Nanobodies® – creating better
medicines
Corporate Presentation
November 2014
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.
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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 (POC)
• >10 new clinical programmes anticipated over the next 3 years
Partners
• AbbVie, Boehringer Ingelheim, Eddingpharm, Merck & Co,
Merck Serono and Novartis
Financials
• >€200M in cash expected end 2014
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Three-pronged business strategy
Fully-funded programmes with
milestones and royalties
•
•
•
•
Co-discovery/co-development deals
• 3 co-co deals
• 3 programmes
• 50:50 ownership and option to convert into
licensing deals
• >€50M in cash received
approx. 20 programmes
5 discovery and 5 licensing deals
>€285M in cash received
Approximately €3bn in future milestones
plus royalties
Balancing
risk and
reward
Wholly-owned product pipeline
• approximately 9 programmes
• aim to retain the optionality to partner if and when appropriate
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Fully partnered
CoCo
Fully owned
Pipeline of proprietary and partnered programmes
Therapeutic area
Product name
Target
Haematology
caplacizumab
vWF
Inflammation/
Immunology/Infection
Various
Oncology
Various
Respiratory
ALX-0171
Discovery Pre-clinical
Phase I
Inflammation/
Immunology
NA
NA
NA
Oncology/Neurology
Immunology
Various
Immunology/
Inflammation
ALX-0761
ALX-0061
ozoralizumab
IL-17F/IL-17A
IL-6R
TNFα
Greater China
Bone disorders
ALX-0141
RANKL
Greater China
Neurology
NA
ALX-0751
NA
Respiratory
NA
Various
NA
NA
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Filing
Various
NA
Immuno-oncology
Phase III
RSV
Ocular
Oncology
Phase II
Various
CXCR2
Validated targets (clinic)
1st in class
5
Unique technology
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
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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
Ablynx’ platform – rapid generation of high quality biologics
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
~12-18 months
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* glycine-serine linkers from C-terminus to N-terminus
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Ablynx’s unique biologics 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
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PEG
Nb drug conjugates
Tissue-specific
targeting
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Products in the clinic
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 Nb delivered to infection site
Highly potent trivalent construct
Stage
Start Phase III
mid-2015:
results end 2017
Start POC infant
study Q4 2014:
results Q3 2015
Partnered
Programme (target)
Indication
ALX-0061 (IL-6R)
RA, SLE
ALX-0761 (IL-17A/F)
Psoriasis
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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 2016
Potent neutralisation of both IL-17A and
IL-17F
POC achieved in primate CIA* model
Psoriasis Phase
Ib on-going:
results 2016
* 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
Nanobody
with
Nanobodies® Inspired by nature
Acquired TTP – significant unmet medical need
Severe fatigue,
headache, coma,
abdominal pain,
weakness, nausea,
bizarre behaviour,
vertigo, seizures
Sudden onset
Healthy person
Daily PEX in hospital
until recovery of
platelet count
Emergency
Potentially life threatening rare disorder of the blood coagulation system
•
•
incidence of 11.3 per million2
~10,000 acute events annually in US and Europe
Extensive microscopic thrombi formed in small blood vessels throughout the body
High unmet medical need
•
mortality remains high (10-20%)1 and ~ 36% of patients have relapses2
•
major morbidities after first TTP episode such as neurocognitive impairment
•
no approved medicinal product for treatment available
•
standard of care is plasma exchange (PEX) plus immune suppressants
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1.Allford
et al, 2003, Kremer Hovinga, 2010; Benhamou 2012;
2Scully
et al, Br J Haematology 2012
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Caplacizumab – prevents formation of microthrombi in 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
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Randomisation
Caplacizumab – Phase II TITAN design and schedule
PEX
30 days
30 days
Placebo N=39
1 year follow-up
1:1
Target – 110 subjects
Actual – 75 subjects
PEX
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
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Primary endpoint – time to confirmed platelet normalisation
Median days to confirmed platelet response – subjects with
no prior plasma exchange (95% CI)
25th & 75th percentile
Median days to confirmed platelet response – subjects with
one prior plasma exchange (95% CI)
25th & 75th percentile
Overall Hazard Rate Ratio for caplacizumab vs. placebo
(95% CI), N = 75
Stratified log-rank test
p-value
caplacizumab
Placebo
3.00 (2.74, 3.88)
4.92 (3.21, 6.59)
N = 34
N = 35
2.72 & 4.31
3.01 & 11.37
2.44 (1.92, 2.97)
4.31 (2.91, 5.68)
N=2
N=4
1.92 & 2.97
3.37 & 5.23
N = 36
N = 39
2.197 (1.278, 3.778)
0.013
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
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Secondary endpoints – exacerbations and remission
Caplacizumab
Placebo
N* = 36
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%)
13 (36.1%)
13 (33.3%)
0
2
Subjects with an exacerbation and/or relapse
at 1 month follow-up after study drug treatment was completed
Deaths
These top line secondary endpoints illustrate the potential protective effect of
caplacizumab treatment in the acute phase of TTP
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*Intention-to-Treat (ITT) population: 75 subjects, all randomised to caplacizumab (36) or placebo (39)
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TITAN trial summary – strong clinical proof-of-concept
Primary endpoint
Secondary endpoint
Safety
•
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
In 2015, caplacizumab will be the first Nanobody to enter Phase
III clinical development
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Caplacizumab – commercial opportunity
“If the manufacturer can achieve these data at
launch, this is a winning product” - US payer
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
€300-400 million*
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* US, EU5, Japan, other mkts / Jefferies estimates: $400 million peak sales (14 Oct 2014)
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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 to start in Q4 2014
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
• ~3.5% mortality rate in hospitalised high-risk infants (~400 deaths/year in the US)
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
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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 – proof-of-concept achieved in RSV lamb model
Mean viral titers in BALF
(day 6 post infection)
7
Mean % Involvement
Log10 FFU/mL BAL
6
5
4
3
2
1
Lung viral lesions
(day 6 post infection)
60
50
40
30
20
10
0
0
Vehicle
RSV Vehicle
RSV ALX-0171
Vehicle
RSV Vehicle
RSV 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)
Daily inhalation of ALX-0171 markedly reduced viral titres and
lung lesions in RSV infected neonatal lambs
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ALX-0171 – highly effective in RSV infected lambs
“Malaise”
% la m b s w it h s c o r e  1
% of lambs with score ≥ 1
G e n e r a l i ll n e s s s c o r e
-1
100
vehicle
M o c kRSV
V e h ic
le
M o c kRSV
A L X ALX-0171
-0 1 7 1
80
R S V V e h ic le
Vehicle
R S V A L X -0 1 7 1
60
40
20
0
1
2
3
4
5
6
D a y s p o s t in f e c tio n
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
Daily inhalation of ALX-0171 markedly reduced symptoms
of illness in RSV infected neonatal lambs
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*0 = no clinical signs
4 = animals down
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ALX-0171 – successful Phase I inhalation studies in adults
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
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ALX-0171 – first-in-infant inhalation study
Infants aged 5 to <24 months who are hospitalised for RSV infection
24 EU centres and additional centres 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:
Start Q4 2014
Results expected H2 2015
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* 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 – commercial opportunity
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)
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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
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 of adverse events upon extension of treatment
• No anti-drugs antibodies were reported
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ALX-0061 – global licensing deal with AbbVie
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 – key data points 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 II in RA
top line results
potentially continues development in RA
Phase II in SLE
top line results
potentially continues
development in SLE
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ALX-0061 – commercial opportunity
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 ~$1.5bn in 20161 and ~$4.8bn by 20202
ALX-0061 as a novel option for the treatment of severe SLE
•
•
•
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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 $4bn in 20213
1
Decision Resources 2014
2
SG Cross Asset Research 2012
3
Decision Resources 2014
31
Additional clinical assets
•
ALX-0761 – anti-IL-17A/F
Merck Serono
licensed
to
•
ALX-0141 – anti-RANKL licensed
Eddingpharma (rights in Greater China)
to
•
Ozoralizumab – anti-TNFα licensed to
Eddingpharm (rights in Greater China)
Nanobodies® Inspired by nature
ALX-0761 – bi-specific Nanobody in psoriasis
ALX-0761 blocks both IL-17A and IL-17F (involved
in inflammation); binds human serum albumin for
improved PK
anti-IL17F
Targeting both IL-17A and IL-17F could be more
effective in blocking the inflammatory response
anti-IL17A
anti-HSA
• IL-17F forms homodimer and heterodimers with IL-17A
Proof-of-concept achieved in primate
collagen induced arthritis model1
• IL-17F exerts similar in vitro biological activity as IL-17A but
is secreted by different cell types
• completed Phase I SAD study in healthy volunteers
• ongoing Phase Ib study in patients with psoriasis (results
expected in 2016)
Arthritis score
Development by Merck Serono
80
60
40
20
0
-4
Secukinumab (Novartis) most advanced anti-IL-17A
in development (registration phase) with estimated
peak sales of ~$500M*
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*Analysts estimates 2014
1Poster
6
16
26
36
46
56
Days
available on Ablynx website: R&D>pipeline
33
Clinical stage products licensed in China
Total pharma market in China expected to grow to $163bn by 20171
Anti-TNFα – ozoralizumab – inflammation
• Phase II proof-of-concept achieved in patients with RA (Pfizer)
anti-TNF
anti-TNF
• Ablynx regained worldwide rights to anti-TNFα Nanobodies from Pfizer
anti-HSA
• 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
anti-RANKL
anti-RANKL
anti-HSA
• pre-clinical study in China currently on-going
• Ablynx will have access to the clinical data generated by Eddingpharm
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1
Espicom
34
Partnerships
Nanobodies® Inspired by nature
Broad platform exploitation and cash generation
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
4 deals: 10 programmes (1 Phase I) on-going in inflammation, immunology,
oncology, immune-oncology, neurology and osteoarthritis
2 discovery deals: ion channel deal in neurology; immune-onco deal (focus on
multi-specifics) 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 (challenging target: CXCR2)
>€335M in non-dilutive cash received from collaborators to date
~€3Bn in potential future milestones plus royalties
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Outlook
Nanobodies® Inspired by nature
A successful 2014 and a strong 2015 ahead
2014 achievements
Potential value enhancing events in 2015
• 5 clinical trial read outs
including clinical proof-of-concept
(POC) for caplacizumab in TTP data being presented at ASH
• Start of Phase IIb with ALX-0061 (IL-6R) in RA
• 4 clinical trials initiated
• Start of Phase IIa with ALX-0061 (IL-6R) in SLE
• Further validation of the platform
through immune-onco deal with
Merck & Co focusing on multispecifics
• Start of multiple Phase I studies for partnered
programmes
• Expansion into Asia through 2nd
licensing deal with Eddingpharm
for the development and
commercialisation of
ozoralizumab in Greater China
• Results from Phase IIa with ALX-0171 (RSV) in
infants, potentially the 4th clinical POC for Ablynx
• Start of Phase III with caplacizumab (vWF) in
TTP
• Results from various technology feasibility
studies across multiple applications
• Continued discussions on partnering various
early stage and later stage assets
• Milestone payments from on-going partnerships
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Value creation – clinical data expected from patient studies
2018
ALX-0061 Phase IIa
(SLE)
AbbVie have option to
caplacizumab Phase III license worldwide
(TTP)
Wholly-owned
Results from a number of
patient studies with
ALX-0171 Paediatric
partners
Phase IIb (RSV)
Wholly-owned
2017
2016
2015
ALX-0171 Infant
Phase IIa (RSV)
Wholly-owned
2014
caplacizumab
Phase II (TTP)
Wholly-owned
www.ablynx.com
ALX-0061 Phase IIb
(RA)
AbbVie have option to
license worldwide
ALX-0761 Phase Ib
(severe psoriasis)
Licensed to Merck
Serono (worldwide)
ALX-0141 and
ozoralizumab Phase I/II
in China
Licensed to
Eddingpharm (China)

39
Financials/Shareholders
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
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41
Shareholder structure
Investors
Abingworth (UK);
9,08%
Geography
Boehringer
Ingelheim (DE);
3,97%
Biotech Value
Fund (US); 4,48%
Other
27%
US
24%
Aviva (UK); 3,19%
Perceptive
Advisors (US);
3,85%
Other institutional
and retail
investors; 72,09%
France
3%
Fidelity
Management
Research LLC
(US); 3,35%
UK
21%
Benelux
25%
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%
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42
Nanobodies® – creating better
medicines
www.ablynx.com
investors@ablynx.com
Nanobodies® Inspired by nature
Back-up slides
Nanobodies® Inspired by nature
Nanobodies – pushing the limits of antibody technology
scFv
lgG
1st generation
•
•
•
•
150 kDa
bi-valent
fixed half-life
mono-specific
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Diabody
Bi-specific, tetra-valent
DVD-lg
2nd generation
•
•
•
•
30-210 kDa
mono- or bi-valent
short or long half-life
bi-specific
Nanobodies
3rd generation
•
•
•
•
12-75 kDa
valency of choice
short or long half-life
multi-specific
45
Nanobodies – compared to other platforms and mAbs
Darpins
(Molecular
Partners)
mAbs
Nanobodies
arGEN-X
DARTS
(MacroGenics)
Speed of discovery
++/+++
++/+++
++
++
++/+++
Formatting flexibility
+++
ND
++
++
-
++/+++
ND
++
++
++
+++
++/+++
++
++
++
++/+++
ND
ND
ND
+/-
Tailored in vivo half-life
+++
-
++
++
-
Alternative routes of
administration
+++
ND
ND
+/-
-
Broad target applicability incl.
GPCRs and ion channels
+++
++
ND
ND
+/-
Clinical validation
Ph II
Ph I
Ph I
Ph II
Multiple
marketed
Features
Bi-specific formats
Manufacturability
High concentration formulation
www.ablynx.com
ND: not demonstrated
46
Nanobodies – most versatile and clinically validated
Technology
Ablynx
Affimed
Macrogenics
Pieris
Molecular
partners
F-Star
Genmab
Nanobodies
TandAb
DART
Anticalins
DARPINs
mAb2FcAb
Duobodies
4
2
1
0
0
0
0
Clinical
programmes*
Amgen
Abbvie
Chugai
GSK
Genentech
Roche
Sanofi
BiTE
DvD-Ig
Bispecific
mAb
Domain
Ab
2-in-1
CrossMab
Bispecific
mAb
FynoMab
Centyrins
Adnectins
1
1
1
1
1
1
0
Technology
J&J
BMS
PharmaBiotech
Clinical
programmes*
4
3
1
*No. of molecules binding to more than one target or epitope in clinical development
www.ablynx.com
47
ALX-0061 – potentially best-in-class anti-IL-6R
Features
Potential benefits
Small (26kD)
• penetrates faster and more effectively into
tissues
anti-IL-6R
anti-HSA
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
www.ablynx.com
48
IL-6(R) and JAK inhibitors – ACR50 scores from # studies
80
71
Week 12
70
Week 24
60
% of patients
60
50
50
46
44
44
40
40
38
35
32 32
30
37 37
34
32
34
35
27
25
20
10
0
ALX-00611
61
1.
2.
3.
4.
5.
6.
7.
Tocilizumab
Tcz
(Roche)2
Sirukumab
Siru
(J&J)3
Sarilumab
Sari
(Sanofi)4
Clazakizumab
claza (12
(BMS)5
weeks)
Tofacitinib
tofa (24
(Pfizer)5
weeks)
All unmodified ALX-0061 treated patients (pooled) at week 12 and week 24
Data extracted from LITHE (4 and 8 mg/kg), OPTION (4 and 8 mg/kg), TOWARD (8 mg/kg) trials
Smolen JS, et al. Ann Rheum Dis 2014 (100 mg Q2W)
Phase IIb MOBILITY trial; 150 mg Q2W and 200 mg Q2W
Phase II trial, Q8W; 80 mg, 160 mg, 320 mg
Data extracted from Phase III Scan, Sync and Standard trials; 5 mg BID and 10 mg BID
Phase II trial; 100 mg BID and 200 mg QD at week 4
www.ablynx.com
49
Global RA market – opportunity for anti-IL6(R) drugs
Global RA market – market share and CAGR for the different drug classes*
In 2013, Humira (AbbVie) for the treatment of auto-immune disorders, was the world
largest selling drug with ~$11bn 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
~$1.5bn in 20161 and ~$4.8bn by 20202
www.ablynx.com
Source: First Word Pharma 2012
1
Decision Resources 2014
2
SG Cross Asset Research 2012
50
Anti-IL-6(R) drugs in development
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
RPharm/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
Tocilizumab
biosimilar
IL-6R
BioXpress
Research
Tocilizumab
biosimilar
IL-6R
Panpharmaceuticals
Research
www.ablynx.com
* Graft versus host disease
Phase II (Crohn’s)
** Neuromyelitis optica
51
Multi-valent formatting to improve potency
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
1 .0
0 .6
0 .4
0 .2
OD450-520 nm
0 .8
1 .0
0 .8
B-strain
Total
32
29
61
0 (0%)
11 (38%)
11 (18%)
ALX-0171
30 (94%)
23 (79%)
53 (87%)
p value
<0.0001
<0.0001
<0.0001
M o n o v a le nMt o n o v a len
nt
palivizumab
S y n a g is
0 .6
0 .4
A-strain
T riv a le n t T riv a le n t
B iv a le n t B iv a le n t
7,000-fold
S y n a g is
palivizumab
0 .2
0 .0
-7
-6
-5
-4
1 0 - 1 1 1 0 -0110.00 1- 101 - 91 0 1- 100 - 81 01- 0
9
8
7
1 01- 0
1 01- 0
1 01- 60 1 0 - 5
1 0 -4
Concentration (M)
Improved potency over mAb
www.ablynx.com
Number of strains neutralised below lower limit of
detection
Increased strain coverage
52
Therapeutics in the clinic to treat infant RSV infection
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
* 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.)
www.ablynx.com
53
Key products in the RSV pipeline
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
GSK3003891
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 immunecompromised 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 ongoing
ALX-0171
Ablynx
Anti-RSV
Nanobody
Infants and children
3 Phase I’s in adults completed; Phase
IIa to start in Q4 2014
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
www.ablynx.com
*other Medimmune vaccine candidates for infants in NIAID sponsored studies
54
Anti-IL-17A/F drugs in development
Drug
Target
Company
Disease
Stage
secukinumab
IL-17A
Novartis
Psoriasis
Filed
Psoriatic arthritis; ankylosing spondylitis;
RA in patients IR to TNF
PhII and PhIII
ixekizumab
Il-17A
Eli Lilly
Psoriasis
Psoriatic arthritis
PhIII
PhIII
brodalumab
IL-17RA
Amgen
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
ABT-122
IL-17A/TNFa
AbbVie
RA in patients with an inadequate
response to methotrexate
PhII
COVA-322
IL-17A/TNFa
Covagen AG
Psoriasis
PhI/II
www.ablynx.com
55