investor presentation - ablynx · < 2.6; low disease activity: 2.6 ≤ das28 crp ≤ 3.2 up to...
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Nanobodies®
creating better medicines
September 2016
Investor 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
Powerful platform generating potentially innovative medicines
• Platform technology and late-stage clinical development company
• >350 staff in Ghent, Belgium
• >45 wholly-owned and partnered programmes
• 8 Nanobodies in clinical development
• First potential launch in 2018
• AbbVie, Boehringer Ingelheim, Eddingpharm, Genzyme, Merck &Co., Inc.,
Merck KGaA, Novartis, Novo Nordisk and Taisho Pharmaceuticals
• >€380M cash received; >€7Bn in potential milestones; and royalties
• €289M in cash at 30th June 2016
• €100M of issued Convertible Bonds maturing in 2020
CORPORATE
PARTNERS
PRODUCTS
FINANCIALS
• Pioneer in next generation antibody-derived drugs – Nanobodies®
• >500 patent applications and granted patents; critical know-how
• Validation through multiple partnerships with top tier pharma companies
TECHNOLOGY
4
Ablynx
Diversified shareholder base – August 2016
• Ordinary shares listed on Euronext Brussels (ABLX)
• Sponsored Level I ADRs on the US OTC market (ABYLY)
• 60.9M shares outstanding
• 2.6M outstanding warrants (in number of shares)
Breakdown of share capital
5% 5%
5%
5%
4%
4%
3%
Van Herk Investments B.V. (NL)
Bank of America (US)
Perceptive Advisors (US)
Fidelity Management Research (US)
Taube Hodson Stonex Partners (UK)
Boehringer Ingelheim (DE)
Oppenheimer Funds (US)
Other shareholders
US 41%
UK 21%
Belgium 24%
The Netherlands
9%
Scandinavia 1%
France 2% Other
1%
% of Institutional Shareholders by Geography (representing 78% of total S/O)
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 and robust
• easily linked together
• sequence homology comparable
to humanised/human mAbs
• nano- to picomolar affinities
• able to bind and block challenging
targets
• multiple administration routes
• manufacturing in microbial cells
CH2
CH3
CH1
CL
VL
VH 12-15kDa
CH2
CH3
VHH
VHH
7
Ablynx’s drug discovery engine
Rapid generation of novel biologics
~12-18 months
and/or
Use proprietary synthetic
Nanobody phage libraries
Wide range of highly
diverse Nanobodies with
0.1-10nM affinities
Formatted
Nanobodies
Cloned into microbial
systems and produced
through fermentation
Immunise llamas
with antigen
8
Ablynx’s Nanobodies
Platform advantages
Albumin-
binding
Nanobody Fc
Hours/days/weeks
Customised
half-life extension
Nanobodies
against ion
channels and
GPCRs
Able to bind and block
challenging targets
Manufacturing
High-yield,
high-
concentration,
low-viscosity,
microbial
production
Inhalation
Oral-to-topical
Ocular
Multiple delivery routes Mix and match
Multi-specific/multivalent Nanobodies
that address multiple targets in a
single drug molecule – flexible GS
linker lengths
Broad product pipeline
10
Hybrid business model fuels the pipeline
>45 programmes, 8 Nanobodies in clinical development
Indication Product Target
aTTP
RSV
vobarilizumab
Pre-clinical Phase I Phase II Phase III
IL-6R
caplacizumab vWF
ALX-0171
ALX-0141 RANKL
ALX-0761
RSV
Bone disorders Greater China
IL-17A/IL-17F
ozoralizumab TNFα
Greater China
Filing
Japan
RA
RA
SLE
RA
Psoriasis
Immuno-Oncology
~ 15 wholly-
owned and
partnered
programmes
Up to 17
programmes
IL-6R
IL-6R
TNFα RA
Various
Various
+
CXCR2 Inflammation NA
Oncology VEGF/Ang2 BI 836880
Chronic kidney disease CX3CR1 BI 655088
Key value drivers
Vobarilizumab (anti-IL-6R)
Potential to be best-in-class in RA
13
Vobarilizumab – anti-IL-6R Nanobody
Potential to be the best-in-class in RA
• Global exclusive option licensing deal with
AbbVie
• Compelling results from 2 Phase IIb RA
studies in a total of ~600 patients
• RA open-label extension study ongoing (94%
rollover rate)
• Phase II SLE study ongoing
• Opportunity in multi-billion dollar markets
RA: rheumatoid arthritis
SLE: systemic lupus erythematosus
14
Vobarilizumab Phase IIb study results in RA High ACR responses consistent across the two studies
MTX: methotrexate
Week 12
Phase IIb monotherapy
(vobarilizumab N=187; tocilizumab: N=64)
% r
esp
on
ders
* nominal p<0.05 vs. placebo; ** nominal p<0.01 vs placebo
Phase IIb combination therapy (+ MTX)
Week 12 Week 24
(vobarilizumab N=276; placebo: N=69)
% r
esp
on
ders
High response rates with vobarilizumab are consistent across studies
Continued improvement in ACR50 and ACR70 scores from 12 to 24 weeks
Opportunity for monthly dosing confirmed
15
Vobarilizumab Phase IIb study results in RA Strong impact on disease activity confirms best-in-class potential
Remission: DAS28CRP < 2.6; low disease activity: 2.6 ≤ DAS28CRP ≤ 3.2
Up to 49% of patients in clinical remission at week 24
Week 12
Phase IIb monotherapy
* nominal p<0.05 vs. placebo; ** nominal p<0.01 vs. placebo; *** nominal p<0.001 vs. placebo
*** *** *
*** **
***
* ** ***
** *** ***
Phase IIb combination therapy (+ MTX)
Week 12 Week 24
% s
ub
jects
% s
ub
jects
42
57 60
44
16
1 PhIIb: (sc) 150mg Q4W and 225mg Q2W + MTX; 2 Data from OPTION PhIII: (iv) 8mg/kg Q4W + MTX and BREVACTA PhIII (sc) 162mg Q2W + MTX; 3 MOBILITY PhIII: (sc) 150 mg Q2W and
200mg Q2W + MTX; 4 PhIII: (sc) 50mg Q4W and 100mg Q2W + csDMARDs; 5 Weinblatt et al, Arthritis & Rheumatology, Sept 2015; 6 DARWIN 1: (oral) 100mg QD, 200mg QD + MTX; 7
BALANCE-2 PhIIb: oral 6mg BID, 12mg BID + MTX
Potential to be the best-in-class in RA
0
10
20
30
40
50
60
% o
f p
ati
en
ts
Effect on clinically meaningful endpoints
tocilizumab
(Roche)2
vobarilizumab1
sarilumab
(SASY/REGN)3
sirukumab
(J&J/GSK)4
filgotinib
(GLPG/Gilead)6
Note: 24-week data reported in listed publications, not resulting from head-to-head studies
adalimumab
(AbbVie)5
sc
Q4W
sc
Q2W
sc
Q2W sc
Q2W
sc
Q2W
sc
Q4W sc
Q2W sc
Q2W
oral
daily
oral
daily
iv
Q4W
tocilizumab
(Roche)2
vobarilizumab1
sarilumab
(SASY/REGN)3
adalimumab
(AbbVie)5
filgotinib
(GLPG/Gilead)6
sc
Q4W
sc
Q2W
sc
Q2W
sc
Q2W
sc
Q2W
sc
Q2W
oral
daily oral
daily
iv
Q4W
DAS28CRP remission ACR70 response
17
Safety results from RA combination studies
Vobarilizumab has favourable safety profile
Note: data reported in listed publications, not resulting from head-to-head studies
18
Vobarilizumab
Potential to be the best-in-class in RA
18
µ$
µµ
µ
µ
µµ
• Very strong impact on disease activity as measured by DAS28CRP
• Favourable safety and tolerability profile across all doses tested
• Opportunity for convenient monthly dosing
Potential to become a positively differentiated treatment option for patients suffering from RA
19
Vobarilizumab
Major milestones achieved
24-week Phase IIb
RA combination
therapy study
Phase II SLE study
2015 2016 2017 2018
RA open-label
extension study
12-week Phase IIb
RA monotherapy
study
Topline results
Top line results
opt-in decision for RA
opt-in decision for SLE
Topline results
Top line results
Caplacizumab (anti-vWF)
For the treatment of acquired thrombotic
thrombocytopenic purpura
21
Caplacizumab – anti-vWF Nanobody
First-in-class potential for the treatment of aTTP
• Orphan Drug Status and patent protection to
2035
• Phase III ongoing with results expected by
end of 2017
• Planned filing for conditional approval in
Europe (Q1 2017) and BLA submission in
USA (2018)
• Ablynx to lead commercialisation in Europe
and the US
• Anticipated first launch in 2018 with peak
sales potential of ~€300M1
1 US, EU, Japan and other major markets
aTTP: acquired thrombotic thrombocytopenic purpura
22
Caplacizumab unique mode of action
Rapidly stops formation of micro-clots
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 an aTTP patient
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
Caplacizumab blocks the platelet – ULvWF interaction
Ultra-Large (UL)
vWF multimers UL-vWF multimers
cause platelet string
formation
ADAMTS13 activity is
impaired
endothelium
Caplacizumab binds to A1
domain of vWF and thereby
inhibits platelet string formation
23
Acquired TTP (aTTP)
• aTTP is caused by impaired activity of ADAMTS13 (<10% of that in normal plasma1)
– extensive microclot formation in small blood vessels throughout the body
– leads to tissue ischemia and damage to vital organs
• Ultra-rare condition with incidence estimated at up to 11 per million2
• High unmet medical need with no approved therapeutic drug currently available
– high mortality in acute phase (10-20%)3 and ~ 36% of patients have a recurrence2
– significant thromboembolic complications, including brain (e.g. stroke), heart and kidney damage
– impacts life expectancy and quality of life
1 Scully et al, BJH 2012; 2 George et al, EJH 2008; 3 Allford et al, BJH 2003, Kremer Hovinga, Blood 2010; Benhamou, Haematologica 2012
Life-threatening ultra-rare acute blood clotting disorder
aTTP patient Emergency Room ICU/haematology unit
episode diagnosis treatment
Sudden onset in otherwise healthy
person (nausea, fever, coma,..)
Initial diagnosis based on
thrombocytopenia & haemolysis
Plasma exchange until normalisation of
platelet count + immune suppressants
24
TITAN Phase II study of caplacizumab
Clinical proof-of-concept achieved in aTTP patients
• Primary endpoint met with high statistical significance (p=0.005) - nearly 40% reduction in time to platelet normalisation
= faster reversion of thrombocytopenia and reduced use of plasma exchange
• 71% fewer patients with recurrences during treatment - potential prevention of organ damage
• Post-hoc analysis - caplacizumab treated patients experienced fewer major thromboembolic
events as compared to placebo (11.4% vs 43.2%)
- fewer caplacizumab treated patients refractory to plasma exchange
treatment compared to placebo (5.7% vs 21.6%)
Three aTTP experts
describe the impact of
the TITAN trial for the
aTTP community
25
HERCULES Phase III study
Started in Q3 2015 with top line results expected in Q4 2017
* iv bolus (10mg) followed by daily sc (10mg) ** incl. corticosteroids at start of daily PEX until underlying disease activity resolved
Primary endpoint: time to confirmed normalisation of platelet count
Secondary endpoints: recurrences; mortality rate; severe morbidity; organ damage biomarkers (troponin,
creatinine, LDH); PEX parameters; days in ICU/hospital; AEs; PD; PK; immunogenicity
RA
ND
OM
ISA
TIO
N
1:1
Caplacizumab* N=46
30 days
30 days
FOLLOW-UP PERIOD (4 weeks)
Potential extension of blinded study drug if recurrence, restart daily PEX and open label caplacizumab
Daily PEX
Recurrence restart daily PEX and open label caplacizumab
Placebo* N=46
TREATMENT PERIOD**
Daily PEX
132 patients
26
Caplacizumab positioning
Potential new component in standard of care for aTTP
26
Tre
ate
men
t du
ratio
n
Daily PEX Immuno-
suppression
Removes ULvWF
& auto-antibodies
Replenishes
ADAMTS13
Reduces activity
of immune
system to
resolve the
underlying
cause of aTTP
Caplacizumab
Rapidly inhibits platelet
aggregation, micro-clot formation
and small blood vessel occlusion
Reduces PEX duration
Protects during the acute phase
Prevents organ damage
Reduces recurrences
Reduces thromboembolic events
Future standard of care could be based on three pillars
Caplacizumab may become the first approved product for the
treatment of aTTP
27
Caplacizumab for the treatment of aTTP
Potentially Ablynx’s first marketed product
27
• Concentrated patient presentation
• Established KOL network and reference centres
• Modest commercial infrastructure requirements
• Contract sales, distributors and/or commercial partners in
other territories
• No direct competition in aTTP
• Potential key component in future standard of care
• Orphan Drug status with patent protection to 2035
• Peak sales potential in aTTP of ~€300M
Planned launch in 2018
Market opportunity
Strategic opportunity to
self-commercialise in
EU5 and USA
Inhaled ALX-0171 (anti-RSV)
For the treatment of RSV infections
29
ALX-0171 – inhaled anti-RSV Nanobody
First-in-class potential for the treatment of RSV infections
• Biological drug delivered by inhalation – major
platform advantage
• Most advanced product in clinical development
to treat RSV infections in infants
• Critical pre-clinical and clinical milestones
achieved
• Phase II dose-ranging efficacy study in infants
planned to start in Q4 2016
• Opportunity in multi-billion dollar market
30
RSV infection in infants
• 90% of children infected by 2 years of age1
• 33.8 million episodes (infants <5 years) globally p.a.1
• 3.4 million hospital admissions (infants <5 years) globally p.a.1
• 66,000-199,000 deaths (infants <5 years) globally p.a.1
• No approved therapeutic
1 Mazur et al, Lancet 2015; 2 Shi et al, J Med Econ, 2011; 3 Sigurs et al, Thorax, 2010; Backman et al, Acta Pediatr, 2014
Leading cause of infant hospitalisation
Evolves to
distressing
symptoms
Up to 20%
hospitalised Symptomatic treatment
• Long-term disease burden
– increased medical cost in the first year following RSV infection2
– prolonged wheezing and increased risk of asthma development3
31
Anti-RSV Nanobody – ALX-0171
Incorporating unique Nanobody platform advantages
Platform advantage Product features
Multivalent formatting
• 3 Nanobodies linked together that bind to the F-protein of RSV
• 7,000 fold increase in potency over monovalent construct
• 10,000 fold reduction in viral titres in vitro
• Neutralises 87% of a broad range of clinical RSV isolates
Delivery via inhalation • Biological activity maintained after nebulisation
• Delivered directly to the site of infection
• Very encouraging efficacy in neonatal lamb model for infant RSV
infection
• Safe and well-tolerated in healthy adults and adults with hyperreactive
airways
• Phase I/IIa study in 53 infants successfuly completed
32
Inhaled ALX-0171
• Recruitment from Q4 2014 to Q1 2016
• Study centres in Europe and Asia-Pacific region
• Adapted infant inhalation device (vibrating mesh)
• Inhaled ALX-0171 administered once/day, for 3 consecutive days
Phase I/IIa study in 53 hospitalised RSV-infected children
Primary endpoint:
Safety and tolerability of ALX-0171
Secondary endpoints:
Assessment of clinical effect (feeding, respiratory rate, O2
saturation, wheezing, coughing, general appearance), PD,
PK and immunogenicity
RA
ND
OM
ISA
TIO
N
2:1
Placebo N=10
ALX-0171 N=20 Open-label lead-in
N=5 Infants aged 3-24
months
Placebo N=6
ALX-0171 N=12
Infants aged 1-5
months Infants aged 5-24
months
DMC*
review
DMC*
review
* Data monitoring committee
33
First-in-infant Phase I/IIa study
Safety and tolerability
Excellent safety and tolerability profile confirmed in the target population
Open-label group
ALX-0171 (N=5)
Randomised group
ALX-0171 (N=30)
Randomised group
Placebo (N=16)
Adverse events (AEs)
- number (%) of subjects with an AE 4 (80.0) 9 (30.0) 4 (25.0)
- number (%) of subjects with a treatment-related AE 1 (20.0) 2 (6.7) 0 (0.0)
Serious adverse events (SAEs)
- number (%) of subjects with an SAE 3* (60.0) 1** (3.3) 0 (0.0)
- number (%) of subjects with treatment-related SAEs 0 (0.0) 0 (0.0) 0 (0.0)
* 1 of whom discontinued ** subject discontinued
• Most common AEs were infections and respiratory disorders
• 3 AEs related to ALX-0171: mild cough, mild rhinorrhoea, mild fever 11 days after last dose
• 5 SAEs reported: hypo-responsiveness, hypotonia, pneumonia (2) and atelectasis
34
First-in-infant Phase I/IIa study
Anti-viral effect – time to undetectable virus in culture
Pro
po
rtio
n o
f p
atie
nts
with
de
tecta
ble
RS
V
All Placebo (N=13)
All ALX-0171 (N=22)
Time (hours)
Treatment with ALX-0171 had an immediate and significant impact on viral replication in RSV-infected infants
Cox model to compare ALX-0171 and placebo with respect to time to first undetectable virus in culture (undetectable at 2
consecutive time points) from time of start of treatment
Time to undetectable virus ALX-0171 Placebo
Median hours 25.3 51.9
Nominal p-value 0.014
35
First-in-infant Phase I/IIa study
Overall disease severity assessment – Global Severity Score*
Encouraging initial indication of therapeutic effect
* Overall disease severity assessment including feeding intolerance, medical intervention, respiratory difficulty, respiratory frequency, apnoea, general
condition and fever
Nominal p-value=0.0092
based on longitudinal analysis comparing ALX-0171
and placebo with respect to the Global Severity
Score, adjusting for baseline score and time
All ALX-0171 (N=26)
All Placebo (N=15)
Glo
ba
l S
eve
rity
Sco
re (
me
an
+ S
E)
36
Inhaled ALX-0171
Potential breakthrough for the treatment of RSV infections
36
µ$
µµ
µ
µ
µµ
• Direct delivery to the site of infection through inhalation
• Good safety profile and no treatment-related SAEs in hospitalised
RSV infected infants
• Demonstrated anti-viral-effect in pre-clinical and clinical studies
• Encouraging indication of therapeutic effect in the clinic
Phase II dose-ranging efficacy study in ~180 hospitalised RSV-infected infants planned to start in Q4 2016
Immuno-oncology
Major collaboration with Merck & Co, Inc. and
wholly-owned programmes
38
Immuno-oncology
*BofA Merrill Lynch July 2015
Changing the cancer treatment paradigm
• Market expected to grow to >$43bn by 2020*
• I/O drugs expected to treat 60% of cancers*
• Proven substantial survival impact
Huge market potential
• Increasing number of targets
• Combination therapies are the future
Multiple targets
Nature Reviews - 2012
• Bind multiple targets (2, 3, 4 or 5) with one Nanobody molecule
• Potential to increase efficacy and avoid escape mechanisms
• Technology allows rapid exploration of combinations
• Manufacturing simplicity and cost-effectiveness
Multi-specific Nanobodies -
the next wave!
39
Immuno-oncology
Multi-specific Nanobodies versus combination mAbs
One tri-specific Nanobody is 4x smaller than a mAb
mAb
Tri-specific
Nanobody
mAb 3
mAb 2
mAb 1
More difficult for mAbs to bind to
different targets simultaneously
Target 1
Target 2 Target 3
Multi-specific Nanobodies may block
multiple targets simultaneously
Target 3
Target 1 Target 2
40
Multi-specific Nanobodies
• Heavily investing in I/O R&D pipeline (~80% of total R&D budget*)
• Keytruda® approved in advanced melanoma (first line) and metastatic
NSCLC
• Sales of Keytruda® estimated to reach $6Bn by 2020**
• >160 clinical studies for Keytruda® in >30 tumor types
*Bryan Garnier Oct 2015 **Leerink August 2015
Major immuno-oncology collaboration with Merck & Co., Inc.
First in vivo pre-clinical milestone (€3.5M) achieved and
first clinical studies planned to start in 2017
Merck & Co., Inc.
leader in the field
Merck & Co., Inc. and
Ablynx in collaboration
• Initially signed in Feb ‘14; significantly expanded in July ‘15
• Targeting multiple immune-checkpoint modulators
• Up to 17 fully-funded Nanobody programmes; focus on multi-specific
combinations
• €33M upfront; up to €5.7Bn in potential future milestones plus royalties
Outlook
42
2016-2017 outlook confirmed
Focus on sustainable value creation
2016 2017
• Q1 2016
- Phase I start with VEGF/Ang2 (BI) - €8M
- publication of data from TITAN study in the NEJM
• Q2 2016
- Phase I start with CX3CR1 (BI) - €8M
- Phase I start with CXCR2 (Novartis)
- Phase I/IIa results with ALX-0171 (53 infants)
- successfully raised €74M in a Private Placement
• Q3 2016
- vobariluzumab PhIIb RA monotherapy study results
- vobariluzumab PhIIb RA combination study results
- start follow-up study with HERCULES patients
• Q4 2016
- opt-in decision by AbbVie for vobarilizumab in RA
- start Phase II dose-ranging efficacy study of ALX-0171
- pre-clinical milestones
• Caplacizumab (aTTP) – wholly-owned
- filing for conditional approval in Europe (H1)
- HERCULES Phase III study results (H2)
- life cycle management activities
• Vobarilizumab (RA) – preparations for
Phase III study initiation
• ALX-0171 (RSV) – wholly-owned
- life cycle management activities
• Immuno-oncology – with Merck & Co., Inc.
- start of multiple IND enabling studies
- pre-clinical milestones
• Various partnered programmes
advancing in the clinic
CONTACT DETAILS
Questions
+32 9 262 00 00 Investor
Relations
investors@
ablynx.com www.ablynx.com
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