stageParkinson’s

Of 60,000 US people diagnosed per year,

4% (2,400) are <50 years old.

• GBA-associated PD causes 31 vs 21% dementia.

• GBA-associated PD progresses faster.

Unmet needEarly PD

with high risk

No specific treatments for GBA-PD are available.

Fast progression shortens trial duration.


ASDERA – Market Need / Opportunity (Atherosclerosis)

CoronaryArtery

Disease

About 92M Americans are living with a cardiovascular disease / had stroke.

More people die of cardivascular diseases, than of all cancers combined.

Risk factors

Risk factors for coronary artery disease (CAD) are

• recent myocardial infarction / stroke

• current smoking / obesity

• uncontrolled blood pressure / LDL / T2DM

Unmet NeedOver the last 50 years, incidence has declined 67%,

but treatments with a direct mode of action are still

ugently needed.

High riskTarget

populations

Risk population / outcome

• recent stroke (14% of 700,000 within one year)

• include MI into outcome to increase power.

Macrophage

LDL

AP2

Clathrin

Lysosome

Foam Cell

Plaque


ASDERA – Market Need / Opportunity (Multiple Sclerosis)

MultipleSclerosis

About 400K Americans are living with multiple sclerosis.

About 10,000 US cases are diagnosed each year.

Age at diagnosis is 10–80 years, with the marjority being 20–40

Immune system (macrophages) destroyes myelin

Risk factors

Risk factors for multiple sclerosis (MS) are

• genetics, IBD, smoking

• living away from the equator (vitamin D?)

Unmet Need

There is cure available.

• Cortecosteroids, plasmapheresis

• Ocrelizumab (anti-CD20 on B-cells, $65K/yr) reduces

progression, but halted in RA/SLE due to AEs

High riskpopulations

About 15% of patients have primary progressive MS.

PPMS starts ~10 years later.

Microglia

Neuron

Blood-Brain Barrier

Myelin fragments

Myelin-Phagocytosis

Myelin-Endocytosis

LY

Macrophage activation T/B-cells

Microglia

Neuron

Blood-Brain Barrier

Myelin fragments

Myelin-Phagocytosis

Myelin-Endocytosis

LY



DiscoveryPlatform

Analyzed three breast cancer (BC) populations ( https://doi.org/10.1101/152405 )

Results suggested a novel treatment concept for a pliotropic risk factor under lying several age-related diseases

Geneticresults

Consistent results showed metastases are associated with

• variations along the endo-/exocytosis (EEC) pathway

• variations in the PI cycle, which regulates EEC.

Considerable overlap with genetic risk factors of AD and PD.

IndependentConfirmation

Of the 27 EEC genes identified, 24 have known function in BC.

“Derailed endocytosis”[Mosesson 2008] is a known component of BC etiology.

“Deranged endocytosis”[vanDooren 2014] is also a known component of AD.

Mode of Action

ASD-003..006 is an innovative (optionally oral) derivatives of αCD;

they down-regulate endocytosis by scavenging serum phospholipids.

βCD was effective in models of BC, AD, PD, CAD, ...

ASDERA’s Discovery Technology and next (α-cyclodextrin) Hit


Genes significant in

muGWAS (s6) / ssGWAS (s1)

(Genes significant in previous

GWAS of first study boxed)

Membrane associated (GPCR, FcR, HA, RTK, Ion channels), incl. FGFR2

MAP Kinases, incl. PRKCQ

Nuclear processes (cell cycle control,

transcription, splicing). incl. BUB3

Endo-/Exocytosis (EEC) !

Consistent Gene Families Across Three StudiesCGEMP923 EPICPA27 PBCSPB02

s6 s1 Othr Mbrn PI/EC MPK Ncls s6 s1 Othr Mbrn PI/EC MPK Ncls s6 s1 Othr Mbrn PI/EC MPK Ncls

6.70 PRKCQ 8.58 5.42 SOHLH2 7.74 5.83 DOCK86.26 TRPM3 6.59 4.73 AGPAT3 6.63 NCOR26.20 6.20 BUB3 6.51 4.11 CELF2 6.59 4.95 CACNA1C6.02 SCARB2 6.48 4.56 STARD13 6.39 4.07 MEGF116.00 5.57 FGFR2 6.37 PCSK5 6.22 4.82 GPC65.95 4.89 POLR1A 6.33 4.68 mirLET7B 6.14 PTENP15.89 GNG7 6.26 4.87 ATP8A1 6.06 4.60 CDH45.86 VWA3B 6.13 5.66 CHD3 6.05 CLLU15.85 SYK 5.88 4.19 TNS1 5.97 5.80 RGS35.81 MSL3 5.85 4.36 TRAPPC9 5.70 TMCC35.79 CALN1 5.82 4.34 CDKAL1 5.63 SSTR45.58 ATP8B1 5.43 EDN15.49 TCF15 5.6 TAS2R1 5.39 ANAPC135.48 4.65 LPPR1 5.50 TMEM132C/D 5.35 4.86 TRPC35.44 4.63 HAS2 5.49 4.05 SIX2 5.34 4.15 COL11A15.42 NUP54 5.40 GLB1 5.33 PRH15.38 4.46 BRCAT49 5.35 4.13 SPATA19 5.32 4.27 EEA15.38 KCND3 5.33 ASTN2 5.22 4.46 RBM235.37 MDGA1 5.27 CHMP7 5.22 4.13 HAPLN3 5.36 SYT17 5.26 PRKCQ 5.21 5.08 PTPRG5.30 SYNJ2 5.24 E2F3 5.21 RNASE11

5.23 NEFL/M 5.17 4.42 ANXA45.22 MACROD2 5.21 NCCRP1 5.14 CADM25.14 SHANK2 5.21 FLT3 5.13 4.39 CDK185.13 4.24 AK5 5.16 EPHB15.12 LYZL1 5.15 4.12 CFAP36 5.12 SLC13A35.09 4.95 MMRN1 5.14 4.08 GRIA1 5.11 KIF255.08 CTNNBL1 5.13 RASD2 5.07 MMD25.06 SAMHD1 5.08 COL3A1 5.05 TRIM365.06 MEGF11 5.08 RARB 5.05 PAX25.04 NLRP4 5.06 SLC43A3 5.02 GLIS25.03 DMRTB1 5.05 VAV3 5.02 CYB5RL5.02 ZMAT4 5.05 HMGXB4 5.00 3.83 ISM15.00 ALPP 5.04 VWC2L 4.99 4.45 BCL104.99 ABCA1 5.03 4.32 PRKAG2 4.98 4.19 ZNF984.98 SCMH1 5.02 LZTS1 4.98 ZFAT4.98 LPHN3 5.00 LARGE 4.95 SDK14.97 HNF1B 5.00 LSMD1 4.95 4.29 TRMT114.97 SMARCAL1 4.98 IGSF9B 4.92 HDAC44.95 4.81 BRCAT54 4.93 ACAN 4.91 MDFI4.94 AGPAT4 4.90 FKBP1A SDCBP2 4.91 TFAP2A4.94 ZBTB20 4.88 KPNA3 4.91 HLA-C

4.52 4.47 PTCD3 4.77 4.77 OR52K2 4.61 4.48 FHIT4.89 4.47 BMPR1B 4.64 4.26 GPHN 4.91 4.41 UNC13C4.29 4.29 FBXO38 4.83 4.24 BMP7 4.42 4.41 CHIT14.86 4.24 PARK2 4.22 4.22 RAPGEF4 4.38 4.38 SYNDIG14.21 4.21 ANO4 3.68 4.20TNFRSF10A 4.74 4.28 SLC25A264.24 4.19 ABO 4.20 4.20 MICAL2 4.84 4.14 RAB324.97 4.18 DGKQ 3.90 4.18 SFRS8 4.12 4.12 A2BP14.28 4.19 DAP 3.57 4.16 PNOC 4.59 4.07 N4BP34.59 4.11 STXBP1 4.81 4.06 USP444.49 4.07 MRGPRE4.82 4.06 NTSR14.04 4.04 MRPL35


Branches of Endocytosis

Late endosome andmultivesicular body

PI(3,5)P

PAS complex: PIKFYVE/VAC14/FIG4

SNX5

Lysosome

GLB1

SCARB2(LIMP-2)

RAB7

CHMP4

SYT1 UNC13C

RAB32SNARE

complex

VAMP7SNAP25

STX7/8STXBP1 (MUNC18)

VPS11,39

16–3318,41HOPS

complex

ANXA4

SNARE

complex

VAMP7SNAP23STX4 STXBP4

Ca2+

TRPM2

MTMR1

PI(5)P

PI4K

PI(4,5)P

RAB25

RAB11FIP1RAB11

lon

g lo

op

/ slo

w re

cyc

ling

M

YO

10

CLIC3

ACAP2

RAB9

Recycling endosome

SYT17Trans-Golgi

network

β1 integrin

active �

STX6/VAMP3complex

LRRK2

RAB27

Exo

so

me

s

RAB8RAB13

RAB11

GBAGC

H+

ATP13A2PSEN1

vATPase

Re

cyc

lin

gS

ign

alin

g

Fu

nc

tion


Lysosomal Dysfunction in .... Cancer AD/PD Atherosclerosis

Modified from (Mosesson et al. 2008)(X. Chen et al. 2014) (Schreij et al. 2015)

BC CAD

14© ASDERA (2017) Non-confidential Information 14

... can be Compensated by Down-Regulating the PI Cycle

Colored arrows sequence of PIPs involved in EEC.

Pink genes associated with BC in genetic analysis.

Hypothesis:

Scavenging serum phospholipids “re-rails” endocytosis

© ASDERA (2017) Confidential Information

Recycling of β1 Integrin by Endo- and Exocytosis (EEC) ...

CCV

UCV

EE

LE

LY

PC/PS

α-cyclodextrin


Cyclodextrins scavenge Lipids

βCD

��

αCDn=6 / βCDn=7

α- and β-Cyclodextrin (αCD, βCD)scavenge Phospholipids

hyd

rop

hob

ic

�

βCD also scavenges Cholesterol

PermanentHearing Loss

αCD


ASDERA – High aCD Specificity for Phospholipids

α

β

α

β

α

β

α

β

PC PC SMSM

Mo

difie

d f

rom

: (O

hta

ni e

t al. 1

98

9) M

od

ified

from

: (Mo

nn

ae

rt et a

l. 20

04)

Solubility of Lipids in PBS by HP-CD

Modified from (Irie et al. 1992)


Relative Ototoxicity and NPC (Cholesterol Storage) Efficacy of CDs

So

un

d P

ressu

re L

ev

el (d

B)

Wild-type NPC−/−

Modified from (Davidson et al. 2016, Figure 5B) Modified from (Davidson et al. 2016, Figure 1)

White spots: unesterified choledsterol


αCD is more effective than HPβCD in Lysosomal Storage Diseases


0

20

40

60

80

100

4 0

Dose [mM]

p = .0001

p = .0252

0 1 2 4 0 1 2 40 1 2 4 0 1 2 4

ASD-003 (HPαCD*) is >2× as effective as HPβCD against migration

MCF-7 human ER+ BC cells MDA-MB-231 human ER− BC cells

ASD-003 HPβCD ASD-003 HPβCD

p = .0252 p = .0442

p = .0001

ANOVA: p = .0252

Cancer

Ce

ll M

igra

tio

n


PI-Cycle overlap between epithelial cancer and neurodegeneration Gene PI-Cyclepower KEGG EC ND References ATP8A1 ATP8B1

Increase extracellular PC and PS; enhance endocytosis

(Farge et al. 1999; Levano et al. 2009; Levano et al. 2012)

BC (da Costa et al. 2012; Sjöblom et al. 2006) PC (B. H. Lee et al. 2013; Sekine et al. 2010; Trasino et al. 2009) PD (Levano et al. 2012) ATP8A2: (X. Zhu et al. 2012) AD (Soderberg et al. 1992) ATP8B4: (H. Li et al. 2008) ANO4 Ca+ dependent PL scramblase (Picollo et al. 2015) SC (Weber 2015) AD (Sherva et al. 2014) ABCA1 Regulates cellular lipid efflux; hsa02010 (Hamon et al. 2006) interacts with MEGF10 BC (Schimanski et al. 2010; Zhao et al. 2016) PC (B. H. Lee et al. 2013; Sekine et al. 2010) PD (Y. Dong et al. 2015; X. Dong et al. 2016; Loane et al. 2011; Pinho et al. 2016) AD (Boehm-Cagan et al. 2016; Koldamova et al. 2014; Nordestgaard et al. 2015; Pahnke et al. 2014) HD (Valenza et al. 2015) AGPAT3 AGPAT4

convert lysophosphatidylinositol (LPI) into phosphatidylinositol (PI)

hsa00564 (Bradley et al. 2015)

BC (Hopkins et al. 2016; Sahay et al. 2015) PC AGPAT6: (Gatto et al. 2015) PD (D. Cheng et al. 2011) AD (Sherva et al. 2011) DGKQ Regenerates PA from hsa00564, (Sakane and Kanoh 1997) diacylglycerol (DAG) hsa04070 BC (Filigheddu et al. 2007) PC AGK: (Bektas et al. 2005) PD (Lill et al. 2012; Nalls et al. 2014) AD (X. C. Zhu et al. 2016) LPPR1 complexes with LPPR3/4/5, regulates PIS (CDIPT) LPPR4: (Yu et al. 2015) PD (Moran et al. 2006) SYNJ2 is recruited to the nascent hsa04070 (Schmid and Mettlen 2013) clathrin coated pit BC (Ben-Chetrit et al. 2015) PC (Rossi et al. 2005) PD SYNJ1 = PARK20 AD (Koran et al. 2014) PTENP1 PI3K/PTEN and PI(3,4,5)P3 are hsa04070 PTEN: (Erneux et al. 2016) involved in endocytosis/ cancer BC (H.-Y. Zhang et al. 2013) PC (Pourmand et al. 2007) PD PINK1:(Choubey et al. 2014) AD (Frere and Slutsky 2016) HD PINK1: (Khalil et al. 2015)


ASDERA – HPβCD in Autophagy: Previously Unknown Mechanism

modified from Song (2014)

? confidential

EndocytosisPhagocytosisMacro-

pinocytosis

ClathrincoatedVehicle

(Auto-)Phagosome

Macro-pinosome

EarlyEndosome

IntermediatePhagosome

IntermediateM-pinosome

MVB / LE

(Auto-)Phago-lysosome

MVB / LEMVB / LE

LysosomeMacropino-lysosome

4

3,4

(5)

3,5

3

4,5

PI

AutophagyMitophagy

TFEB mTOR


Phago-/Endocytosis in MS HPαCD Restores LY Function

Microglia

Neuron

Blood-Brain Barrier

Myelin fragments

Myelin fragmentPhagocytosis

Myelin-Endocytosis

LY


Microglia

Neuron

Blood-Brain Barrier

Myelin fragments

Myelin fragmentPhagocytosis

Myelin-Endocytosis

LY


Evolutionarydefault

“Starvation”Overfilling

TFEB

````

Endo-/Pino-/Phagocytosis

HPαCD

(Macro-) Autophagy

Ca2+H

MCOLN1(TRPML1)v-ATPase

MTORC1 TFEBP

calcineurin

ATGsBECN1

SQSTM1...

(Kilpatrick 2015)(Sardiello 2016)(Moors 2017)(Song 2014)

HPβCD

resveratrolrapamycin

?

PLs

PI-cycle

LY

AD: Aβ/tauPD: α-synCAD: LDLSCA: ATX1/3 MS: myelinALS: SOD1...


Selectivity in Scavenging (PC/PS) aCD regulates PI-cycle and AA

AA: Arachidonic AcidCOX 1/2 and LOX precursor

PI-cycle

Hu

man

:F

PL

C o

f N

ext D

ay

Morn

ing U

rine


Anti-Inflammatory Effect

HPaCD*

HPaCD

GWASGWAS

Arachidonic acid

Platelets Inflammation Lung/Asthma

COX-1 COX-2 LOX

TXA2 PGE2 & PGI2 LTC4 & LTD4

NSAIDs

montelukast

zileuton

• �vasoconstriction • anti-platelet

• �bronchorestriction• anti-inflammatory

Therapeutic effect

sPLA2

PC

corticosteroids

LPC

• anti-inflammatory• analgesic

ASA

aCD

Arachidonic acid

Platelets Inflammation Lung/Asthma

COX-1 COX-2 LOX

TXA2 PGE2 & PGI2 LTC4 & LTD4

NSAIDs

montelukast

zileuton

• �vasoconstriction • anti-platelet

• �bronchorestriction• anti-inflammatory

Therapeutic effect

sPLA2

PC

corticosteroids

LPC

• anti-inflammatory• analgesic

ASA

aCD

aCD regulates PI-cycle and AA

HPaCD

modified from (Cummings 2007, black lines)


ASDERA – Successful tests of bCD in many disease models (Px)

CAD T2DMNAFLD/NASHSLE/ALS/MS CF/IPF

PDGWAScommon genes

PI-cycle

BC AD

Endocytosis

Endocytosis(Chol)

common genes

(Px)

in vitro

αCDαCD (Px)βCD

(Chol)

(Chol)

βCD

(Chol)

clinical

co

mo

rbid

co

mo

rbid

“deranged EC”“derailed EC”

MOSSESON (2008) VANDOOREN (2014)


ASDERA – in vitro / Animal Evidence for Efficacy of CDs in BC

In vitro

βCD reduces migration of human BC cells [Raghu 2010, Donastello 2012, Guerra 2016]

αCD is >2× as effective as βCD in two BC cell lines (p=.0252)

=> βCD acts by scavenging PLs (like αCD) not by scavenging cholesterol

ex vivoβCD inhibits angiogenesis in chick embryo and rat aorta assays,

without altering cell proliferation [Watson 2013]

in vivo

βCD, in mice implanted with human tumor cells,

• reduces tumor volume from MCF-7 BC and A2780 OC cells [Grosse 1998]

• reduces lung metastases from H7-O Lewis lung cancer cells [Zhang 2006]

• reduces invasion of melanoma cells [Fedida-Metula 2008]

ClinicalLPA� has been linked to BC risk.[Wang 2016]

Trials of alkyl-LPCs against BC metastasis showed GI toxicity.[Rios-Marco 2017]

US approvalαCD is approved for injection (Caverject®)

αCD is GRAS for oral use, ASD-003/004 are ready for 505(b)(2)


ASDERA – in vitro / Animal Evidence for Efficacy of CDs in AD

In vitro

MβCD inhibits neuronal Aβ secretion in APP transfected rats.[Simons 1998]

MβCD promotes the non-amylogenic α-secretase pathway.[Kojro 2001]

MβCD reduces β/a secretase ratio and APPsβ in SH-SY5Y cells.[Cole 2005]

αCD inhibits, but βCD/HPβCD accelerate Aβ fibril formation,[Wang 2009]

although αCD cannot fit Aβ12-28 in buffer (at pH 5.0).[Qin 2002]

HPβCD “dramatically” lowered Aβ42 in SwN2a cells.[Yao 2012]

in vivo

HPβCD reduced tissue damage from Aβ injected into rat brain.[Waite 1992]

div βCDs inhibit transthyretin amyloid formation in ATTR tg rats.[Jono 2011]

HPβCD reduced Aβ/tau and was neuroprotective in Tg19959 mice.[Yao 2012]

βCD intra-hippocampal injection reduced Aβ40/42 toxicity in rats.[Jameson 2012]

Clinical CAD and AD are comorbid,[Song 2004] but chol and AD unrelated.[Tan 2003]

US approval (see BC/CAD)


ASDERA – in vitro / Animal Evidence for Efficacy of CDs in PD

In vitro

MβCD “dramatically reduces” α-syn in HeLa cell lipid rafts.[Fortin 2004]

MβCD inhibits secretion of γ-syn in SH-SY5Y cells.[Surgucheva 2012]

βCD suppresses α-syn aggregation in E. coli.[Gautam 2014]

HPβCD prevents α-syn aggregation in hs neurons via upregulation of auto-

phagy by TFEB, but “the underlying mechanisma are unclear.” [Kilpatrick 2015]

βCD > HPβCD > αCD reduce α-syn aggregation in E. coli.[Gautam 2017]

in vivo MβCD reduces α-syn accumulation in tg mice.[Bar-On 2006, Abeliovich 2016]

Clinical Increased plasma levels of phospholipid in Parkinson’s disease.[Li 2015]

US approval (see BC/CAD)


ASDERA – in vitro / Animal Evidence for Efficacy of CDs in CAD

In vitro aCD is less cytotoxic in serum than 3MβCD and HPβCD.[Shityakov 2016]

in vivo

po aCD lowers LDL chol and PLs in LDLR ko mice fed WD.[Wagner 2008]

sc HPbCD improves NAFLD in LDLR ko mice.[Walenbergh 2015]

sc bCD reduces AS plaques in mice via MΦ reprogramming.[Zimmer 2016]

po aCD reduces atherosclerosis in Apo E deficient mice.[Sakurai 2017]

Clinicalpo aCD reduces BW and lipids in obese adults with T2DM.[Grunberger 2007]

po aCD reduces BW, cholesterol, and LDL in healthy adults.[Comerford 2011]

US approvalαCD is approved for injection (Caverject®)aCD is approved as a food additive and nutritional supplement (GRAS)ASD-003/004 ready for 505(b)(2)


ASDERA – IP and Market

IP Protection US/EU patent for aCD derivatives, expiration 2039, ...

Market Size(US only)

BC: R+BC: 250,000 × 10 yr × 10% × $20,000/yr = $5.0 B of $50.0 BTNBC: 37,000 × 4 yr × 50% × $20,000/yr = $1.5 B of $3.0 B

ND: AD: 5,500,000 × 10% × $20,000/yr = $11.0 B of $110.0 BPD: 1,000,000 × 10% × $20,000/yr = $2.0 B of $20.0 BMS: 500,000 × 10% × $20,000/yr = $1.0 B of $10.0 B

CAD (prev): 100,000,000 × 10% × $1,000/yr = $10.0 B of $100.0 B

Time to Market 0.5 yr (CAD, ... ), 3 yr (GBA-PD, MS), 5 yr (TNBC); 505(b)(2)

PartneringOptions

• Investment

• Licensing/Joint Development Partnership with options for consideration:

◦ Milestones

◦ Royalty

◦ Right-to-acquire option

◦ Regional or global commercialization rights


ASDERA – Summary

Ready for phase 3 under 505(b)(2) after 1 bridging animal model

3-5 years to market for trial in progressive disease forms (e.g., GBA-PD)Status

ASD-003/4/5Proposed first drug to target metastases in BC, progression in AD/PD/MS Proposed first drug to prevent the BC/AD/PD/CAD (“baby αCD”).

Unmet Need

No treatment for TNBC, except radiation and chemotherapy

No treatment for AD, PD, and MS

No prevention for BC (metastases), AD, and PD; limited success in CAD

Product Market-exclusive derivatives of α-cyclodextrin (aCD), pat. pending

MoA αCD down-regulates endocytosis by scavenging serum phospholipids

PoCβCD was effective in animal models, but may cause hearing lossαCD is 2× as effective against endocytosis (β1 integrin), without ototoxicity

IPMarket

Patents filed in US, EU, ... .

Total US market (at 10% market penetration) ~$30B/yr.


ASDERA – Use of Platform in Phase 2/3 Data

Phase 3 Results

Population:

200 response400 non-

response

ssGWAS:

inconclusive results

muGWAS:

few mutationsin drug target

many variationsin alternate pathway

1

2

3

4

5

6A: Outcome 1

1

2

3

4

5

6

1

2

3

4

5

6A: Outcome 1A: Outcome 1

muGWAS

ssGWAS


END


ASDERA – Frequently Asked Questions

1. Why do you get GWAS results where others don’t ?

2. Has the discovery platform been validated ?


Genetics ofHeritableDiseases

If a disease are caused by a single genetic ‘letter’ variation (SNP), that variation is ‘selected against’ in just a few generations. Hence, most heritable diseases are ‘epistatic’. Some variations of SNPs (‘words’) cause the disease and are selected against, but the individual letters remain in the populations and recombine (no need for de-novo mutations).

Limitations ofBioinformatics

Tools

Most bioinformatics tools in genetics are based on the statistical methods that were feasible in the 20th century, where memory was scarce. Hence, most GWAS are analyzed one SNP at a time and, thus, can detect only recent (de novo) mutations (‘letters’), but not the common cis-epistatic risk factors (‘words’). Others ignore the sequence of the letters (rwdo = word).

The ASDERADiscoveryPlatform

The ASDERA platform is based u-statistics for multivariate data, which were conceived in the 1940s, but never fully developed, because of memory constraints. Only after 2001 (32-bit OS) became it possible to extend u-statistics to incorporate genetic ‘grammar’ (letter sequence, ...) to increase power and avoid artifacts.

Result Where others fail with 100,000s of subjects, ASDERA succeeds with 100s.

ASDERA – FAQ: Why do you get GWAS results where others don’t ?


The platform identified all known targets of epilepsy drugs in a sample of 185 cases only. http://www.ncbi.nlm.nih.gov/pubmed/23438886

Epilepsy(PoC)

Mutismin

Autism

The platform identified ineffective hyperpolarization dueto ion-channel defects as causing “regression” and a MFA prodrug to prevent it. http://www.nature.com/articles/tp2013124 (outlicensed)

Crohn’s Disease

(CD)

In CD, the platform identified several fucosylation defects, suggesting supplementing dietary L-fucose as a novel treatment for the many patients who do not respond to anti-AI drugs. https://www.researchgate.net/publication/309375820 )

Breast Cancer

(BC)

As a finalist of the NCI’s U4C breast cancer challenge, the platform identified excessive influx of phospholipids into the PIP cycle as the cause for “derailed endocytosis” and, thus, aCD as a drug to regulate supply of phospholipids for the prevention of metastases.( https://doi.org/10.1101/152405 )

Phase 2/3

subset GWAS

Since the platform can find the “missing heritability” in samples of 100s of subjects only, it can identify genetic risk factors for non-response in phase 3 clinical trials.(confidential)

ASDERA – FAQ: Has the drug discovery platform been validated ?

a common treatment strategy alzheimer’s/parkinson’s, · ©asdera (2017) non-confidential...

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