A GLOBAL LEADER IN EPIGENETICS
I N V E S T O R P R E S E N TAT I O N
M A D X : O R Y
S a n F r a n c i s c o - J a n u a r y 2 0 1 6
L E G A L N O T I C E
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2
COMPANY HIGHLIGHTS
MADX: ORY A publicly traded company in the
Madrid Stock Exchange since December 14th 2015
Trading started at €3.39 = €96.5M Market Cap
A clinical stage biopharmaceutical company
developing innovative therapies in oncology and
neurodegeneration leading the field of Epigenetics
Two therapeutic programs in clinical development
with multiple indication opportunities & additional
assets in preclinical development
Signed global strategic partnership with ROCHE for
ORY-1001 valued at 500M USD
Strong IP portfolio with technology developed in-
house
Strong financial profile with €+20M cash on balance
sheet with runway till 2018
Experienced management team
3
E P I G E N E T I C S : THE CRITICAL ROLE OF HISTONE CODING
Epigenetics − the study of heritable changes in genome function that occur without a change in DNA
sequence
These changes mainly occur due to variations in the structure of chromatin that silence or activate
whole regions of the chromosome and all the genes that reside in this region
These variations are caused by post-translational modifications on histones, the proteins that serve as
scaffold for the DNA to conform the chromatin
Lysine methylation and demethylation is one of the key epigenetic modifications of the Histone tails
4
EPIGENETICS COMPETITIVE LANDSCAPE
EPIGENETICS is a new Space being explored by the Pharma Industry: Clinical Programs are still in Early Phases.
ORYZON, Epizyme and Constellation are the only Biotechs developing more than one compound.
GSK, Roche, Merck, Pfizer ,Celgene and other Big Pharmas are also entering in the field either through their own programs or through
alliances.
C O M P A N Y C O M P O U N D D E S C R I P T I O N I N D I C A T I O N S T A T U S
Reverlogix RVX-208 BET bromodomain inhibitor Atherosclerosis -Diabetes Phase II b
Acetylon
Pharmaceuticals
(ACY-1215) lic. to
Celgene Oral selective HDAC6 inhibitor Multiple myeloma (MM) Phase I/II
Oryzon Genomics
ORY-1001 lic. to Roche
Lysine-specific demethylase 1
(LSD1) inhibitor
Acute myelogenous leukemia (AML) Phase I/IIa
ORY-2001
LSD1-MAOB dual inhibitor
Alzheimer's Disease
Other Neurodegenerative disorders
CTA filed
Constellation
Pharmaceuticals
CPI-1205 EZH2 inhibitor lymphoma Phase II
CPI-0610 BET bromodomain inhibitor Progressive Lymphoma
AL, MDS, myeloproliferative neoplasms
Multiple myeloma Phase I
Epizyme
EPZ 6438 Tazemetostat EZH2 inhibitor non-Hodgkin B-cell lymphoma
Synovial Sarcoma
Phase I/II
IND / Phase I
EPZ-5676 lic. to Celgene HMT DOT1L inhibitor MLL- AML Phase I/II
Tensha Therapeutics TEN-010 BET bromodomain inhibitor Cancers including NUT midline carcinomas Phase I
5
EXTENSIVE PIPELINE WITH MULTIPLE INDICATIONS
6
L S D 1 P R O G R A M : AN EPIGENETIC “ERASER”
Lysine-specific histone demethylase 1 (LSD1 or KDM1A) is an enzyme that demethylates
histones (removes methyl groups), specifically mono and di-methylated H3K4 and H3K9
LSD1 belongs to the family of flavin adenine dinucleotide, dependent amine oxidases,
which include known drug targets such as MAO-A and MAO-B
LSD1 is located in the nucleus, unlike MAOs
LSD1 expression has a high correlation in many solid tumors
In some aggressive Leukemia, Leukemia Stem Cells are addicted to LSD1 activity
The pan-MAO inhibitor tranylcypromine: a chemical starting point to design covalent LSD1
inhibitors.
Protected by 19 patent families filed globally with 10 granted in US
7
ORYZON’s CLINICAL ONCOLOGY PROGRAM: O R Y- 1 0 0 1
KDM1A is a key effector of the differentiation block in MLL leukemia
KDM1A sustains expression of the MLL-AF9 oncogenic program
Nanomolar KDM1A inhibitor concentrations induce differentiation of human AML cells
KDM1A inhibition in vivo targets MLL-AF9 cells, but spares normal repopulating cells.
Modified from Harris et al., Cancer Cell. 2012: 21(4):473-87)
Oryzon’s LSD1 inhibitor (OG-86) blocks
progression of leukemia cells into the
circulation MLL-AF9 mice model
Oryzon’s LSD1 inhibitor (OG-86) targets
leukemia stem cells but spares normal
hematopoietic stem cells
8
O R Y- 1 0 0 1 : O N C O L O G Y P R O G R A M
ORY-1001 a highly potent and selective LSD1
inhibitor with orphan drug status granted by the
European Medicines Agency (EMA)
Pharmacological Properties
• High druggability
• Optimal ADMET and PK profiles
• Orally bioavailable once daily
• Easy to scale up
• Good pharmaceutical properties
Currently in Phase I/IIA
• Completed Part 1 of the study (Phase I) in acute
leukemia
• Extension Arm (Phase II-A) ongoing
Potential for additional indications, such as solid
tumors (like SCLC) and sickle cell disease
Global strategic collaboration with ROCHE
valued >500M USD
9
O R Y- 1 0 0 1 : ROCHE PARTNERSHIP
Development and sales milestones total >500M USD
Payment at contract signing plus near term milestone total 21M USD
Sales royalty rates tiered up to mid-teens.
10
In April 2014, Oryzon and ROCHE entered into a global collaboration to research,
develop and commercialize LSD1 inhibitors, including ORY-1001, for oncology,
hematology and non-malignant conditions
Licensed compounds are covered by 2 patents in the Oryzon IP portfolio
Remaining LSD1 inhibitors in Oryzon’s LSD1 IP portfolio are not part of the
ROCHE license agreement
Clinical development and all related investments beyond the ongoing Phase I/IIA
trial are the responsibility of ROCHE
Parties will collaborate on R&D through the ROCHE Translation Clinical Research
Center (TCRC)
P H A S E I H I G H L I G H T S : ORY-1001 LEUKEMIA
T R I A L D E S I G N
Refractory & Relapsed
Acute Leukemia Multi-Center (5)
Multiple Ascending Dose (8
Cohorts)
P R I M A R Y E N D P O I N T
Evaluate Safety (hematological and non-hematological toxicities) and Tolerability
S E C O N D A R Y E N D P O I N T S
Characterize PK
Assess Responses
(CR/Cri/PR), particularly for
rMLL gene
Evaluate surrogate PD
markers for target
engagement
P R E L I M I N A R Y R E S U LT S
Excellent safety profile with no SAEs
Demonstrated impact on pharmaceutical target
PD clear readings several biomarkers
Good PK
Established maximum recommended dose
11
PHASE IIA: O R Y- 1 0 0 1 L E U K E M I A
After the MRD , an Expansion arm (Phase II-A) to include patients with target mutations (MLL
and others) to evaluate preliminary signs of efficacy
9 Patients to be included
Status: 3 patients enrolled and actively recruiting
Completion Date: 2Q-2016
C E N T E R S
10 Hospitals in 3 Countries
UK
• Christie Hospital, Manchester
• University College London hospitals NHS, London
FRANCE
• Gustave Roussy, Paris
• CHU Hopitaux, Bordeaux
• Hôpital Purpan - (CHU), Toulouse
SPAIN
• Valle de Hebron, Barcelona
• La Fe, Valencia
• Virgen del Rocío, Sevilla
• 12 de Octubre, Madrid
• Gregorio Marañón, Madrid
12
ORY-1001 CLINICAL & MARKET POTENTIAL
ORY-1001 market capture opportunity above $1.8 billion.
A number of scientific reports point out the potential of LSD1 inhibition as a target in a number of solid
tumors
Non oncological diseases as SCD and others may also be a CDP option
Small Cell Lung Cancer
15% of all Lung Cancers
32.420 new cases in US in
2014 1,3
Global Mk Potential of $684
million in 2017 5
Sickle Cell Disease
SCD Epidemiology
US/EU Prevalence ~150K
US Mk Potential of $200
million in 2017, (Market to grow at 17% CGAR till 2019)
Acute Myeloid Leukemia
12% of all Blood Cancers
18.860 new cases in US in
2014 1,2
Global Mk Potential of $932
million in 2024, CAGR of 10.5% 4
NOTE: ROCHE is the sole responsible for the further clinic development Plan for ORY-1001. The indications and markets
mentioned above are only presented on its likelihood based on the development of competitors or published scientific reports
1. ACS, Cancer Facts & Figures 2014
2. www.hematology.org
3. www.lungcancer.org
4. Global Data 2015
5. Decision Resources 2015
13
R O L E O F E P I G E N E T I C S : NEURODEGENERATIVE DISORDERS
Studies suggest epigenetic modifications
that induce alterations in gene expression
programs contribute to neurodegenerative
disorders:
• Alzheimer’s Disease (AD)
• Parkinson’s Disease (PD)
• Huntington’s Disease (HD)
Epigenetic alterations on related genes
may also result in neurodegeneration,
partially accounting for the etiology
Epigenetic drugs target the proteins
responsible for modifications on DNA or
histone
• HDAC inhibitors (HDACi)
• HAT modulators
• DNA methyltransferase inhibitors
• Histone demethylase inhibitors
Identical twins (monozygotic)
Same DNA with GBA risk
mutation
Disconcordant for symptoms of
Parkinson’s
Up to 20 years difference in
onset
Patient derived iPSCs: difference in MAO-B levels
14
E N V I R O N M E N T
G E N E S E X P E R I E N C E
15
Luca Lovrečić, et al., 2013 The Role of Epigenetics in
Neurodegenerative Diseases
HDACi improves HD symptoms in animal
models
HDAC2 inhibition recovers memory on the
bi-transgenic CK-p25 Tg mouse model
HDAC inhibition improves FTD
However, while pan-HDAC inhibitors have demonstrated
preclinical proof of concept that inhibition of HDACs
improves cognitive function, these drugs have dose limiting
side effects that make them unsuitable for the chronic
settings needed in neurological indications.
Developing more selective HDAC inhibitors is not an
insignificant challenge as HDACs are highly conserved
proteins
HDAC2 selective
inhibitors in AD
HDAC i in Prodromal to Moderate
FTD with Granulin Mutation
Efforts to develop Selective HDACi
R O L E O F E P I G E N E T I C S : NEURODEGENERATIVE DISORDERS
LSD1 IN THE NERVOUS SYSTEM
LSD1 is a key component of the LSD1-REST-
CoREST-HDAC1/2 repressor complex
involved mainly in controlling developmental
programs and modulating neuronal
morphology in the CNS
LSD1 is known to be an important regulator in
the maintenance of pluripotency and in
specification of neuronal commitment of pluri-
or multipotent cells
Different to what happens in HDACs, it has
been proven that it is possible to develop
extremely selective LSD1 inhibitors with
excellent pharmacological properties
Oryzon has the wider IP portfolio in the LSD1
space with drug candidates specially suitable
to be developed in neurological indications
16
O R Y- 2 0 0 1 : CNS PROGRAM
ORY-2001 is a highly selective dual LSD1-MAO-B inhibitor
Preclinical Proof of Concept: LSD1 Against AD and HD
Clinical development
• CTA Filed
• Phase I to start in 1Q2016
Alzheimer’s Disease is lead indication
Potential for additional indications: PD, HD and others
Exclusively owned by Oryzon
Pharmacological Properties
• Optimal ADMET and PK profiles
• Crosses efficiently the BBB
• Once daily oral bioavailable
• Good pharmaceutical properties
• Selectivity against MAO-A demonstrated in-vitro and in-vivo
• High therapeutic window in animals
17
The SAMP8 mouse is an excellent model to examine the pathophysiology of early defects seen in
Alzheimer’s disease. They develop accelerated aging and senescence and show deficits in learning
and memory as well as other similarities to pathology of AD
ORY-2001 cognitive effect tested by NORT in five different studies
After 2 and 4 month of oral treatment, ORY-2001 provides a robust protective effect in the medium and
long-term memory of female mice, compared to age-matched SAMP8 mice
We lowered dose in males (Study #2)
PoC studies in SAMP8 mice
18
2 months treatment
Tested 2 h after training
LSD1+MAOB LSD1 alone MAOB alone
*** ***
***
14/15 3/16 16/16 15/16
SAMPR1 Veh
SAMP8
3.20mpk 0.96mpk
Dis
crim
inat
ion
In
dex
SAMPR1 Veh
SAMP8
3.20mpk 0.96mpk
LSD1+MAOB LSD1 alone MAOB alone
***
***
5/5 0/5 5/5 4/5
***
4 months treatment
Tested 2 h after training
SAMP8 male animals (n=8 per group)
LSD1+MAOB LSD1 alone MAOB alone
LSD1+MAOB LSD1 alone MAOB aloneLSD1+MAOB LSD1 alone MAOB
alone
***
***
***
SAMPR1 Veh
SAMP8
0.96mpk 0.32mpk 3.0mpk
ORY-2001 ORY-2001 Rasag.
MAOB inhibition alone shows a trend
on cognitive improvement on the
SAMP8 animals but it is not
significant
• p=0.12 at 2h
• p=0.22 at 24h
LSD1 inhibition is therefore crucial to
obtain the recovery on cognitive
improvement on the SAMP8 animals
Dissecting the LSD1 and MAOB components
19
PoC studies in SAMP8 mice
SAMP8 female animals (n=8 per group)
ORY-2001 provides a robust
protective effect in the medium and
long-term memory of mice, compared
to age-matched SAMP8 mice
LSD1 inhibition alone is also able to
produce an effect but less
pronounced
Protection is driven by the LSD1
inhibition and not by MAO-B, but the
combination with MAO-B inhibition
(i.e. a dual compound,ORY-2001)
enhances the effect
Dissecting the LSD1 and MAOB components
LSD1+MAOB LSD1 alone MAOB alone
SAMPR1 Veh
SAMP8
0.96 mpk
0.32 mpk
0.1 mpk
ORY 2001
ORY 2001
ORY LSD1
ORY LSD1
0.3 mpk
PoC studies in SAMP8 mice
20
ORY-2001 has a pleiotropic effect on the hippocampal gene expression pattern and increases
memory associated genes and reduces levels of inflammatory genes.
Down-regulation of the pro-inflammatory S100A9 protein by ORY-2001 is particularly interesting,
since S100A9 is emerging as an important contributor to inflammation-related neurodegeneration.
S100A9 was found to be increased in patients with AD, postoperative cognitive dysfunction
(POCD) and traumatic brain injury (TBI). In addition, knockout or knockdown of S100A9 has been
shown to be beneficial to memory in APP/PS1 and Tg2576 models of Alzheimer’s disease
BIOMARKERS : We have identified different biomarkers upon ORY-2001 treatment:
ORY-2001 - PROOF OF CONCEPT IN SAMP8 MICE
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Delta
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*** ***
***
SAMPR1 Veh
SAMP8
3.2 mpk 0.96 mpk
***
0
8
10
12
14
2015 2016 2017
3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017
CMC / 4W
Reg Tox IB / IMPD
CTA
Phase I
(SAD)
Phase I
(MAD)
6M Reg Tox
Additional Preclinical Work to Broaden CDP
Phase II
Dossier
Phase II AD
Phase II Additional
Indications
ORY-2001 DEVELOPMENT TIMELINE
22
ORY-2001 CLINICAL & MARKET POTENTIAL
ORY-2001 market capture opportunity above $3 billion.
Further development may include Neuro- inflammatory disorders
1. Alzheimer’s association www.alz.org
2. Alzheimer Europe www.alzheimer-europe.org
3. European Parkinson’s Diesease Association http://www.epda.eu.com/
4. American Parkinson Disease Association http://www.apdaparkinson.org/ ,
http://www.ninds.nih.gov/
5. http://www.huntington-assoc.com/
6. http://www.fiercebiotech.com/
7. http://www.strategyr.com
ALZHEIMER’S DISEASE
5.4 M people currently affected in US. By 2025 the number of patients will rise to 7.1 million in USA1
8.7 million Europeans are also affected 2 and in Asia another potential 10 to 12 million people are
diagnosed or suspected to suffer AD.
Drug market projected to reach US $9.5 billion by 2017 6
PARKINSON’S DISEASE
Around 6.3 million people have the condition worldwide3
It affects over 1 million people in the US, with nearly 60,000 people newly diagnosed every year. 4
Drug market projected to reach US $2.6 billion in 2020 in the 7MM
HUNTINGTON’S DISEASE
Worldwide prevalence of HD is 5–10 cases per 100,000 persons. There are around 30,000 symptomatic
Americans and more than 200,000 at-risk of inheriting the disease 5
Up to 71,000 patients in Europe.
Drug market projected to reach US$1.3 billion by 2020 7
23
EXPERIENCED LEADERSHIP TEAM
Respected team in the European biopharmaceutical industry
Experienced in drug discovery and development. Able to bring assets to clinical stages in a cost efficient
manner
Proven track record to promote and close world class deals
Ability to lead and unite teams. Leading international consortia
ANNA BARAN
IR Director
TAMARA MAES
CSO and FOUNDER
CARLOS BUESA
CEO and FOUNDER
ENRIC RELLO
COO and CFO-Spain
NEUS VIRGILI
CIPO
EMILI TORRELL
CBO
CESAR MOLINERO
CMO
24
FINANCIAL HIGHLIGHTS
Strong balance sheet with €+20m in cash
$5 million payment from ROCHE in 2015
Secured €2.6M in public aids in 2015
Unused credit line of €6 M from commercial banks
€10M in debt with low interest rates
• Repayment terms over either 3-4y or 8-10y (commercial loans or Public R&D loans)
• Rates from 0-3% (average cost of debt 1,3%)
Expected cash burn of €10-12M annually for next 2 years
Raised €31 M since inception
Spanish GAAP rules adapted to IFRS
Accounts audited by Grant Thornton since 2003 and through 2014
Audited in 1H 2015
35 employees
25
KEY INVESTMENT HIGHLIGHTS
E P I G E N E T I C S
E X T E N S I V E
P I P E L I N E
P R O V E N
T R A C K
S O L I D I P
L E A D E R S H I P
F I N A N C I A L S
• Global leader in Epigenetics, an emerging field recognized by the pharmaceutical
industry as a novel approach to varying diseases and personalized medicine
• 2 programs in clinical development
• Both clinic programs can expand in multiple indications
• An Epigenetic platform with additional assets
• Collaborative agreement with ROCHE valued at $500 million
• Cutting edge science endorsed by international agencies
• Strong patent portfolio with19 patent families and10 granted in US
• All patented technology developed in-house with no owed royalties
• Highly experienced management team
• €+20M on balance sheet with runway till 2018
• Plan to grow as a public company in Europe and dual list on NASDAQ in the future
26
ORY-1001: LEAD CANCER ASSET
• Conclude Phase I dosing study
• Receive recommended dose milestone payment from Roche
• Phase IIA first patient-in
• Complete Phase IIA and report target efficacy
• Roche execute ongoing clinical development plan
ORY-2001: LEAD CNS ASSET
• Complete preclinical toxicology package
• File CTA/IND
• Begin Phase I patient enrolment
• Complete Phase I dosing safety study
• Layout of a multiple Phase II clinical study
CORPORATE
• €16.5M cross over funding in Spain
• List on the Spanish Main Market
• Prepare to List on the NASDAQ in the future
CATALYSTS 2015 - 2016
27
INTERNATIONAL RESEARCH NETWORK
28
ORYZON IS A TRANSATLANTIC COMPANY
UNITED STATES
ORYZON Corp.
245 First Street
Suite 1800
Cambridge, MA 02142
Investor Relations
US Clinical Operations
Business Development
EUROPE
ORYZON
Sant Ferran, 74
08940 Cornellà de LL.
Barcelona, Spain
Research and Development
European Clinical Trials
Intellectual Property
29
THANK YOU VERY MUCH!
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