slide title text (source sans pro 36pt bold) · start phase iii h2 2015 and maa filing in h1 2017...
TRANSCRIPT
Nanobodies®
creating better medicines
May 2015
Corporate presentation
2
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.
2
3
Ablynx
Corporate snapshot
• Drug discovery and development company in Ghent, Belgium
• >300 employees
• Pioneer in next generation biological drugs – Nanobodies®
• >500 granted and pending patents
• >30 programmes – six at the clinical development stage
• Three clinical proof-of-concepts (POC)
• 2 wholly-owned products in later stage clinical development (Phase III & Phase II)
• >10 new clinical programmes anticipated over the next 3 years
• AbbVie, Boehringer Ingelheim, Eddingpharm, Merck & Co, Merck Serono
and Novartis
• €193M in cash at 31 March 2015
CORPORATE
TECHNOLOGY
PARTNERS
PRODUCTS
FINANCIALS
4
2014
A year of great progress
4
Pipeline value
creation 1
Expanding
existing
collaborations 2
Corporate
development 3
• 6 clinical trial read outs – of which Phase II clinical proof-of-concept
with caplacizumab in TTP
• 4 clinical trials initiated – of which first inhaled Nanobody in patient
population
• Immune-onco deal with Merck & Co worth €20M upfront, €10.7M
research funding and up to €1.7Bn in future milestones plus royalties
• 2nd licensing agreement with Eddingpharm
• 1st step in a building commercial infrastructure with appointment of
Chief Commercial Officer
• Financial position strenghtened through oversubscribed private
placement of new shares (raised €41.7M)
What are Nanobodies?
Unique technology
6
Nanobodies
• Camelid heavy-chain only antibodies are stable and fully functional
• Nanobodies represent the next generation of antibody-derived biologics
Derived from heavy-chain only antibodies
Conventional
antibodies
Heavy chain only
antibodies
Ablynx’s Nanobody
• 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
CH2
CH3
CH1
CL
VL
VH 12-15kDa
CH2
CH3
VHH
VHH
7
Ablynx’s platform
*Glycine-serine linkers from C-terminus to N-terminus
Rapid generation of high quality biologics
~12-18 months
Immunise llamas
with antigen or
use synthetic library
Wide range of highly
diverse Nanobodies
with 0.1-10nM affinities
Formatted*
Nanobodies ready
for in vivo testing
Cloning and production in microbial systems
8
Nanobody platform
Competitive advantages
Mix and match
Cell specificity
Immune cell
recruitment
Tissue-specific
targeting
Cell- /tissue-homing
Albumin-
binding
Nanobody Fc
Weeks/days/hours
Customised
half-life extension
Nanobodies
against ion
channels and
GPCRs
Nanobodies can
reach conserved
cryptic epitopes
Challenging and
intractable targets
Manufacturing
High-yield,
high-
concentration,
low-viscosity,
microbial
production
Inhalation
Oral-to-topical
Needle-free
Ocular
Alternative delivery routes
Nanobody-
drug
conjugates
Cell killing
Ag-1 Ag-1 Ag-2
Targeting different pathways at once
with a single Nanobody construct, e.g.
multiple checkpoint inhibitors
Product pipeline
>30 programmes in development
Two wholly-owned in later stage clinical development
10
Proprietary and partnered programmes
Multiple shots on goal
Inflammation/
Immunology
FU
LL
Y O
WN
ED
Therapeutic area Product name Target
Inflammation/
Immunology
Haematology
Oncology/
Immuno-oncology
Respiratory
Discovery
ALX-0061
Pre-clinical Phase I Phase II Phase III
IL-6R
caplacizumab vWF
ALX-0171
Neurology
Various
ALX-0141 RANKL
ALX-0761
Various
Various
Various
RSV
Various
Various
PA
RT
NE
RE
D
Bone disorders Greater China
IL-17F/IL-17A
Ocular
Oncology/
Immuno-oncology
ozoralizumab TNFα Greater China
Filing
CXCR2
Various
Other
Clinically validated targets
First-in-class
11
PARTNERED
Programme (target) Indication Key differentiating features Stage Partner
ALX-0061 (IL-6R)
RA, SLE
Best-in-class opportunity
Monovalent interaction; strong affinity
and preferential binding to soluble IL-6R
3 Phase II studies
(RA; SLE) in 2015
RA results
expected in 2016
ALX-0761 (IL-17A/F)
Psoriasis
Potent neutralisation of both IL-17A
and IL-17F
POC achieved in primate CIA* model
Psoriasis Phase
Ib on-going:
potential clinical
POC results
expected in 2015
Leading programmes in the clinic
* Collagen induced arthritis model
Pipeline value drivers
11
PROPRIETARY
Programme (target) Indication Key differentiating features Stage
Caplacizumab (vWF)
Thrombotic
thrombocytopenic
purpura
First-in-class orphan drug
Novel mode of action
Inhibition of microthrombi formation
Start Phase III H2
2015 and MAA filing
in H1 2017 in EU for
conditional approval
ALX-0171 (RSV)
Respiratory
syncytial virus
infection
First-in-class addressing high unmet need
Inhaled Nanobody delivered to infection site
Highly potent trivalent construct
Start first-in-infant
study Q4 2014:
results expected in
H1 2016
12
Caplacizumab
Wholly-owned anti-vWF Nanobody
• First-in-class bivalent Nanobody with
Orphan Drug Status
• Developed for the treatment
of acquired thrombotic thrombocytopenic
purpura (TTP)
• Phase III study to start in H2 2015
• Filing expected in H1 2017 for conditional
approval in Europe based on Phase II
results
• Peak sales potential of €300M-€400M1
1 US, EU, Japan, other markets (Brazil, Canada, Russia, Mexico, Australia)
13
Caplacizumab
What is the biological basis of TTP?
Caplacizumab blocks the platelet –
ULvWF interaction
ULvWF and anti-vWF Nanobody
ULvWF
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
Caplacizumab inhibits the formation of platelet strings and potentially
the associated microvascular thrombi in many organs
Ultra-Large (UL)
vWF multimers Platelet string
formation in patients
with TTP
ADAMTS13 activity is
impaired
endothelium
Caplacizumab binds to A1
domain of vWF and thereby
inhibits platelet string formation
14
Acquired TTP
• 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
– mortality remains high (10-30%)2 and ~ 36% of patients have relapses1
– major morbidities after TTP episode such as neurocognitive impairment
– standard of care is plasma exchange (PE) plus immune suppressants
1 George et al, 2008; 2 Allford et al, 2003, Kremer Hovinga, 2010; Benhamou 2012
Significant unmet medical need
HEALTHY PERSON
Daily PE in hospital
until recovery of platelet
count
Severe fatigue,
headache, coma,
abdominal pain,
weakness, nausea,
bizarre behaviour,
vertigo, seizures
SUDDEN ONSET EMERGENCY
15
Caplacizumab
Phase II TITAN design and schedule R
AN
DO
MIS
AT
ION
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
1:1
Safety & efficacy endpoints
PE
PE
Caplacizumab N=36
1 year follow-up
1 year follow-up
Long-term endpoints:
ADA; relapse; non focal neurological
symptoms
Target
110 subjects
Actual
75 subjects
Placebo N=39
30 days
30 days 30 days
30 days
16
TITAN trial summary
• 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)
Strong clinical proof-of-concept
• 71% fewer patients with an exacerbation
• No deaths in the caplacizumab arm compared to 2 deaths in the
placebo arm
• Increased bleeding tendency (but believed to be manageable)
• Overall, caplacizumab has an acceptable safety profile
PRIMARY
ENDPOINT
SECONDARY
ENDPOINT
SAFETY
17
Caplacizumab
Current status and next steps
17
Caplacizumab could be approved for sale in Europe in 2018
• Confirmed clinical activity and good safety profile in the clinic
• Intention to file for conditional approval in EU in H1 2017 based on Phase II
• Preparations progressing to start Phase III study in H2 2015
• Intention to submit BLA in USA following Phase III study completion
• Commercialisation/partnering strategy currently under evaluation
18
ALX-0171
Wholly-owned anti-RSV Nanobody
• First-in-class trivalent Nanobody for the
treatment of respiratory syncytial virus
(RSV) infection in infants
• Delivered by inhalation
• First-in-infant Phase IIa on-going with
results expected in H1 2016
• Opportunity in multi-billion dollar market
19
RSV infection in infants
• 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 first year following RSV infection3
– prolonged wheezing and increased 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)
* Extrapolation based on estimated US prevalence 1 Hall et al, NEJM, 2009; 2 Lee et al, Human Vaccines, 2005; 3 Shi et al, J Med Econ, 2011; 4 Sigurs et al, Thorax, 2010; Backman et al, Acta Pediatr, 2014
High unmet medical need
Evolves to
distressing
symptoms
8-20%
hospitalised
Symptomatic treatment
including inhaled
corticosteroids & bronchodilator
20
ALX-0171
• Well tolerated in multiple Phase I clinical studies in adults
• In vitro and in vivo 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 in neonatal lamb model for infant RSV
demonstrated markedly reduced symptoms of illness (“Malaise Score”)2
1 Vaccines of the World (Oct 2013) 2 RSV Symposium (Nov 2014) – presentations on http://www.ablynx.com/rd-portfolio/clinical-programmes/alx-0171/
Key milestones achieved
0
20
40
60
80
100
0 1 2 3 4 5 6% o
f la
mb
s w
ith
sco
re ≥
1 RSV vehicle
RSV ALX-0171
Vehicle
RSV
infection
Treatment ALX-0171 or
formulation buffer
21
ALX-0171
• Infants aged 3 to <24 months who are hospitalised for RSV infection
• 24 EU centres and additional centres Southern Hemisphere (risk mitigation)
• Custom-developed infant inhalation device (vibrating mesh)
* Data monitoring committee
First-in-infant inhalation study
RA
ND
OM
ISA
TIO
N
2:1
Placebo N=10 Inhaled ALX-0171 once/day
3 consecutive days
ALX-0171 N=20
Open-label lead-in
N=5
Review by
DMC*
Inhaled ALX-0171 once/day or placebo
3 consecutive days
Primary endpoint:
Safety and tolerability of ALX-0171
Secondary endpoints:
Clinical effect (feeding, respiratory rate,
wheezing, coughing, general appearance)
PD (viral load), PK (ALX-0171 systemic
concentration) and immunogenicity
Started Q4 2014
Results expected H1 2016
22
ALX-0171
• 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 Northern Hemisphere; lead-in phase
successfully completed and placebo-controlled phase of the study on-going
• Recruitment of Phase IIa study to continue in parts of Asia-Pacific region with the
goal to complete recruitment of the placebo-controlled phase by end 2015 with
results anticipated in H1 2016
Current status and next steps
22
With ALX-0171, Ablynx could potentially achieve its fifth clinical proof-of-
concept for Nanobodies, and its first for an inhaled Nanobody
23
ALX-0061
Anti-IL-6R Nanobody partnered with AbbVie
• 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 started and Phase
II study in SLE to start around mid 2015
• Opportunity in multi-billion dollar markets
RA: rheumatoid arthritis
SLE: systemic lupus erythematosus
24
ALX-0061
Compelling Phase IIa results in RA patients
83
71
58 63
29
0
20
40
60
80
100
% o
f p
ati
en
ts
All unmodified ALX-0061 at week 24 (N=24)
ACR20 ACR50 ACR70 DAS28 remission Boolean remission
• Treatment was highly efficacious and was well tolerated
• No increase in adverse events upon extension of treatment
• No anti-drug antibodies were reported
ACR50 score as potential
differentiating factor
25
ALX-0061
• $175M upfront at signing in September 2013
• $665M total potential milestones plus double-digit royalties
Global licensing deal with AbbVie
25
Economics
Ablynx • Perform and fund Phase I study with subcutaneous formulation
(successfully completed in 2014)
• Perform and fund Phase II studies in RA and SLE (start 2015)
AbbVie
Commercialisation
• 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
26
ALX-0061
• First patient dosed in March 2015
• Adult subjects with moderate to severe RA despite MTX therapy
• Worldwide, randomised, double-blind, placebo-controlled 24 week dose finding study
• Eligible subjects will be invited to roll-over into open-label extension (OLE) study
* methotrexate
Phase IIb RA combination study with MTX* R
AN
DO
MIS
AT
ION
1:1:1:1:1
Placebo
ALX-0061 dose 1, Q4W
330 subjects
ALX-0061 dose 2, Q4W
ALX-0061 dose 2, Q2W
ALX-0061 dose 3, Q2W
Primary endpoint at week 12:
ACR20 response
Secondary endpoints:
ACR responses over time, disease
activity scores, EULAR DAS28
response, remission, effects on
quality of life
Other assessments:
pharmacokinetics,
pharmacodynamics,
safety/tolerability, immunogenicity
27
ALX-0061
• First patient dosed in April 2015
• Adult subjects with moderate to severe RA who are intolerant to MTX or for whom
continued MTX is inappropriate
• Worldwide, randomised, double-blind 12 week study
• (Ro)Actemra® arm to obtain parallel descriptive information on efficacy and safety
• Eligible ALX-0061 treated subjects will be invited to roll-over into an OLE study
Phase IIb RA monotherapy study
1:1:1:1
ALX-0061 dose 1, Q4W Primary endpoint at week 12: ACR20 response
Secondary endpoints: ACR responses over time, disease
activity scores, EULAR DAS28 response,
remission, effects on quality of life
228 subjects
ALX-0061 dose 1, Q2W
ALX-0061 dose 2, Q2W
(Ro)Actemra® 162mg
Q1W (EU) or Q2W (US)
Other assessments: pharmacokinetics, pharmacodynamics,
safety/tolerability, immunogenicity
RA
ND
OM
ISA
TIO
N
28
ALX-0061
Key data points in clinical development
Phase I
sc study
Phase IIb
combination and
monotherapy
studies in RA
Phase II study
in SLE
2014 2015 2016 2017 2018 2019
Top line results
Top line results
potentially continues development in RA
potentially continues
development in SLE
Results announced 23 Oct 2014
ALX-0061 showed >80% bioavailability after sc injection
Phase II RA OLE
study
29
Additional clinical assets
Licensed to partners
• ALX-0761 – anti-IL-17A/F
Merck Serono (global)
• ALX-0141 – anti-RANKL
Eddingpharm (Greater China)
• Ozoralizumab – anti-TNFα
Eddingpharm (Greater China)
Partnerships
Broad platform exploitation and cash generation
31
Current partnerships
Broad platform exploitation and value creation
>20 active programmes; >€340M in non-dilutive cash received
~€3Bn in potential future milestones plus royalties
Global licensing deal for ALX-0061 (anti-IL-6R) in RA and SLE
2 discovery deals: ion channel deal; immune-onco deal with focus on multi-specifics
Strategic discovery alliance (focus on bi-specifics) – multiple programmes on-going
4 agreements: multiple programmes on-going (lead project in Phase Ib)
2 licensing deals in Greater China for ALX-0141 and ozoralizumab
Target-based discovery deal
Outlook
Potential value enhancing events
33
2015
Potential value drivers
33
Developing the pipeline Programme read outs Commercial
An important year ahead!
• Caplacizumab (vWF): i) confirm regulatory pathway
ii) start Ph III in acquired TTP
• ALX-0061 (IL-6R): dose first
patient in: i) Ph IIb RA combination therapy
ii) Ph IIb RA monotherapy
iii) Ph II in SLE
• ALX-0171 (RSV): complete
recruitment of Phase IIa
• Partnered programmes:
potential start of 3 Phase I’s
• ALX-0761 (IL-17A/F)
(Merck Serono): expect
POC Phase Ib results in
psoriasis patients in H2
2015
• Potential in vivo pre-clinical
POC results from initial
programmes as part of IO
collaboration with Merck &
Co
• Caplacizumab (vWF):
determine partnering and
commercialisation
strategy
• Potential milestone
payments from on-going
partnerships
• Continuing partnering
discussions
• Extend existing
collaborations/ enter into
new collaborations
34
Long term value creation
Some potential clinical and regulatory key events
2015
2016
2017
2018
ALX-0171 Infant Phase IIa (RSV)
Wholly-owned
ALX-0061 Phase IIb combination therapy (RA)
AbbVie have option to license worldwide
ALX-0061 Phase IIb monotherapy (RA)
AbbVie have option to license worldwide
ALX-0761 Phase Ib POC (psoriasis)
Licensed to Merck Serono (worldwide)
Caplacizumab MAA filing EU Phase III results (TTP)
Wholly-owned
ALX-0171 Infant Phase IIb (RSV)
Wholly-owned
ALX-0141 and ozoralizumab Phase I/II in China
Licensed to Eddingpharm (China)
ALX-0761 Phase IIa (psoriasis)
Licensed to Merck Serono (worldwide)
Caplacizumab conditional approval EU and BLA filing in US
Wholly-owned
ALX-0061 Phase II (SLE)
AbbVie have option to license worldwide
Results from various patient studies with partners
Clinical study results
Key regulatory events
CONTACT DETAILS
Questions
+32 9 262 00 00 Investor
Relations
investors@
ablynx.com www.ablynx.com
Addendum
37
Shareholders
• Ordinary shares listed on Euronext Brussels (ABLX)
• Sponsored level I ADRs on the US OTC market (ABYLY)
• 54.3M shares outstanding
• 2.7M outstanding warrants
• Free float is ~90%
Diversified shareholder base
Abingworth (UK); 9,03%
Boehringer Ingelheim (DE);
3,94%
Aviva Investors (UK); 5,00%
Perceptive Advisors (US);
3,82%
Polar Capital Funds Plc (UK);
3,05%
FMR LLC (US); 3,01%
Other institutional and retail
investors; 72,15%
Total shares outstanding by type
US; 33,87%
UK; 20,97%
Benelux; 32,59%
Scandinavia; 4,49%
France; 2,86%
Other; 5,23%
% of Institutional and Private Bank Owners by Geography (representing 65% of total S/O)
38
Financial summary
1 Cash, cash equivalents, restricted cash and short-term investments at the end of the period
Full year results 2014
Anticipated net cash burn for 2015 of approx. €70-80M
€M 2012 2013 2014
Revenue 26.7 35.9 49.3
Operating result (29.8) (17.7) (16.2)
Cash position1 62.8 200.4 206.2
39
Ablynx shares
Three-year performance
40
Nanobodies
Pushing the limits of antibody technology
scFv
Bi-specific,
tetra-valent
DVD-lg
Diabody lgG
1st generation
• 150 kDa
• bi-valent
• fixed half-life
• mono-specific
2nd generation
• 30-210 kDa
• mono- or bi-valent
• short or long half-life
• bi-specific
3rd generation
• 12-75 kDa
• valency of choice
• short or long half-life
• multi-specific
Nanobodies
41
Nanobodies
ND: not demonstrated
Compared to other platforms and mAbs
41
Features Nanobodies DARTS
(MacroGenics)
Darpins
(Molecular
Partners)
mAbs
Speed of discovery ++/+++ ++ ++ ++/+++
Formatting flexibility +++ ++ ++ -
Bi-specific formats ++/+++ ++ ++ ++
Manufacturability +++ ++ ++ ++
High concentration formulation ++/+++ ND ND +/-
Tailored in vivo half-life +++ ++ ++ -
Alternative routes of
administration +++ ND +/- -
Broad target
applicability incl. GPCRs and
ion channels
+++ ND ND +/-
Clinical validation Ph II Ph I Ph II Multiple
marketed
42
Nanobodies
* No. of molecules binding to more than one target or epitope in clinical development
Most versatile and clinically validated platform
Ablynx Affimed Macro-
genics Pieris
Molecular
partners F-Star Genmab
Technology Nano-
bodies TandAb DART Anticalins DARPINs mAb2-FcAb Duo-bodies
Clinical
programmes* 4 2 1 0 0 0 0
Amgen Abbvie Chugai GSK Genentech Roche Sanofi J&J BMS
Technology BiTE DvD-Ig Bispecific
mAb
Domain
Ab 2-in-1 CrossMab
Bispecific
mAb
Fyno
Mab Centyrins Adnectins
Clinical
programmes* 4 3 1 1 1 1 1 1 1 0
43
Bi-specific Nanobodies
Synergistically improve potency
• All HIV strains need the primary receptor CD4 and a chemokine co-receptor to enter and
infect host CD4+ T cells
– X4 type viruses use CXCR4; R5 type viruses use CCR5
• Synergistic improvement in HIV-1 blockade of CXCR4-CD4 bi-specific Nanobody over
monovalent Nanobodies
– up to 320-fold enhancement with bi-specific Nanobody over mono-specific
– only 2-fold enhancement with combination of monovalents in solution (1:1) over monospecific
– linking of the Nanobodies is essential for strong enhancement
Collaboration with Dr. Dominique Schols, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
CXCR4
CD4
anti-CXCR4/CD4
anti-CXCR4
anti-CD4
anti-CXCR4 + anti-CD4 +
Blockade of HIV infection in vitro*
* Infection of HIV1 X4 NL4.3 in
human MT-4 T cells
44
10 -11 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 10 -4 0.0
0.2
0.4
0.6
0.8
1.0
Nanobodies
• Tri-valent anti-RSV (ALX-0171)
– improve activity and strain coverage by multi-valency
– superior virus neutralisation as compared to palivizumab
– 5-fold more clinical isolates neutralised below LLOD with ALX-0171 compared with palivizumab
Multi-valent formatting to improve potency
Improved potency over mAb Increased strain coverage
A-strain B-strain Total
n 32 29 61
palivizumab 0 (0%) 11 (38%) 11 (18%)
ALX-0171 30 (94%) 23 (79%) 53 (87%)
p value <0.0001 <0.0001 <0.0001
OD
45
0-5
20
nm
Concentration (M)
palivizumab
Number of strains neutralised
below lower limit of detection
7,000-fold
45
Nanobody formatting
Biparatopic format yields the required potency and efficacy
Biparatopic is both potent and efficacious
Lower potency but efficacious Potent but not efficacious
46
Caplacizumab Phase II study
Time to confirmed platelet normalisation
Primary endpoint
N = 36 N = 39
Overall Hazard Rate Ratio for caplacizumab vs. placebo
(95% CI), N = 75 2.197 (1.278, 3.778)
Stratified log-rank test p-value 0.013
Caplacizumab Placebo
Median days to confirmed platelet response – subjects with
no prior plasma exchange (95% CI)
3.00 (2.74, 3.88)
N = 34
4.92 (3.21, 6.59)
N = 35
25th & 75th percentile 2.72 & 4.31 3.01 & 11.37
Median days to confirmed platelet response – subjects with
one prior plasma exchange (95% CI)
2.44 (1.92, 2.97)
N = 2
4.31 (2.91, 5.68)
N = 4
25th & 75th percentile 1.92 & 2.97 3.37 & 5.23
The group of patients treated with caplacizumab in conjunction with the standard
of care achieved confirmed platelet normalisation at more than twice the rate
of the group receiving the standard of care plus placebo
47
Caplacizumab Phase II study
* Intention-to-Treat (ITT) population: 75 subjects, all randomised to caplacizumab (36) or placebo (39)
Secondary endpoints
Caplacizumab
N* = 36
Placebo
N* = 39
Subjects with an exacerbation within 30 days after
stopping daily PEX 3 (8%) 11 (28%)
Subjects in complete remission within 30 days after
stopping daily PEX as measured by confirmed platelet
response and absence of exacerbations
29 (81%) 18 (46%)
Subjects with an exacerbation and/or relapse at 1 month
follow-up after study drug treatment was completed 13 (36.1%) 13 (33.3%)
Deaths 0 2
These top line secondary endpoints illustrate the potential protective
effect of caplacizumab treatment in the acute phase of TTP
48
Caplacizumab
Safety profile in TITAN Phase II trials
Proportion of subjects Caplacizumab
N = 35
Placebo
N = 37
Subjects with any TEAE 97% 100%
- with bleeding event 54% 38%
Subjects with any TE Serious AEs 57% 51%
- with serious bleeding event 6% 5%
Subjects discontinued due to TEAE 8% 0%
Increased bleeding tendency in caplacizumab arm • 80% of reported events were mild
• only 3 subjects required drug treatment (tranexamic acid, methylergonovine)
• no requirement for vWF/FVIII substitution
Number of events Caplacizumab
N = 35
Placebo
N= 37
Number of TEAEs 574 545
Number of TE Serious AEs 44 36
49
Caplacizumab
• TITAN investigators, other KOLs and payers overwhelmingly positive about
caplacizumab product profile and value proposition
– Orphan Drug addressing a high unmet medical need
– innovative MOA providing specific platelet protective effect, thereby having the potential to
reduce morbidity due to organ damage
– potential for shorter duration of acute and life-threatening episodes
– potential for less exacerbations and relapses
– potential cost savings (reduction in volume and days of plasma exchange; shorter time in
intensive care)
• Ablynx estimates peak sales for caplacizumab to be in the range of €300M-
€400M*
* US, EU5, Japan, other mkts / Jefferies estimates: $400 million peak sales (14 Oct 2014)
Commercial opportunity
“If the manufacturer can achieve these data at
launch, this is a winning product” – US payer
50
RSV therapeutics
* Based on 375 mg dosing schedule in adult challenge trial (see press release Jul 2014)
** Assuming abstract from 8th RSV conference Oct 2012 refers to ALS-8176 but not explicitly mentioned (Deval et al.)
Studies currently on-going in infants
ALS8176 (Alios/J&J) ALX-0171 (Ablynx)
Administration oral
suspension
pulmonary
nebulisation
Entity NCE
nucleoside analogue
biologic
Dosing 2/day
5 mg/kg*
1/day
MOA polymerase inhibitor fusion inhibitor
In vitro potency
serotype A
200 nM** IC50 ≈ 0.1 nM
Development status PhII infant study started July
2014 (SAD/MAD; N=168)
Results: Nov 2015
PhIIa infant study to start Q4
2014 (MD; N=35)
Results: Q3 2015
51
RSV pipeline
* Other Medimmune vaccine candidates for infants in NIAID sponsored studies
Therapeutics and vaccines currently in development
Product Company Class Target population Phase
RI-002 ADMA Biologics Anti-RSV antibody
prophylaxis
Immune-compromised
patients
Phase III ongoing
RSV vaccine Novavax RSV F-vaccine Infants (maternal
immunisation)
Phase II in pregnant women initiated
Q3 ‘14
GSK-3003891 GSK RSV vaccine Infants and children Phase I in adults
MEDI-7510* MedImmune/
AstraZeneca
RSV vaccine Older adults Phase I in older adults
MEDI-8897 MedImmune/
AstraZeneca
Anti-RSV antibody
prophylaxis
Infants and children Phase I in adults
RSV-001 Okairos/GSK RSV vaccine Infants and immune-
compromised adults
Phase I completed
ALS-8176 Alios/J&J Nucleoside
analogue
Infants Phase II in infants
GS-5806 Gilead RSV fusion inhibitor (Older) adults and bone
marrow transplant patients
(BMT)
First-in-infant study withdrawn
Phase IIb in (older) adults and BMT on-
going
ALX-0171 Ablynx Anti-RSV Nanobody Infants and children 3 Phase I’s in adults completed; Phase
IIa in infants ongoing
ALN-RSV01 Alnylam/Hyowa
Hakko Kirin
Nucleocapsid gene
siRNA
Immune-compromised
adults
Phase II in lung transplant patients but
no longer mentioned as part of pipeline
MDT-637 Microdose
/Teva
RSV fusion inhibitor Infants and children Healthy adult volunteer challenge study
ongoing
52
ALX-0171
Suitability of neonatal lamb model compared with human challenge model
• Lambs develop lower respiratory tract infection which is associated with general malaise and specific
lung pathology (comparable to infants)
• Treatment at peak of viral load on day 3 post infection (symptoms and lung pathology are already clearly
present)
• Lambs develop clinical symptoms such as wheezing (comparable to infants)
In vivo proof-of-concept achieved
0
1
2
3
4
5
6
7
Vehicle RSV Vehicle RSV ALX-0171
Lo
g10
FF
U/m
L B
AL
Mean viral titers in BALF
(day 6 post infection)
0
10
20
30
40
50
60
Vehicle RSV Vehicle RSV ALX-0171
Me
an
% I
nvo
lve
me
nt
Lung viral lesions
(day 6 post infection)
53
ALX-0171
* 0 = no clinical signs; 4 = animals down
Highly effective in RSV infected lambs
0
20
40
60
80
100
0 1 2 3 4 5 6
% o
f la
mb
s w
ith
sc
ore
≥ 1
“Malaise” Score
RSV vehicle
RSV ALX-0171
Vehicle
Daily inhalation of ALX-0171 markedly reduced symptoms
of illness in RSV infected neonatal lambs
RSV
infection
Treatment ALX-0171 or
formulation buffer
• Subjective scoring
(0 to 4*) of parameters that measure
general health
– “Malaise” score: weakness, depression,
lethargy, drooping of ears, and not eating
• Daily inhalation of ALX-0171 markedly
reduced symptoms of illness
54
ALX-0171
• September 2012 – Phase I first-in-human study
– 60 healthy volunteers
– single-ascending dose and multiple dose up to 210 mg inhaled twice daily for 5 days
– well tolerated, with no clinically relevant adverse events or effects on lung function
• May 2014 – Phase I safety study in adults with hyper-reactive airways
– 24 subjects
– single-ascending dose and multiple dose part up to 200 mg inhaled daily for five days
– some cases of mild bronchoconstriction which could be immediately reversed
• May 2014 – Phase I PK study
– 41 healthy volunteers
– single and multiple dose of 200 mg inhaled daily for 5 days and single dose of 0.3
mg/kg iv
– local half-life of ALX-0171 is approximately 20 hours, confirming potential for once-daily
dosing
Successful Phase I inhalation studies in adults
54
55
ALX-0171
• First-in-class potential addressing a disease with a high unmet medical need
– no adequate therapeutic treatment for RSV infections in infants
• Most infants are infected with RSV during their first year of life
• Nearly all children will have had an RSV infection by the age of 2
• Opportunity to treat RSV infection in infants
– hospitalised setting (~300,000 infants per year in the 7 major markets)
– out-patient setting (~2 million infants <1 year of age per year in 7 major markets)
Commercial opportunity
“Current prophylaxis with a mAb is expensive and
only partially protective. Any new treatment strategy
for RSV bronchiolitis is very welcome” – BE KOL
56
ALX-0061
Potentially best-in-class anti-IL-6R
Features Potential benefits
Small (26kD)
• Penetrates faster and more effectively into
tissues
Targets human serum albumin (HSA) • Prolongs half-life
• Improved trafficking to inflamed tissue
Monovalent binding • Avoids target cross-linking
Preferential binding of soluble vs.
membrane bound IL-6R
• Superior benefit/risk profile
Strong affinity to soluble IL-6R • Fast target engagement resulting in fast onset
of action
Low immunogenic potential • Improved safety profile
Tailored PK • Extended therapeutic window
• Convenient dosing and scheduling
anti-HSA anti-IL-6R
57
IL-6(R) and JAK inhibitors
25
32
46
32
27
44
55
71
32
60
37
48
34
44 46
45
37 38
43
37 35
0
10
20
30
40
50
60
70
80
% o
f p
ati
en
ts
Week 12 Week 24
1 All pooled/unmodified ALX-0061 treated patients (pooled) at week 12 and week 24; 2 Data extracted from LITHE (4 and 8 mg/kg), OPTION (4 and 8
mg/kg), TOWARD (8 mg/kg) trials; 3 Smolen JS, et al. Ann Rheum Dis 2014 (100 mg Q2W); 4 Phase III MOBILITY trial; 150 mg Q2W and 200 mg
Q2W; 5 Phase IIb trial (ACR 2013), Q4W; 25 mg, 100 mg, 200 mg; 6 Data extracted from Phase III Scan, Sync and Standard trials; 5 mg BID and 10
mg BID; 7 Data presented by Galapagos (100 mg BID) on 14th-15th April 2015
ACR50 scores from different clinical studies
Tocilizumab
(Roche)2
ALX-00611
Sarilumab
(Sanofi)4
Clazakizumab
(BMS)5
Sirukumab
(J&J)3
Tofacitinib
(Pfizer)6
Filgotinib
(Galapagos)7
58
50%
0%
4%
0%
20%
40%
60%
80%
100%
Pbo Pooled
ALX-0061, 12w Data
Remission Low disease activity
7%
36%
7%
14%
0%
20%
40%
60%
80%
100%
Pbo 100mg BID
DARWIN1, 12w Data
Remission Low disease activity
DAS28CRP Response of ALX-0061 vs. filgotinib
ALX-0061 as presented on October 4, 2012
DARWIN1 as presented by Galapagos on April 14/15, 2015
Pooled data vs. highest reported responses
59
ALX-0061
• Potential to treat moderate to severe RA
– first line biologic
– monotherapy or in combination with methotrexate (MTX)
– patients refractory or intolerant to anti-TNFα
• (Ro)Actemra® (the only marketed IL-6R blocker) generated sales of $840M in
2013 and sales are expected to grow to ~$1.5B in 20161 and ~$4.8B by 20202
• ALX-0061 as a novel option for the treatment of severe SLE
– high unmet medical need among moderate and severe SLE populations
– ~5 million people worldwide suffer from a form of lupus
– SLE market expected to grow to $4B in 20213
1 Decision Resources 2014 2 SG Cross Asset Research 2012 3 Decision Resources 2014
Commercial opportunity
“I would definitely consider it as a first line
biologic RA treatment.” – IT KOL
60
Global RA market
• In 2013, Humira (AbbVie) for the treatment of auto-immune disorders, was the world’s largest selling
drug with ~$11B in sales (approved in 7 indications)
• (Ro)Actemra (Roche/Genentech/Chugai) is currently the only IL-6R inhibitor on the market (used as
2nd and 1st line biologic)
• (Ro)Actemra generated sales of $840M in 2013 and sales are expected to grow to ~$1.5B in 20161 and
~$4.8B by 20202
Source: First Word Pharma 2012 1 Decision Resources 2014; 2 SG Cross Asset Research 2012
Opportunity for anti-IL6(R) drugs
60
Global RA market – market share and CAGR for the different drug classes*
2011 2016
Class
Sales
($m)
CAGR (2006–11)
(%)
Market share
(%)
Sales
($m)
CAGR (2011–16)
(%)
Market share
(%)
TNF inhibitor 13.721 17% 84% 16,076 4% 69%
B-cell depletion 1,221 0.5% 7.5% 1,285 1% 6%
T-cell modulator 910 59% 5.6% 2,010 17% 9%
IL-6 inhibitor 679 178% 4.2% 2,034 24% 9%
JAK inhibitor 0 0% 0% 1,566 0% 7%
Syk inhibitor 0 0% 0% 313 0% 1.3%
IL-17 inhibitor 0 0% 0% 90 0% 0.4%
61
Therapeutics targeting IL-6(R)
* Graft versus host disease; ** Neuromyelitis optica
Drugs currently in development
61
Drug Target Company Disease Dosing Stage
SAR153191
REGN88
IL-6R Sanofi/
Regeneron
RA, uveitis 150 or 200 mg
q2w
PhIII/Phii
Launch RA mid-2017
CNTO 136 IL-6 J&J/
GSK
RA 50 mg q4w, 100
mg q2w
PhIII
Launch end 2017
ALD518 IL-6 Alder RA,
NSCLC,
GVHD*
25-100-200 mg
q4w
PhII dose finding
Launch >2018 (following BMS
returning the asset)
CDP6038 IL-6 R-Pharm/
UCB
RA 60-120-240 mg
q2w
PhII
PF-04236921 IL-6 Pfizer SLE, CD,
RA
RA q4w
SLE, CD q8w
RA PhI
SLE, CD PhII
SA237 Actemra
follow-on
IL-6R Chugai RA, NMO Q4w or less
frequent
RA PhI
NMO/NMOSD PhIII
FE999301 IL-6 Ferring Various Phase II (Crohn’s)
Tocilizumab
biosimilar
IL-6R BioXpress Research
Tocilizumab
biosimilar
IL-6R Panpharma-
ceuticals
Research
62
Rheumatoid arthritis
Source: AbbVie; Decision Resources 2014
Current and emerging therapies
• TNFα inhibitors dominate the RA market; but for >30% of patients, alternative
treatment approaches are needed (patients may not respond or may not tolerate
the drug, or become refractory)
• Anti-IL-6R treatment is clinically validated with (Ro)Actemra®; ALX-0061 falls within
the anti-IL-6R drug class
• AbbVie is committed to various drugs with differents MOAs (transcript Q1 2015
conf call): “Behind HUMIRA we have a rich pipeline of mid- and late-stage immunology
assets in clinical development. We're also working to advance several other mid-stage
immunology programs, including ABT-122 (our anti-IL-17 TNF combination) and an anti-IL-6
antibody, among others. All of our R&D efforts are focused on advancing the standard of care
in each of our areas of immunology leadership.”
Total RA market 2013: $14bn
Expected to grow to $18bn by 2023
1%
6% 6%
9%
7%
71%
JAK inhibitors
IL-6R inhibitors
B-Cell therapies
Selective costimulationmodulators
Conventional DMARDs
TNFα inhibitors
Source: AbbVie; Decision Resources 2014
63
ALX-0761
• ALX-0761 blocks both IL-17A and IL-17F (involved in
inflammation); binds HAS for improved PK
• Targeting both IL-17A and IL-17F could be more effective
in blocking the inflammatory response
– IL-17F forms homodimer and heterodimers with IL-17A
– IL-17F exerts similar in vitro biological activity as IL-17A but is
secreted by different cell types
• Developed by Merck Serono
– completed Phase I SAD study in healthy volunteers
– ongoing Phase Ib study in patients with psoriasis (results
expected in 2015)
• Secukinumab (Novartis) most advanced anti-IL-17A in
development (registration phase) with estimated peak
sales of ~$500M*
* Analysts estimates 2014 1 Poster available on Ablynx website: R&D>pipeline
Bi-specific Nanobody in psoriasis
anti-HSA
anti-IL17A anti-IL17F
Proof-of-concept achieved in primate
collagen induced arthritis model1
Art
hri
tis s
co
re
Days
–4 6 16 26 36 46 56 0
20
40
60
80
Vehicle ALX-0761 (2.8mg/kg)
ALX-0761 (10mg/kg)
64
Unmet need in psoriasis
Rationale for targeting IL-17-Th17
64 Source: Nature Biotechnology, Jan 2015; Hilary Bartlett & Ryan Million, Nature Reviews, Drug Discovery, Jan 2015
• IL-17A and TNFα are pro-inflammatory cytokines, produced by lineages of TH1 and TH17 cells, which are found in
blood and skin lesions of people with psoriasis
• ~50% of patients with moderate to severe psoriasis receive only topical or no treatment at all and >50% of
patients dissatisfied with current treatments
• Novartis’ Cosentyx (secukinumab) will be the first anti-IL-17A therapeutic on the market (2015 expected)
• Research suggests that IL-17A(F) blockers maybe more efficacious than anti-TNFα drugs for the treatment of
psoriasis
65
Therapeutics targeting IL-17A/F
Drugs in development
65
Drug Target Company Disease Stage
secukinumab IL-17A Novartis Psoriasis
Psoriatic arthritis; ankylosing spondylitis;
RA in patients IR to TNF
Filed
PhII and PhIII
ixekizumab Il-17A Eli Lilly Psoriasis
Psoriatic arthritis
PhIII completed
PhIII
brodalumab IL-17RA Amgen/Astra
Zeneca
Psoriasis
Psoriatic arthritis
Asthma
PhIII
PhIII
PhII
RG4934 IL-17A Roche Psoriatic arthritis PhI but no update since
2010
RG7624 IL-17A/F Roche Autoimmune
(no specific indication)
PhII to start early 2015
UCB-4940 IL17A/F UCB Psoriasis PhIb MAD in patients
CNTO 6785 IL-17A Janssen RA PhII
ABT-122 IL-17A/
TNFα
AbbVie RA in patients with an inadequate response
to methotrexate
PhII
COVA-322 IL-17A/
TNFα
Janssen/
Covagen AG
Psoriasis PhI/II
Sales potential of $500M - $1Bn for anti-IL-17 drugs in psoriasis1
1Trinity Partners, Nature Reviews, Drug Discovery, Jan 2015
66
Clinical stage products licensed in China
• Anti-TNFα – ozoralizumab – inflammation
– Phase II proof-of-concept achieved in patients with RA (Pfizer)
– Ablynx regained worldwide rights to anti-TNFα Nanobodies from Pfizer
– exclusively licensed to Eddingpharm in Greater China in Aug 2014
• €2M upfront; development and commercial milestones; up to 20% royalties
– pre-clinical study in China on-going
– Ablynx will have access to the clinical data generated by Eddingpharm
• Anti-RANKL – ALX-0141 – bone disorders
– Phase I study successfully completed (Ablynx)
– exclusively licensed to Eddingpharm in Greater China in Oct 2013
• €2M upfront; commercial milestones; up to 20% royalties
– pre-clinical study in China currently on-going
– Ablynx will have access to the clinical data generated by Eddingpharm
1 Espicom
Chinese Pharma market to grow to $163B by 20171
anti-HSA
anti-TNF anti-TNF
anti-HSA
anti-RANKL anti-RANKL