1. health and fitness
2. disease

Nanobodies® – creating better
medicines
Corporate Presentation – January 2015
Nanobodies® Inspired by nature
Forward looking statements
Certain statements, beliefs and opinions in this presentation are forward-looking, which
reflect the Company or, as appropriate, the Company directors’ current expectations and
projections about future events. By their nature, forward-looking statements involve a
number of risks, uncertainties and assumptions that could cause actual results or events
to differ materially from those expressed or implied by the forward-looking statements.
These risks, uncertainties and assumptions could adversely affect the outcome and
financial effects of the plans and events described herein. A multitude of factors including,
but not limited to, changes in demand, competition and technology, can cause actual
events, performance or results to differ significantly from any anticipated development.
Forward looking statements contained in this presentation regarding past trends or
activities should not be taken as a representation that such trends or activities will
continue in the future. As a result, the Company expressly disclaims any obligation or
undertaking to release any update or revisions to any forward-looking statements in this
presentation as a result of any change in expectations or any change in events, conditions,
assumptions or circumstances on which these forward-looking statements are based.
Neither the Company nor its advisers or representatives nor any of its parent or subsidiary
undertakings or any such person ’ s officers or employees guarantees that the
assumptions underlying such forward-looking statements are free from errors nor does
either accept any responsibility for the future accuracy of the forward-looking statements
contained in this presentation or the actual occurrence of the forecasted developments.
You should not place undue reliance on forward-looking statements, which speak only as
of the date of this presentation.
www.ablynx.com
2
Corporate snapshot
Corporate
• Drug discovery and development company in Ghent, Belgium
• >300 employees
Technology
• Pioneer in next generation biological drugs – Nanobodies®
• >500 granted and pending patents
Products
• >30 programmes – six at the clinical development stage
• Three clinical proof-of-concepts (POCs)
• >10 new clinical programmes possible over the next 3 years
Partners
• AbbVie, Boehringer Ingelheim, Eddingpharm, Merck & Co,
Merck Serono and Novartis
Financials
• >€200M in cash expected end 2014
www.ablynx.com
3
2014 – an exciting year for Ablynx
5 clinical trial read outs – including clinical proof-of-concept (POC) for
caplacizumab in TTP
4 clinical trials initiated – including 2 partnered programmes
Further validation of the platform through immune-onco deal with Merck & Co
focusing on multi-specifics – €20M upfront, €10.7M in research funding and
up to €1.7Bn in future milestones plus royalties
Expansion into Asia through 2nd licensing deal with Eddingpharm for the
development and commercialisation of ozoralizumab (anti-TNFa) in Greater
China
Further strengthened the financial position through an oversubscribed private
placement of new shares raising €41.7M
A multi-asset clinical development company with a
powerful discovery platform
www.ablynx.com
4
Fully owned
Proprietary and partnered programmes
Therapeutic area
Product name
Target
Haematology
caplacizumab
vWF
ALX-0171
RSV
Respiratory
Discovery Pre-clinical
Phase I
Phase II
Phase III
Filing
Various
Oncology/
Immuno-oncology
Various
Inflammation/
Immunology/Infection
Various
Ocular
Various
Inflammation/
Immunology
ALX-0061
IL-6R
ALX-0761
IL-17A/F
ozoralizumab
TNFα
Greater China
RANKL
Greater China
Partnered
Various
Oncology/
Various
ALX-0751
Immuno-oncology
Various
Bone disorders
ALX-0141
Neurology
Various
CXCR2
Respiratory
Other
www.ablynx.com
Various
Validated targets (clinic)
1st in class
5
What are Nanobodies?
Nanobodies® Inspired by nature
Nanobodies – derived from heavy-chain only antibodies
Camelid heavy-chain only antibodies are stable and fully functional
Nanobodies represent the next generation of antibody-derived biologics
VH
VHH
CH1
VHH
VL
CL
CH2
CH3
Conventional
antibodies
www.ablynx.com
12-15kDa
Ablynx’s Nanobody
CH2
CH3
Heavy chain only
antibodies
• small
• robust
• sequence homology comparable
to humanised/human mAbs
• easily linked together
• nano- to picomolar affinities
• intractable targets
• multiple administration routes
• manufacturing in microbial cells
7
Nanobody platform – competitive advantages
Alternative delivery routes
Mix and match
e.g. targeting different checkpoint
inhibitors with a single Nanobody
construct
Customised half-life
extension
Weeks/days/hours
Inhalation
Needle-free
Albuminbinding
Nanobody
Fc
Challenging and
intractable targets
Nanobodies against
ion channels and
GPCRs
Nanobodies can
reach conserved
cryptic epitopes
Oral-to-topical
Ocular
Cell killing
Cell / tissue-homing
Cell specificity
Immune cell
retargeting
www.ablynx.com
PEG
Nanobody-drug conjugates
Tissue-specific
targeting
8
Multi-specific Nanobodies – targeting checkpoint inhibitors
Monovalent Nanobodies
against
different targets
Different multi-specific
combinations
In vivo testing
Pardoll, Nature Reviews Cancer (2012) 12:252-264
May need to interfere with
multiple pathways
www.ablynx.com
In vivo POC for different
multi-specific combinations in
18-24 months
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Pipeline value drivers
Nanobodies® Inspired by nature
Leading programmes in the clinic
Proprietary
Programme (target)
Indication
Caplacizumab (vWF)
First-in-class orphan drug
Thrombotic
thrombocytopenic Novel mode of action
purpura
Inhibition of microthrombi formation
ALX-0171 (RSV)
Respiratory
syncytial virus
infection
Key differentiating features
First-in-class addressing high unmet need
Inhaled Nanobody delivered to infection site
Highly potent trivalent construct
Stage
Start Phase III mid2015: results expected
end 2017
Phase IIa infant study
initiated: results
expected H2 2015
Partnered
Programme (target)
Indication
ALX-0061 (IL-6R)
RA, SLE
ALX-0761 (IL-17A/F)
Psoriasis
www.ablynx.com
Partner
Key differentiating features
Stage
Best-in-class opportunity
Monovalent interaction; strong affinity and
preferential binding to soluble IL-6R
Start Phase IIb/a
(RA; SLE) in 2015
RA results exp. 2016
Potent neutralisation of both IL-17A and
IL-17F
POC achieved in primate CIA* model
Phase Ib ongoing in
psoriasis patients:
results exp. 2015
* Collagen induced arthritis model
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caplacizumab – anti-vWF
•
First-in-class bivalent
Orphan Drug Status
•
Developed for the treatment of acquired
thrombotic thrombocytopenic purpura (TTP)
•
Phase III study to start in 2015
•
Peak sales potential €300-400M*
Nanobody
with
Nanobodies® Inspired by nature
* US, EU, Japan, other markets (Brazil, Canada, Russia, Mexico, Australia)
What is the basis of TTP?
caplacizumab blocks the platelet – ULvWF interaction
Caplacizumab binds to A1
domain of vWF and thereby
inhibits platelet string formation
ADAMTS13 activity is
impaired
Ultra-Large (UL)
vWF multimers
Platelet string
formation in patients
with TTP
endothelium
Ex vivo assay for platelet string formation
Fluorescence microscopy image of platelets adhering to UL-vWF in plasma of TTP patients
Without treatment, fluorescently labelled platelets adhere to
UL-vWF, observed as string-like structures
ULvWF
Caplacizumab inhibits the formation of platelet strings and
potentially the associated microvascular thrombi in many organs
ULvWF and anti-vWF Nanobody
www.ablynx.com
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Acquired TTP – significant unmet medical need
Severe fatigue,
headache, coma,
abdominal pain,
weakness, nausea,
bizarre behaviour,
vertigo, seizures
Daily PE in hospital
until recovery of
platelet count
Emergency
Sudden onset
Healthy person
Potentially life threatening rare disorder of the blood coagulation system
•
•
incidence of 11.3 per million1
~10,000 acute events annually in US and Europe
Extensive microscopic thrombi formed in small blood vessels throughout the body
High unmet medical need
•
no approved medicinal product for treatment available
•
standard of care is plasma exchange (PE) plus immune suppressants
•
mortality remains high (10-20%)2 and ~ 36% of patients have relapses1
•
major morbidities after first TTP episode such as neurocognitive impairment
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1
George et al, 2008
2
Scully et al, Br J Haematology, 2012
14
Randomisation
Caplacizumab – Phase II TITAN design and schedule
PE
30 days
30 days
Placebo N=39
1 year follow-up
1:1
Target – 110 subjects
Actual – 75 subjects
PE
30 days
30 days
Caplacizumab N=36
1 year follow-up
Primary endpoint:
time to confirmed normalisation of
platelet count
Secondary endpoints:
plasma exchange frequency and volume;
relapse; exacerbations; mortality; major clinical
events (stroke, MI, organ dysfunction); recovery
from signs/symptoms; ADA
Long-term endpoints:
ADA; relapse; non focal
neurological symptoms
Safety & efficacy endpoints
www.ablynx.com
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Caplacizumab – strong Phase II clinical proof-of-concept
Primary endpoint
Secondary endpoint
Safety
www.ablynx.com
•
patients treated with caplacizumab achieved
confirmed platelet normalisation at more than twice the
rate of the group treated with placebo
•
this effect was statistically significant (p = 0.013)
•
71% less patients with an exacerbation
•
76% more patients in complete remission
•
no deaths in the caplacizumab arm compared to 2
deaths in the placebo arm
•
increased bleeding tendency, which is believed to be
manageable
•
overall, caplacizumab has an acceptable safety profile
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Caplacizumab – current status and next steps
Confirmed clinical activity and good safety profile in the clinic
Data from TITAN study, including post hoc analysis, presented at ASH 20141
Consultation with regulatory authorities in US and EU in Q1 2015
• explore possibility to file dossier for approval (2017 expected) based on TITAN study
Various partnering scenarios currently being evaluated
Preparations progressing to start Phase III trial in mid-2015
In 2015, caplacizumab will be the first Nanobody to enter
Phase III clinical development
www.ablynx.com
1Oral
presentation availabe on Ablynx website
17
ALX-0171 – anti-RSV
•
First-in-class trivalent Nanobody for the
treatment of respiratory syncytial virus
(RSV) infection in infants
•
Delivered through inhalation
•
First-in-infant Phase IIa initiated in Q4
2014
•
Opportunity in a multi-billion dollar market
Nanobodies® Inspired by nature
RSV infection in infants – high unmet medical need
Leading cause of infant hospitalisation and primary viral cause of infant death
• ~300,000 children* (< 5 years) hospitalised per year in 7 major markets1,2
• increased medical cost in the 1st year following RSV infection3
• prolonged wheezing and risk for asthma development4
No widely accepted drug available to treat RSV infections
• Synagis® used as prophylaxis in high-risk pre-term infants only ($1.1bn sales in 2013)
Evolves to
distressing
symptoms
Symptomatic treatment
including inhaled
corticosteroids & bronchodilator
8-20%
hospitalised
* Extrapolation based on estimated US prevalence
www.ablynx.com
1 Hall
et al, NEJM ,2009; 2 Lee et al, Human Vaccines 2005; 3Shi et al, J Med Econ, 2011; 4 Sigurs et al, Thorax, 2010; Krishnamoorthy et al, Nature Medicine 2012
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ALX-0171 – key milestones achieved
In vitro studies demonstrated
• potent anti-viral effect against recent clinical RSV isolates
• 10,000 fold reduction in viral titres and superiority over palivizumab (Synagis®)1
Daily inhalation of ALX-0171 for 3 consecutive days (starting 3 days after
infection) in neonatal lamb model for infant RSV demonstrated
• marked reduction in viral titres, lung lesions and symptoms of illness (malaise)2
with
%% ofla mlambs
re  1 ≥ 1
s c o score
b s w ith
G e n e r a l illn e s s s c o r e
-1
“Malaise score”
100
RSV vehicle
RSV ALX-0171
R S V V e h ic le
Vehicle
R S V A L X -0 1 7 1
M o c k V e h ic l e
M o c k A L X -0 1 7 1
80
60
40
20
0
1
2
3
4
5
6
D a y s p o s t in f e c t io n
Days post infection
Well tolerated in multiple Phase I clinical studies in adults
www.ablynx.com
Oral presentations – 1Vaccines of the World (Oct 2013) and 2 RSV Symposium (Nov 2014) – available on Ablynx website (pipeline section)
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ALX-0171 – first-in-infant inhalation study
Infants aged 3 to <24 months who are hospitalised for RSV infection
>20 EU centres and additional centres in Southern Hemisphere (risk mitigation)
Open-label
lead-in N=5
Review
by DMC*
Inhaled ALX-0171 once/day
Randomisation
Custom-developed infant inhalation device (vibrating mesh)
ALX-0171 N=20
Inhaled ALX-0171 once/day or placebo
2:1
3 consecutive days
Placebo
N=10
3 consecutive days
Primary endpoint:
Safety and tolerability of ALX-0171
Secondary endpoints:
Centres opened for recruitment Dec 2014
Results expected H2 2015
www.ablynx.com
* Data Monitoring Committee
Clinical effect (feeding, respiratory rate, wheezing,
coughing, general appearance)
PD (viral load), PK (ALX-0171 systemic
concentration) and immunogenicity
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ALX-0171 – current status and next steps
Strong therapeutic effect demonstrated in a neonatal animal model for infant
RSV infection
Well tolerated in multiple Phase I studies in adults
First-in-infant Phase IIa study initiated in Europe with the potential to extend to
the Southern Hemisphere as risk mitigation
With ALX-0171, Ablynx could potentially achieve its fourth clinical proofof-concept for Nanobodies, and its first for an inhaled Nanobody
www.ablynx.com
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ALX-0061 – anti-IL-6R
•
Monovalent half-life extended Nanobody
•
Best-in-class potential for the treatment of
auto-immune disorders
•
Global licensing agreement with AbbVie
•
Phase IIb studies in RA and Phase IIa
study in SLE to start in 2015
•
Opportunity in multi-billion dollar markets
Nanobodies® Inspired by nature
ALX-0061 – compelling Phase IIa results in RA patients
ACR50 score as potential
differentiating factor
100
% of patients
83
80
71
58
60
63
40
29
20
0
All unmodified ALX-0061 at week 24 (N=24)
ACR20
ACR50
ACR70
DAS28 remission
Boolean remission
• Treatment was highly efficacious and was well tolerated at all doses
• No increase in adverse events upon extension of treatment
• No anti-drugs antibodies were reported
www.ablynx.com
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ALX-0061 – global licensing deal with AbbVie
Global exclusive licensing deal with AbbVie signed in September 2013 following
compelling Phase IIa proof-of-concept results with ALX-0061 in February 2013
Economics
Ablynx
•
•
$175M upfront at signing in September 2013
$665M total potential milestones plus double-digit royalties
•
perform and fund Phase I study with subcutaneous formulation
(started 2014)
perform and fund Phase II studies in RA and SLE (start 2015)
•
AbbVie
Commercialisation
www.ablynx.com
•
•
pay a fee for each indication if they exercise the right to
license ALX-0061 after completion of the Phase II studies
responsible for Phase III development and registration
•
•
AbbVie is responsible for global commercialisation
Ablynx retains option to co-promote ALX-0061 in the Benelux
RA: rheumatoid arthritis
SLE: systemic lupus erythematosus
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ALX-0061 – Phase IIb RA combination study with MTX*
Study on track to start in Q1 2015
Adult subjects with moderate to severe RA despite MTX therapy
Multi-centre, multi-country, randomised, double-blind, placebo-controlled 24 week
dose finding study
Eligible subjects will be invited to roll-over into open-label extension (OLE) study
ALX-0061 dose 1, Q4W
Primary endpoint at week 12:
Randomisation
ACR20 response
ALX-0061 dose 2, Q4W
Secondary endpoints:
1:1:1:1:1
ALX-0061 dose 2, Q2W
ACR responses over time, disease
activity scores, EULAR DAS28 response,
remission, effects on quality of life
ALX-0061 dose 3, Q2W
330 subjects
Other assessments:
Placebo
www.ablynx.com
* methotrexate
pharmacokinetics, pharmacodynamics,
safety/tolerability, immunogenicity
26
ALX-0061 – Phase IIb RA monotherapy study
Study on track to start in Q1 2015
Adult subjects with moderate to severe RA who are intolerant to MTX or for whom
continued MTX is inappropriate
Multi-centre, multi-country, randomised, double-blind 12 week study
Actemra® arm is included to obtain parallel descriptive information on efficacy and
safety
Randomisation
Eligible ALX-0061 treated subjects will be invited to roll-over into an OLE study
Primary endpoint at week 12:
ALX-0061 dose 1, Q2W
Secondary endpoints:
ALX-0061 dose 2, Q2W
ACR responses over time, disease
activity scores, EULAR DAS28 response,
remission, effects on quality of life
1:1:1:1
228 subjects
www.ablynx.com
ALX-0061 dose 1, Q4W
Actemra® 162mg Q1W
(EU) or Q2W (US)
ACR20 response
Other assessments:
pharmacokinetics, pharmacodynamics,
safety/tolerability, immunogenicity
27
ALX-0061 – key milestones in clinical development
2014
2015
2016
2017
2018
2019
Phase I sc study
results announced 23 Oct 2014
ALX-0061 showed >80% bioavailability after sc injection
Phase IIb RA combination
study with MTX
Phase IIb RA monotherapy
study
top line results
potentially continues development in RA
Phase II in SLE
top line results
potentially continues
development in SLE
www.ablynx.com
28
Partnerships
Nanobodies® Inspired by nature
Partnerships – broad platform exploitation and value creation
Global licensing deal for ALX-0061 (anti-IL-6R) in RA and SLE: $175M upfront and
total potential value of $840M plus royalties
Strategic discovery alliance (8 pre-clinical programmes on-going) – focus on bispecifics - 2 programmes could enter the clinic in 2015
4 deals: 10 programmes (1 Phase Ib) on-going in inflammation, immunology,
oncology, immune-oncology, neurology and osteoarthritis
2 discovery deals: ion channel deal in neurology; immune-onco deal (focus on multispecifics) with €20M upfront, €10.7M research funding and total potential milestones
of up to €1.7bn plus royalties
2 licensing deals in Greater China for ALX-0141 (anti-RANKL) in bone disorders and
ozoralizumab (anti-TNFα) in inflammation
Target based discovery deal
>€335M in non-dilutive cash received from collaborators to date
~€3Bn in potential future milestones plus royalties
www.ablynx.com
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Financials and shareholder
structure
Nanobodies® Inspired by nature
Financial summary
€M
2012
2013
First 9 months
2014
Revenue
26.7
35.9
35.2
Operating Result
(29.8)
(17.7)
(11.7)
Cash Position(1)
62.8
200.4
221.5
Anticipated net cash burn for 2014: €30M - €35M
(1)
cash, cash equivalents, restricted cash and short-term investments at the end of the period
www.ablynx.com
32
Shareholder structure
Investors
Abingworth
(UK); 9.08%
Boehringer
(DE); 3.97%
Geography
Aviva (UK);
3.84%
Other/nonspecified
26%
US
26%
Perceptive
Advisors (US);
3.85%
France
2%
Fidelity
Management
Research LLC
(US); 3.35%
Other/nonspecified
institutional and
retail investors;
75.92%
www.ablynx.com
UK
18%
Benelux
28%
•
Ordinary shares listed on Euronext Brussels (ABLX BB)
•
Sponsored level I ADRs on the US OTC market (ABYLY US)
•
54M shares outstanding
•
3M outstanding warrants
•
Free float is ~90%
33
Outlook
Nanobodies® Inspired by nature
Potential value drivers in 2015
Developing the pipeline
•
•
•
Caplacizumab (vWF):
confirm the regulatory
pathway; start Phase III in
acquired TTP
ALX-0061 (IL-6R): start
two Phase IIb’s in RA and
a Phase IIa in SLE
Partnered programmes:
potential start of three
Phase I’s
Programme read outs
•
•
•
ALX-0171 (RSV): potential
POC from Phase IIa in
hospitalised infants with
RSV infection
Commercial
•
Caplacizumab (vWF):
determine partnering
strategy
•
Potential milestone
payments from
ongoing partnerships
•
Continuing
discussions on
partnering various
assets
ALX-0761 (IL-17A/F):
expect Phase Ib results in
psoriasis patients
Technology: results from
various feasibility studies
across multiple applications
An important year ahead
www.ablynx.com
35
Later stage clinical data expectations
2018
2017
2016
2015
ALX-0061 Phase IIb
ALX-0171 Paediatric
(RA)
Phase IIb (RSV)
AbbVie have option to
Wholly-owned
license worldwide
ALX-0171 Infant Phase
IIa (RSV)
Wholly-owned
2014
caplacizumab
Phase II (TTP)
Wholly-owned
www.ablynx.com
ALX-0761 Phase Ib
(severe psoriasis)
Licensed to Merck
Serono (worldwide)

caplacizumab Phase III
(TTP)
Wholly-owned
ALX-0061 Phase IIa
(SLE)
AbbVie have option to
license worldwide
Results from various
patient studies with
partners
ALX-0141 and
ozoralizumab Phase I/II
in China
Licensed to
Eddingpharm (China)
ALX-0761 Phase IIa
(severe psoriasis)
Licensed to Merck
Serono (worldwide)
36
Nanobodies® – creating better
medicines
Corporate Presentation – January 2015
Nanobodies® Inspired by nature