Corporate Presentation

Corporate Presentation
June 2014
Dr Edwin Moses, C.E.O.
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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2
Corporate snapshot
Corporate
•
•
•
Drug discovery and development company - Ghent, Belgium
NYSE Euronext Brussels (ABLX)
>300 employees
Technology
•
•
Pioneer in next generation biologics – Nanobodies®
>800 healthy volunteers and patients treated with Nanobodies
Products
•
•
~30 programmes – seven in clinical development
Three clinical proof-of-concepts
•
AbbVie, Boehringer Ingelheim, Eddingpharm, Merck & Co,
Merck Serono and Novartis
•
€203M in cash at 31st March 2014
Partners
Financials
www.ablynx.com
3
Key investment highlights
Nanobodies represent a unique, powerful and broadly applicable next generation biologics
platform
• antibody-derived biologics with key competitive advantages
• more than 500 granted and pending patents
Diversified portfolio across various therapeutic indications
• over 30 programs with 7 in the clinic
• potentially up to 12 new clinical programs in the next 3 years
Hybrid business model leveraging fully-funded collaborations, 50/50 co-development deals,
and unencumbered proprietary programs
Validating partnerships with leading players: Abbvie, Merck & Co., Merck Serono, Boehringer
Ingelheim and Novartis
• >€325M received to date with up to €3.3Bn plus royalties in future potential value
• 23 partnered programs with 3 currently in the clinic
Recent events establish important additional value creation opportunities
• positive Phase II proof-of-concept results in TTP, an orphan disease with a significant unmet
medical need
• new alliance in immuno-oncology with Merck & Co. – total potential value of €1.7Bn in
milestones plus royalties
www.ablynx.com
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Three-pronged business strategy
Fully-funded programmes with milestones
and royalties
• ~20 programmes in oncology, immuno-oncology,
neurology, inflammation, pulmonology and bone disorders
• 6 discovery deals
• 3 licensing deals
• >€280M in cash received with future potential value of up
Co-discovery/co-development partnerships
•
•
•
•
3 programmes in oncology, inflammation and osteoarthritis
50:50 ownership
potential to convert into licensing deals
>€45M in cash received
to €3.3Bn in potential milestones plus royalties
Balancing
risk and
reward
Wholly-owned product pipeline
• ~9 programmes in inflammation, ocular, autoimmune, oncology, hematology and infectious disease
• aim to retain the optionality to partner if and when appropriate
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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
VHH
VH
CH1
VHH
Ablynx’s Nanobody
VL
CL
CH2
CH2
CH3
CH3
Conventional
antibodies
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12-15kDa
Heavy chain only
antibodies
• unique formatting flexibility (up to
penta-valent)
• speed and ease of generating
multi-specifics
• nano- to picomolar affinities
• favourable biophysical properties
(Tm, solubility, viscosity)
• tackling intractable targets
• multiple administration routes
• manufacturing in microbial cells
6
Nanobody discovery process – the power of evolution
Immunize llama
with antigen
Draw blood 6–12
weeks later
Conventional
antibodies
VHH
CH2
CH3
Manufacture in
micro-organisms
Clinical trials
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plus half-life
extension
(HLE)
VHH
Ablynx’s
Nanobody®
Select Nanobodies
of interest
Format Nanobody to achieve
desired properties
7
Nanobodies – uniqueness and competitive advantages
Flexible formatting: multivalent, multi-specific, bi-paratopic
Nanobodies in the clinic
Broad target applicability, including challenging targets such
as GPCRs and ion channels
Robustness allows for alternative delivery such as nebulisation
Half-life engineering technology to achieve desired properties
(acute vs chronic diseases) (T1/2 from 2h to 20 days)
Excellent manufacturing (yeast and bacteria), high concentration
formulations and low viscosity (excellent syringeability)
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Multi-specific Nanobodies to checkpoint inhibitors
Monovalent Nanobodies
against
different targets
Different multispecific
combinations
In vivo testing
Pardoll, Nature Reviews Cancer (2012) 12:252-264
May need to interfere
with multiple pathways
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In vivo POC for different
multi-specific combinations
in 18-24 months
9
Merck & Co – new alliance in immuno-oncology (Feb. 2014)
Builds on an existing ion channel collaboration in neurology:
• opportunity in the emerging field of cancer immunotherapy
• focused on the discovery and development of Nanobody-candidates against
immune checkpoints
• exploiting the ability to rapidly generate multi-specific Nanobodies
The deal comprised: €20M upfront; €10.7M in research funding; €1.7Bn
in potential total milestones plus royalties
Following a three-year research term at Ablynx, Merck & Co will be
responsible for further development of the Nanobody-candidates, product
registration and commercialisation
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CoCo
Fully owned
Pipeline – internal and funded programmes
Therapeutic area
Product name
Target
Haematology
Inflammation/
Immunology/
Infection
caplacizumab
vWF
ozoralizumab
TNFα
Various
Various
Bone disorders
ALX-0141
RANKL
ALX-0171
Various
Various
RSV
Pulmonology
Various
NA
Inflammation/
Immunology
NA
NA
NA
Oncology/Neurology
Immunology
Various
Various
IL-17F/IL-17A
ALX-0061
IL-6R
Bone disorders
ALX-0141
RANKL
Neurology
BI 1034020
NA
Fully partnered
ex Greater China
in Greater China
ALX-0751
NA
Pulmonology
NA
Various
NA
NA
Immuno-oncology
Various
www.ablynx.com
Phase III
Potential to evolve into at least 4 co-co programmes
ALX-0761
Oncology
Phase II
Various
Oncology
Immunology
Discovery Pre-clinical Phase I
Validated targets (clinic)
1st in class
11
Clinical assets
Nanobodies® Inspired by nature
Key clinical assets
Anti-vWF – caplacizumab – bivalent Nanobody
• first-in-class opportunity with Orphan Drug Status for TTP
• statistically significant proof-of-concept in Phase II TITAN study
• preparations underway for Phase III study beginning in 2015
Anti-IL-6R – ALX-0061 – monovalent Nanobody with T1/2 extension
• Phase II POC achieved in subjects with RA, best-in-class potential
• global exclusive licensing deal with AbbVie (up to $840m in milestone payments)
• Ablynx responsible for next phases of development
• next data – results of Phase I s.c. study in Q4 2014
Anti-RSV – ALX-0171 – first inhaled trivalent Nanobody
• first-in-class opportunity with high unmet medical need
• pre-clinical and Phase I safety study in healthy volunteers successfully completed
• additional Phase I safety and PK studies reported in May 2014
• first-in-infant study expected to start in Q4 2014
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Significant unmet need in the treatment of acquired TTP
Thrombotic thrombocytopenic purpura (TTP) is a potentially life
threatening rare disorder of the blood coagulation system
Causes extensive microscopic thrombi in small blood vessels throughout
the body
Exists in two forms: congenital (<10%) and acquired (>90%)
No specifically indicated therapeutic drug available
Current standard of care - multiple daily plasma exchanges
Unmet medical need
Anti-vWF
Nanobody
• lengthy hospital stays
• potential clinical complications
• potential relapse after recovering from a first TTP episode
28 kDa
Anti-vWF
Nanobody
Orphan drug indication in US and Europe with ~10,000 TTP-related
annual events
www.ablynx.com
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caplacizumab – designed to prevent formation of
microthrombi in TTP
Anti-vWF Nanobody blocks the platelet – ULvWF interaction
ADAMTS13
ULvWF
multimers
Platelet String
Formation
Endothelium
anti-vWF Nanobody
Ex vivo assay for platelet string formation
Fluorescence microscopy image of platelets
adhering to UL-vWF in plasma of TTP subjects
ULvWF
Without treatment, fluorescently labeled
platelets adhere to UL-vWF, observed as
string-like structures
Anti-vWF Nanobody inhibits platelet
string formation
ULvWF and anti-vWF Nanobody
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caplacizumab in acquired TTP
Sudden onset: severe fatigue,
headache, bizarre behaviour, vertigo,
seizures, coma, etc.
Incidence: 11.3 per million(1)
Currently no drugs specifically
approved to treat acquired TTP
Healthy active adult
+ caplacizumab
Daily plasma exchanges (PEX)
in hospital until recovery of
platelet count
Diagnosis of TTP
caplacizumab on top of PEX could potentially result in:
•
•
•
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fewer days and volume of PEX
reduction in relapse/exacerbations
improved longer term outcome
(1)
George et al., European Journal of Haematology 80 (277-286) 2008
16
Inclusion criteria:
subjects with
acquired TTP
requiring plasma
exchange (PEX)
Randomization
caplacizumab - TITAN design and schedule
PEX
30 days
30 days
Placebo
1 year follow-up
1:1
Exclusion criteria:
• severe infection /
Target –
sepsis
110
• pregnancy
subjects
• bone marrow
transplantation
• disseminated
intravascular
coagulation
• known congenital TTP
30 days
PEX
X
caplacizumab
30 days
1 year follow-up
Primary endpoint:
time to confirmed
normalization of platelet count
Secondary endpoints:
plasma exchange frequency and volume;
relapse; exacerbations; mortality; major clinical
events (stroke, MI, organ dysfunction); recovery
from signs/symptoms.
Long-term endpoints:
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, N = 69 (95% CI)
Overall Hazard Rate Ratio for caplacizumab vs. Placebo
(95% CI)
Stratified Log-rank Test p-value
caplacizumab
Placebo
N* = 36
N* = 39
3.00 (2.74, 3.88)
4.92 (3.21, 6.59)
2.197 (1.278, 3.778)
0.013
The group of subjects 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
*Intention-to-Treat (ITT) population: 75 subjects, all randomized to caplacizumab (36) or placebo (39)
• 69 subjects received no plasma exchange prior to randomization to caplacizumab (34) or placebo (35)
• 6 subjects did receive one plasma exchange prior to randomization to caplacizumab (2) or placebo (4)
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Top line secondary endpoints
caplacizumab
Placebo
N* = 36
N* = 39
3 (8%)
11 (28%)
Complete remission up to 30 days after end of daily plasma
exchange as measured by confirmed platelet response and
absence of exacerbations
29 (81%)
18 (46%)
Proportion of subjects with exacerbation and/or relapse
at 1 month follow-up after study drug treatment was completed
13 (36.1%)
13 (33.3%)
0
2
Exacerbations up to 30 days after the end of daily plasma
exchange
Deaths
These secondary endpoints illustrate the potential protective effect of caplacizumab
treatment in the acute phase of TTP
*Intention-to-Treat (ITT) population: 75 subjects, all randomized to caplacizumab (36) or placebo (39)
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TITAN trial – overall conclusions on top line results
Clinical proof-of-concept demonstrated
• Hazard Ratio of 2.2, p = 0.013 (95% CI [1.28, 3.78])
• Median days to normalised platelet counts: 3.0 days for caplacizumab
vs. 4.9 days for placebo
Reduction in number of exacerbations to 3 in caplacizumab arm compared to 11
in placebo arm
81% of subjects achieved complete remission in the active treatment arm
compared to 46% in the placebo arm
No deaths in caplacizumab arm compared to 2 deaths in placebo arm
TEAEs and serious TEAEs consistent with serious, potentially life-threatening
condition
Increased bleeding tendency, which we believe is manageable
Increased number of immune-related TEAEs, but no impact on treatment
Clinical benefit demonstrated for subjects with acquired TTP with acceptable safety
profile
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caplacizumab – next steps
Complete full analysis of TITAN study and consult with KOLs and
regulatory authorities
Complete a Phase I trial to demonstrate bioequivalence between the
liquid and lyophilized formulations
Continue preparations to start a Phase III study in 2015
Continue to evaluate options to partner or commercialize caplacizumab
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ALX-0061 – compelling proof-of-concept Phase IIa results
100
83
% of patients
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 showed strong efficacy and was well tolerated at all doses
• No increase of adverse events upon extension of treatment
• No anti-drug antibodies were detected
www.ablynx.com
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ALX-0061 – global licensing deal with AbbVie (Sept 2013)
Ablynx received $175M upfront; $665M of potential total milestones plus
double-digit royalties
Ablynx will perform and fund subcutaneous Phase I study (2014) and Phase
II studies in RA and SLE (start in 2015)
AbbVie will pay a fee if they exercise the right to license ALX-0061 after the
completion of Phase II studies
• Phase II results in RA expected in 2016
• Phase II results in SLE expected in 2018
AbbVie is responsible for Phase III development, registration and global
commercialisation
Ablynx retains option to co-promote in Benelux
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ALX-0061 – clinical development to be performed by Ablynx
2014
2015
2016
2017
2018
2019
Phase I s.c. study
Phase II in RA
top line results
potentially continues development in RA
Phase II in SLE
top line results
potentially continues
development in SLE
www.ablynx.com
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ALX-0171 to treat RSV infection in infants – unmet need
~310,000 children* (< 5 years) hospitalised per year in the 7 major markets
• increased medical cost in the 1st year following RSV(1) infection(2)
• prolonged wheezing and risk for asthma development(3)
The leading cause of infant hospitalisation and leading viral cause of infant death
• ~3.5% mortality rate in hospitalised high-risk infants
• estimated 400 deaths/year in US
Evolves to
distressing
symptoms
Symptomatic treatment
including inhaled
corticosteroids & bronchodilator
8-20%
hospitalised
*Extrapolation based on estimated US prevalence
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(1)
Respiratory Syncytial Virus
(2)
Shi et al., J Med Econ, 2011
(3)
Sigurs et al., Thorax, 2010; Krishnamoorthy et al., Nature Medicine 2012
25
Proof-of-concept in lamb model for inhaled anti-RSV Nanobody
RSV infection
Necropsy
Onset of
RSV infection
Day -1
0
1
2
3
4
5
6
7
8
Treatment ALX-0171 or formulation buffer
6
5
4
3
2
1
Lung viral lesions
(day 6 post infection)
60
Mean % Involvement
Log10 FFU/mL BAL
7
Mean viral titers in BALF
(day 6 post infection)
50
40
30
20
10
0
0
Vehicle
RSV Vehicle RSV ALX-0171
Vehicle
RSV Vehicle RSV ALX-0171
Daily inhalation of ALX-0171 markedly reduced viral titres
and lung lesions in RSV-infected lambs
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ALX-0171 – three 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 five 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 dose and multiple dose of 200 mg inhaled daily for five days and single dose of 0.3 mg/kg i.v.
• local half-life of ALX-0171 is approximately 20 hours, confirming potential for once-daily dosing
Plan to initiate Phase II paediatric study in Q4 2014
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Additional programmes in clinical development
Anti-TNFα – ozoralizumab – bivalent Nanobody with T1/2 extension
• Phase II POC achieved
• ongoing licensing discussions in emerging markets
Anti-RANKL – ALX-0141 – bivalent Nanobody with T1/2 extension
• Phase I study successfully completed
• exclusively licensed to Eddingpharm in Greater China
Anti-IL-17A/F – ALX-0761 – bi-specific Nanobody with T1/2 extension
• pre-clinical POC achieved and Phase I study on-going
• Merck Serono has an exclusive license to the programme and bears all the costs
Alzheimer’s – BI 1034020
• Phase I study initiated in October 2013 and terminated in May 2014
• Boehringer Ingelheim fully responsible for this programme which is now under review
www.ablynx.com
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Partnerships
Nanobodies® Inspired by nature
Broad platform exploitation and cash generation
•
Global licensing deal with AbbVie for ALX-0061 (anti-IL-6R) in RA and SLE: $175M upfront and
total potential value of $840M plus royalties
•
Strategic discovery alliance with Boehringer Ingelheim (8 pre-clinical programmes on-going)
and a collaboration in Alzheimer’s (Phase I)
•
4 discovery deals with Merck Serono: 10 programmes (1 Phase I) on-going in inflammation,
immunology, oncology, immuno-oncology, neurology and osteoarthritis
•
2 discovery deals with Merck & Co: ion channel deal in neurology; cancer immunotherapy deal
with €20M upfront, €10.7M research funding and total potential milestones of up to €1.7bn plus
royalties
•
Licensing deal with Eddingpharm in Greater China for ALX-0141 (anti-RANKL) in bone
disorders
•
Target based discovery deal with Novartis
>€325M in non-dilutive cash received from collaborators to date
Up to €3.3Bn in potential future milestones plus royalties
www.ablynx.com
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Further building the clinical pipeline
Number of partnered Nanobodies in clinical development
up to
12
up to
6
3
2013
www.ablynx.com
2014
2015
31
Expected news flow for 2014
Expected
Clinical Data
•
Start of
Clinical Trials
Phase I results from safety
and PK studies with ALX0171 (anti-RSV)

•
Phase II results with
caplacizumab in acquired
TTP in June 2014

•
Phase I results from s.c.
study with ALX-0061 (antiIL-6R)
•
Phase I results from BI for
Nanobody for use in
Alzheimer’s disease
•
Phase I results from Merck
Serono for ALX-0761 (antiIL-17A/F)
up to 5 clinical trial
readouts
www.ablynx.com
Business
Development
•
Start of Phase I study with
s.c. ALX-0061 (anti-IL-6R)
•
Start of Phase II paediatric
study with ALX-0171 (antiRSV)
•
Potential milestone
payments from on-going
collaborations
•
Potential additional
collaborative deals

•
Preparation for start of
Phase II RA and SLE
studies with ALX-0061 (antiIL-6R) in 2015
•
Start of up to three
partnered Phase I studies
up to 5 clinical trials
to be initiated

cash generative
partnerships
32
Value creation – clinical data expected from patient studies
ALX-0061 Phase
IIb s.c. (anti-IL-6R)
in subjects with RA
Licensed to AbbVie
2013
caplacizumab
Phase II (anti-vWF)
in subjects with
acquired TTP 
clinical
ALX-0061 Phase IIa Wholly-owned
asset
i.v. (anti-IL-6R)
in subjects with RA 
ALX-0171 Phase
I/II (anti-RSV) in
infants with RSV
infection
ALX-0761 Phase
IIa (anti-IL-17A/F)
in subjects with RA
Wholly-owned clinical
asset
Licensed to Merck
Serono
Two partnered
Phase I/II
programmes in
cancer
Licensed to AbbVie
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Financial summary
€M
2012
2013
Q1 2014
Revenue
26.7
35.9
11.2
(29.8)
(17.7)
(3.6)
62.8
200.4
203.2
Operating Result
Cash Position*
Anticipated net cash burn for 2014: €30M - €35M
*Cash, cash equivalents, restricted cash and short-term investments at the end of the period
www.ablynx.com
34
Summary
Nanobodies represent a unique, powerful and broadly applicable next generation biologics
platform
• antibody-derived biologics with key competitive advantages
• more than 500 granted and pending patents
Diversified portfolio across various therapeutic indications
• over 30 programs with 7 in the clinic
• potentially up to 12 new clinical programs in the next 3 years
Hybrid business model leveraging fully-funded collaborations, 50/50 co-development deals,
and unencumbered proprietary programs
Validating partnerships with leading players: Abbvie, Merck & Co., Merck Serono, Boehringer
Ingelheim and Novartis
• >€325M received to date with up to €3.3Bn plus royalties in future potential value
• 23 partnered programs with 3 currently in the clinic
Recent events establish important additional value creation opportunities
• positive Phase II proof-of-concept results in TTP, an orphan disease with a significant unmet
medical need
• new alliance in immuno-oncology with Merck & Co. – total potential value of €1.7Bn in
milestones plus royalties
www.ablynx.com
35
Corporate Presentation
June 2014
Dr Edwin Moses, C.E.O.
Nanobodies® Inspired by nature
TITAN trial milestones
January 2011: first patient recruited
September 2013: protocol amended to allow inclusion of subjects who
had undergone 1 plasma exchange
January 2014: trial stopped after 75 subjects* recruited to allow early
analysis of data
March 2014: last patient completes one month follow-up visit
June 2014: initial top-line Phase II results published
*Intention-to-Treat (ITT) population: 75 subjects, all randomized to caplacizumab (36) or placebo (39)
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37
Treatment groups at baseline – demographics
caplacizumab
Placebo
Total
N* = 36
N* = 39
N* = 75
40.6 ± 12.7
42.5 ± 13.2
41.6 ± 12.9
Male
12 (33%)
19 (49%)
31 (41%)
Female
24 (67%)
20 (51%)
44 (59%)
Caucasian
32 ( 89%)
34 ( 87%)
66 ( 88%)
Black
4 (11%)
5 (13%)
9 (12%)
Baseline BMI (kg/m²) mean ± SD (N=72)
28.7 ± 9.1
29.3 ± 6.7
29.1 ± 7.7
Age (years) mean ± SD
Gender
Ethnicity/Race
Balanced treatment groups apart from more women in the caplacizumab arm than in
placebo arm – reflects gender distribution in TTP and not prognostic factor
*Intention-to-Treat (ITT) population: 75 subjects, all randomized to caplacizumab (36) or placebo (39)
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Treatment groups at baseline – disease characteristics
Platelets (10³/mm³) mean ± SD
minimum, maximum
LDH (U/L)
Initial Episode (%)
mean ± SD
caplacizumab
Placebo
Total
N* = 36
N* = 39
N* = 75
21.1 ± 18.2
28.0 ± 20.0
24.6 ± 19.3
2, 70
5, 84
2, 84
1277 ± 853
1270 ± 939
1274 ± 891
24 (66.7%)
27 (69.2%)
51 (68.0%)
Comparable disease severity in both treatment arms
*Intention-to-Treat (ITT) population: 75 subjects, all randomized to caplacizumab (36) or placebo (39)
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39
Safety profile – treatment emergent adverse events (TEAEs)
caplacizumab Placebo
Subjects with any TEAE
Number of TEAEs
Subjects with any TE Serious AEs
- Subjects with TTP as TE Serious AE
Number of TE Serious AEs
Subjects with TEAE leading to study drug
discontinuation
Total
N = 35
N = 37
N* = 72
34 (97%)
37 (100%)
71 (99%)
574
544
1118
20 (57%)
19 (51%)
39 (54%)
13 (37%)
13 (35%)
26 (36%)
44
36
80
4 (11%)
2 (5%)
6 (8%)
Comparable number of subjects between the two treatment arms with
TE Serious AE as well as comparable number of TEAEs
*Safety population: 72 subjects, all randomized and treated with caplacizumab (35) or placebo (37)
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40
Safety profile – TEAEs indicative of bleeding
caplacizumab
Placebo
Total
N = 35
N = 37
N* = 72
66
35
101
- mucosal bleeding
24
16
40
- bruising/haematoma
16
9
25
9
2
11
17
8
25
5
2
7
Number of bleeding related TEAEs
- metro/menorrhagia
- other
Number of bleeding related TE SAEs
Manageable increased bleeding tendency in caplacizumab arm
2 subjects in caplacizumab arm experienced 5 SAEs related to bleeding compared to
2 subjects with 2 bleeding SAEs in placebo arm
*Safety population: 72 subjects, all randomized and treated with caplacizumab (35) or placebo (37)
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41
Safety profile – immune-related TEAEs
caplacizumab
Placebo
Total
N = 35
N = 37
N* = 72
Number of immune-related TEAEs
40
26
66
- of which injection site reactions
6
2
8
11
6
17
22
(1 SAE)
17
39
1
1
2
1
0
1
- of which hypersensitivity including
transfusion reactions
- rash/urticaria
- other
Number of immune-related SAEs
Higher number of manageable immune system related TEAEs with caplacizumab
though only one was serious
*Safety population: 72 subjects, all randomized and treated with caplacizumab (35) or placebo (37)
www.ablynx.com
42
Phase I s.c. bioavailability study for ALX-0061
Initiated in April 2014
70 healthy volunteers
Single doses of 50 mg, 150 mg or 300 mg as a s.c. injection or 50 mg or
300 mg as an i.v. infusion
Due to report in Q4 2014
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Risk Factors
Nanobodies® Inspired by nature
Risks related to Ablynx
1.
Clinical trial risks
Nanobody based drug candidates must undergo rigorous pre-clinical and clinical testing, the results of which are uncertain and could
substantially delay or prevent the drug candidates from reaching the market
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The company is heavily dependent on the success of a limited number of candidate drugs, only a few of which have entered clinical trials, and there is a need
to continue to identify and develop further candidate drugs. The company currently is working on a pipeline of more than 30 potential candidate drugs, including
seven candidate drugs in clinical development, of which three are in Phase II including caplacizumab for haematology (headline results released in June 2014),
ozoralizumab for inflammation/immunology, and ALX-0061 for immunology, and four candidate drugs in Phase I including ALX-0141 which is being developed
for bone disorders (ex Greater China), ALX-0171 for pulmonology, ALX-0761 for immunology, and BI 1034020 for neurology. Other candidate drugs are still in
pre-clinical and discovery stages
All Nanobody based products will be subject to extensive pre-clinical and clinical trials to demonstrate safety and efficacy in humans before they can receive the
necessary regulatory approval to enter the market. Clinical studies are expensive and time consuming and their results are highly uncertain. The Company, its
licensees or other third parties may not successfully complete their pre-clinical and clinical studies of Nanobodies. Failure to do so may significantly delay or
prevent the commercialisation of drug candidates or may potentially invalidate the concept of Nanobodies as a new therapeutic class
The Company cannot guarantee that its drug candidates will demonstrate sufficient safety or efficacy in its studies to obtain marketing approval, and the results
from earlier pre-clinical and clinical trials may not accurately predict the results of later-stage trials. The clinical trials may not reach the primary endpoints and
may not demonstrate the required clinical benefit for approval of the drug in the prospective indication. The Company’s current and future clinical trials involve
and will involve testing in larger patient populations, which could reveal a higher prevalence of certain side-effects compared to previous smaller scale trials.
At any stage of development, based on review of available pre-clinical and clinical data, the estimated costs of continued development, market considerations
and other factors, including the risks detailed in this Prospectus, development of any of the Company’s drug candidates may be discontinued
Delays in clinical trials are common and may have many causes. Such delays could result in increased costs and jeopardise or delay
Ablynx’ ability to achieve regulatory approval and commence product sales as currently contemplated
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Commencing clinical trials is subject to gathering satisfactory information on the quality, non-clinical and clinical safety of the candidate drug, and obtaining an
approval by the relevant authority. Preparing a potential candidate drug for clinical trials is a time-consuming and costly process. The Company faces the
inherent difficulties in selecting the right drugs and drug targets and avoiding unwanted side effects, as well as unanticipated problems relating to development,
testing and obtaining regulatory approvals. The Company may not be successful in identifying, developing, commercializing or otherwise capitalizing on
candidate drugs, and may use its limited resources on efforts that may be significantly delayed or discontinued
Clinical trials can be delayed for a variety of reasons, including delays in obtaining regulatory approval to commence a trial, in reaching agreement on
acceptable terms with prospective contract research organisations and prospective contract manufacturing organizations and clinical investigational sites, in
obtaining institutional review board approval at each site, in recruiting suitable subjects to participate in a trial, in having patients complete a trial or return for
follow-up, in adding new sites or in obtaining sufficient supplies of clinical trial materials or clinical sites dropping out of a trial
If the Company experiences lower than expected enrolment in the trials, the trials may not be completed as currently scheduled. Furthermore, with respect to
the clinical trials conducted by third parties, the Company will have no control over their timing or outcome. Where appropriate under certain circumstances, the
Company may terminate early the recruitment of subjects in order to prioritise the progress of clinical trials for certain key products. For example, prior to
reaching the target of 110 patients, the company decided to stop recruitment for the its worldwide Phase II TITAN study with the anti-vWF Nanobody,
caplacizumab, to treat acquired TTP to allow early analysis of the clinical data for potential proof-of-concept
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Risks related to Ablynx
1.
Clinical trial risks (cont’d)
Ablynx’ drug candidates may not obtain regulatory approval when expected, if at all, and even after obtaining approval, the drugs will be
subject to ongoing regulation. To date, none of the Ablynx drug candidates have reached the stage of submission or evaluation for
regulatory approval
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The company currently has seven candidate drugs in clinical development, of which three are in Phase II and four in Phase I. stages. While the Company’s
most advanced candidate drug, caplacizumab, is expected to commence Phase III study in 2015, there remains significant regulatory hurdles and the Company
cannot guarantee that it will obtain the required regulatory approvals to market its candidate drugs
Clinical results are expected for a number of candidate products in 2014, including Phase I readout from safety and PK studies with ALX-0171, Phase I results
from subcutaneous formulation study with ALX-0061, Phase I results from Boehringer Ingelheim I for Nanobodies for use in Alzheimer’s disease, and Phase I
results from Merck Serono for ALX-0761. Even if positive results are obtained from pre-clinical tests or early clinical trials, the Company may not achieve the
same success in future trials. Up to five clinical trials are also planned to be initiated, including a Phase I study with subcutaneous formulation ALX-0061, a
Phase II paediatric study with ALX-0171, a Phase II RA and SLE studies with ALX-0061, and up to three partnered Phase I studies. Candidate drugs that
appear promising in the early phases of development, such as in early human clinical trials, may fail to achieve regulatory approval for a number of reasons,
such as the candidate drug did not demonstrate acceptable clinical trial results even though it demonstrated positive pre-clinical trial results; the candidate drug
was not effective in treating the specified disease or condition; the candidate drug had harmful side effects on humans or presented unacceptable safety risks;
the governing regulatory authorities (such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)) denied approval to the
candidate drug altogether or denied a commercially important indicated use. The Company may spend several years completing testing for any particular
candidate drug, and failure can occur at any stage
The regulatory approval process is expensive and time consuming and the timing of marketing approval is difficult to predict. The Company has not yet applied
for marketing approval for any of its drug candidates and may lack the necessary experience to efficiently and successfully conduct such proceedings. Delay or
failure to obtain marketing approval for the drug candidates could adversely impact the ability to commercialise the drug candidates and could substantially
impair the Company’s ability to generate revenues
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Risks related to Ablynx
2.
Financial risks
Ablynx has a history of operating losses and an accumulated deficit. Ablynx may never become profitable or may not be able to sustain
profitability in subsequent periods
•
The Company has incurred significant operating losses since it was founded , principally resulting from costs incurred in research and development, market
research and business development, clinical development and from general and administrative costs associated with the Company’s operations. Under IFRS, it
experienced net losses of approximately €19.5 million in 2013 and had €195.3 million of retained losses at the end of 2013 and net losses of approximately
€2.8 million in the first three months of 2014. The Company will continue to need significant financial resources to conduct ongoing research and development,
market research and business development, clinical testing and regulatory compliance activities and this could result in the Company sustaining significant
losses for the foreseeable future
Ablynx may need additional funding, which may not be available on acceptable terms when required, if at all, and which may cause
existing shareholders to experience significant dilution
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The Company has stated that it expects to keep net cash burn in the €30-€35 million range for 2014. The Company does not expect its existing capital
resources to be sufficient to enable the Company to fund the completion of all its current clinical development programmes through to commercial introduction.
The Company may seek additional funding through collaboration agreements and public or private financings. Additional funding may not be available to the
Company on acceptable terms or at all. If the Company is unable to obtain funding on a timely basis, it may be required to significantly curtail one or more of its
research or development programmes
The Group’s revenue is generated by a limited number of clients, including strategic partners
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Over the last two years, Ablynx’s revenue included license fees, R&D service fees and reimbursement of R&D costs and milestone payments stemming from
the Company’s research collaboration agreements, as well as governments grants. In 2013, revenue principally included milestones from Boehringer Ingelheim
and Merck Serono, as well as an upfront payment received from AbbVie.
The Company relies on the revenue it generates from this limited number of clients, together with its own cash resources, to continue to fund its operations,
including its ongoing research and development activities
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Risks related to Ablynx
3.
IP related risks
The Company’s patents and other intellectual property rights may not adequately protect its products and drug candidates, which may
impede the Company’s ability to compete effectively
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The success of the Company depends in part on its ability and that of its collaborators to obtain, maintain and enforce patent protection in Europe, the United
States and elsewhere for technologies and products, and to maintain other intellectual property rights. For example, the first of the Hamers I patent family,
which describes the basic structure, composition, preparation and uses of Nanobodies, expired in Europe in 2013 and expires in the United States in 2015. The
expiration of these patents allows third parties to use such technologies to enter the market for Nanobody based therapeutics, and although the Company
directly holds more than 500 patents and patent applications, and licenses the rights to other patents, covering specific technologies, targets and indications of
a later date, include patent applications that the Company has filed around its specific product leads, around targets and classes of targets, around its novel
and proprietary half-life extension techniques, and around its proprietary techniques for generating, optimising, formatting and administering Nanobodies, there
can be no assurance that patents will be of sufficient breadth to provide adequate protection against competitors with similar technologies or products, that
patents granted to the Company or its collaborators will not be successfully challenged, that the Company will develop products that are patentable or that
patents will be granted under pending or future applications
The Company may infringe the patents or other intellectual property rights of others and may face patent or other intellectual property
litigation which may be costly and time consuming
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The Company’s success will depend in part on its ability to operate without infringing or misappropriating the proprietary rights of others. If there are valid third
party rights, the Company could have to obtain appropriate licences under any relevant patents or cease and/or alter certain of its activities or processes,
initiate proceedings to have these patents revoked or declared invalid, or develop or otherwise obtain alternative technology. The Company has brought
proceeding to challenge or oppose third party patent claims. For example, the Company was engaged in opposition proceedings against the European patent
EP 1 517 921, which was originally granted to Domantis Ltd. in 2006 and which related to one specific technique for the half-life extension of immunoglobulin
single variable domains. In 2010, the European Patent Office decided to revoke the Domantis patent in full. This decision has been appealed and, although the
Company does not believe that the appeal will be successful, if the Domantis patent were to be reinstated, the Company could have to obtain appropriate
licences or alter certain of its development programmes to use alternative technologies. There can be no assurance that the Company’s efforts to search for
existing proprietary rights before embarking on a research and development programme with respect to a particular technology or product, will uncover all
relevant third party rights relating to such technology or product or that the Company’s activities will not infringe upon the intellectual property rights of others
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Risks related to Ablynx
4.
Competition and technological progress within the sector
The Company faces, and will continue to face, significant competition and rapid technological change which could limit or eliminate the
market opportunity for its products and drug candidates.
The fields in which the Company operates are characterised by rapid technological change and innovation. The Company’s main competitors in
terms of ‘‘next-generation’’ protein-based products can (broadly) be classified into three main categories:
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Technologies based on antibodies with optimised Fc regions in order to optimise half-life or influence Fc functions such as antibody dependent cellular
cytotoxicity or complement activation. These technologies retain the basic structure (and therefore size) of the original antibody and therefore are faced
with many of the same problems as traditional antibody based therapeutics
Antibody scaffold/fragment-based technologies. An alternative to full length antibodies is provided by antibody scaffolds/fragment based technologies.
Alternative scaffold-based technologies. These novel, non-antibody based scaffolds offer opportunities to develop either therapeutics with a profile
comparable to that of traditional antibodies, or therapeutics that combine certain advantages of antibodies and small molecule drugs and even include
certain additional beneficial properties
Within the current technological competitive landscape, antibody based fragment technologies represent the closest analogue to the Company’s
Nanobody technology in terms of size and antibody based source of origin. However, in terms of stability, robustness and (potential) beneficial
properties, certain of the newer alternative scaffold technologies have the potential to compete directly against the Company’s technology
As a drug development platform company, Ablynx also competes with a number of innovative biotechnology platforms such as Dicerna, Five
Prime, Sangamo and uniQure. These companies have managed to build a broad pipeline of development programmes including candid ates
targeting both large indications and orphan diseases, which may in the future compete with the Company’s products
There can be no assurance that competitors of the Company are not currently developing, or will not in the future develop, technologies and
products that are equally or more effective, that have better side-effect profiles and/or are more economical in comparison with any current or
future technology or product of the Company. Medical advances or rapid technological development by competitors may result in the
Company’s drug candidates becoming non-competitive or obsolete before the Company is able to recover its research and development and
commercialisation expenses. If the Company or its drug candidates do not compete effectively, the Company’s business would be materially
adversely affected
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Risks related to Ablynx
5.
Agreements with third parties
Ablynx is reliant on collaborative partners for the development and commercialisation of most of its existing and future drug candidates.
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The Company is, and expects to be, dependent on current and future licence, collaboration and other agreements with experienced partners relating to the
development of most of its existing and future drug candidates and to the successful commercialisation thereof. These collaborative arrangements currently and
may in the future place the development and commercialisation of most of its drug candidates outside of the Company’s control and may require the Company
to relinquish important rights, including intellectual property, marketing and distribution rights. Under its collaborations, the Company may also not be able to
control the amount or timing of resources that its collaborative partners devote to the development or commercialization of its drug candidates, or may
experience the incurrence of additional costs or delays beyond its control
In particular, the programmes for the anti-IL-6R Nanobody, ALX-0061 (global license agreement with AbbVie), and for the anti-RANKL Nanobody, ALX-0141
(license agreement with Eddingpharm), as well as the discovery and development collaborations with Novartis, Boehringer Ingelheim, Merck Serono and Merck
& Co. largely depend on Ablynx’s collaborative partners’s strategy, willingness and ability to continue and carry through the programmes in cooperation with
Ablynx. If the Company’s partners did not perform as expected as to the collaboration agreement, the Company’s business would be materially adversely
affected
Ablynx relies on outsourcing arrangements with third parties for some of its activities including manufacturing and clinical trials
management.
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The Company relies on outsourcing arrangements with third parties for some of its activities, including pharmacology, toxicology, manufacturing, clinical trials
management, data collection and analysis and market research. While the Company seeks to outsource activities only to reputable firms with relevant specialist
expertise, it may have no or limited control over these third parties and the Company cannot guarantee that they will perform their obligations in an effective and
timely manner
Specifically ,with respect to manufacturing, the Company is reliant on specialist organisations in the field of microbial expression. In two instances in the past,
the Company has experienced these organisations changing their business model away from the provision of services, and being acquired and no longer
providing services to third parties. In both cases, ithe Company has had to transfer its processes to another party, incurring significant cost and delays
Ablynx may not have adequate insurance cover, particularly in connection with product liability risk.
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The Company is exposed to potential product liability claims that are inherent in clinical testing and could potentially be exposed to product liability claims
relating to the sale and marketing of drugs and drug candidates. The Company faces the risk of substantial liability for damages if its drugs or drug candidates
were to cause adverse side-effects in clinical studies or once they are on the market. As the Company does not yet have a commercialised product, it only
maintains product liability insurance for its clinical trials. The Company’s current insurance coverage may not be adequate to cover it against all potential claims
and the Company may not be able to obtain sufficient liability coverage on reasonable terms or at all in the future
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Risks related to Ablynx
6.
Operational risks
The commercial success of Abynx will depend on attaining significant market acceptance of its drug candidates among physicians,
patients, healthcare payers and the medical community. Ablynx has not yet commercialised any product. There can be no guarantee
Ablynx will be able to obtain reimbursement of its drug candidates by healthcare payers in individual countries. A lack of such
reimbursement could severely affect the commercial prospects of the drug candidate
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To date, none of the Company’s drug candidates have been commercialised. Even if approved by the appropriate regulatory authorities for marketing and sale,
physicians may not prescribe the Company’s drug candidates. Market acceptance by physicians, patients and healthcare payers will depend on a number of
factors, many of which are beyond the Company’s control, including the clinical indications for which the product candidate is approved and the acceptance by
physicians, patients and healthcare payers as a safe and effective treatment; relative convenience, ease of administration and other perceived advantages over
competing treatments; prevalence and severity of adverse side-effects; the cost of treatment in relation to alternative treatments; the extent to which the product
candidate is approved for inclusion on formularies of hospitals and managed care organisations; whether the product candidate is designated under physician
treatment guidelines as initial or first-line therapy or as therapy in relapsing/recurrent disease; the availability of adequate reimbursement by third parties, such
as insurance companies and other healthcare payers; and limitations or warnings contained in a product candidate’s approved labelling
If Ablynx fails to attract and retain qualified personnel, it may be unable to successfully develop its technologies, conduct its clinical trials
and commercialise drug candidates
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www.ablynx.com
The Company’s success depends in part on its continued ability to attract, retain and motivate highly qualified clinical and scientific personnel and on its ability
to develop and maintain important relationships with leading academic institutions, clinicians and scientists. The Company may not be able to attract or retain
qualified personnel on acceptable terms in the future due to the intense competition for qualified personnel among biotechnology, pharmaceutical and other
businesses
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Risks related to Ablynx
7.
Tax related risks
Tax legislation in Belgium might change over time.
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As a research company, the Company enjoys a favorable tax regime in Belgium where it is are eligible for tax credits and grants for research companies. In
2013, the Company has accounted for a tax receivable of €8.0 million following an R&D incentive scheme in Belgium under which the tax can be refunded after
five years if not offset against taxable basis over that period. The R&D incentives are recorded net against the relating R&D expenses in the Company’s
consolidated statement of comprehensive income. The Company expects to receive this amount gradually from year 2015 onwards. The Company’s income
from government grants was €2.8 million in 2013. The Company is also eligible for tax rebates in the form of reductions on withholding taxes on salaries of
scientific research personnel in Belgium who hold a PhD or Master’s Degree. These government grants and tax incentives may be discontinued in future
The Company may be or become a passive foreign investment company, which could result in adverse US federal income tax
consequences to US investors.
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The Company believes that it was not a passive foreign investment company (a ‘‘PFIC’’) for US federal income tax purposes in respect of 2013 although the
Company has been a PFIC in the past and may become a PFIC in respect of 2014 or in future years. The Company’s status as a PFIC must be determined
annually and depends upon the nature of the Company’s income, the composition and quarterly average value of the Company’s gross assets and the market
price of its shares. Whether the Company will be a PFIC in respect of 2014 will depend in large part on whether the Company’s share price is maintained at or
above its current levels. If the Company were treated as a PFIC for any taxable year during which a US investor held its shares, certain adverse US federal tax
consequences could apply to such US investor. For example, if the Company is a PFIC, U.S. holders of the Company’s shares may become subject to
increased tax liabilities under U.S. tax laws and regulations and will become subject to annual reporting requirements. The PFIC rules are extremely complex,
and prospective investors are urged to consult their own tax advisors regarding the potential consequences to them of the Company being classified as a PFIC
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