1. Healthcare

The PENTRA®Body Company
January 2015
1
Agenda
Summary
Introduction
PENTRA®Body Platform
Dermatology
Oncology
January 2015
2
Summary
Delenex at a Glance
• Delenex was founded in 2009 as a spin-off from the ESBATech-Alcon/
Novartis acquisition
• Delenex has a unique, proprietary and validated platform to generate
PENTRA®Bodies which
- are highly variable in CDR sequences targeting different epitopes
- are highly stable and soluble
- have excellent affinity/potency in the low picomolar to high femtomolar range
• Delenex is a clinical stage company
- DLX105 (anti-TNFα) in phase 1/2 by Delenex in psoriasis and Behçet disease
• Our pipeline focuses on dermatology and oncology
• Current main investors: BioMedInvest, HBM Partners, Novo Ventures, SV
Life Sciences, VI Partners
January 2015
3
Agenda
Summary
Introduction to Delenex
PENTRA®Body Platform
Dermatology
Oncology
January 2015
4
Introduction
Corporate Background
• Founded as spin-off from the ESBATech-Alcon acquisition in 2009
- ESBATech is now part of Novartis following the acquisition of Alcon in 2010
• Based in Schlieren (Zurich), Switzerland
• Key investors:
-
BioMedInvest
HBM Partners
Novo Ventures
SV Life Sciences
VI Partners
January 2015
5
Introduction
The PENTRA®Body Platform
• Proprietary technology platform for the development of locally and
systemically administered antibody fragment therapeutics
• PENTRA®Bodies are highly stable, humanized antibody fragments that are
small in size, very potent, convenient to manufacture, easy to convert into
other antibody formats and carry excellent tissue penetration characteristics
• Ideal drug format for development in:
- Dermatology (primary focus)
- Oncology
- Inflammation
• Allows the development of treatments that would allow patients to stay off
costly systemic antibody therapies for prolonged periods
January 2015
6
Introduction
The Platform: Key Properties and Applications
PENTRA®Body Properties
•
Highly potent
•
Excellent antigen recognition and specificity
•
Small (excellent tissue penetration, short t1/2)
•
GMP production at low COGS
•
Clinical study in dermatology established proof-ofprinciple
•
Safe and well tolerated
•
Allow expansion of therapeutic areas and number of
eligible patients
•
In many aspects superior to other, small (non-) antibody
scaffolds
Routes of Administration
Topical/local
•
•
•
•
Dermatology
Oncology
Ophthalmology
Respiratory
Systemic
•
•
•
•
Flaring diseases
Oncology
Intoxication
Infectious diseases
Enteral
•
January 2015
Gastrointestinal
7
Introduction
Applications: Focus on Dermatology and Oncology
Cardiovascular
Treatment of acute conditions such as reperfusion injury where rapid onset of
action, good distribution, fast clearance of drug are beneficial
CNS
Intranasal or IV applications (with BBB-crossing), distribution in brain tissue
Dermatology1
Topical application and penetration into skin tissue
Gastrointestinal diseases
Topical, rectal or oral administration with penetration into mucosal tissue
Infections
Conjugated with a pay-load, immediate recognition and elimination of the
pathogen; rapid neutralization of toxins
Inflammation
Treatment of flares in immunological disorder such as gout by rapid onset of
action, good distribution, fast clearance of drug
Oncology1
Conjugated with pay-load, rapid and targeted distribution in tumor mass or
facilitated access to hidden (micro)metastases
Ophthalmology2
Topical application (eye drops) or injection into the eye
Pain
Rapid pain relief with a fast acting, local antibody fragment drug
Respiratory diseases
Inhalation and distribution in entire lung tissue
Rheumatology
Local injection with subsequent distribution in joint/tissue in osteoarthritis,
rheumatoid arthritis, etc.
1 Areas
2 Rights
of Delenex’ focus
to ophthalmology indications owned by Novartis, through ESBATech/Alcon acquisition in 2009
January 2015
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Introduction
Expanding the Treatment Options in Dermatology
• Focus on topical, local and short systemic administration of therapeutic
antibodies addressing unmet needs in dermatology
 Expanding access to biologics to a much wider range of patients by non-systemic application
 Overcoming limitations of long-acting biologics by predominantly local/topical treatments
 Prolongation of periods with non-systemic therapy resulting in cost-efficient treatment options
• Rich proprietary pipeline against validated molecular targets for all major
indications
• Phase 2 clinical study with DLX105 (anti-TNFα) in psoriasis has already
provided proof-of-principle for topical administration of PENTRA®Bodies in
dermatology
January 2015
9
Introduction
Products and Platform for Oncology/Inflammation
• Focus on (short) systemic/local administration in selected tumors and
inflammatory conditions
• Targeting diseases with high medical need
• Rich proprietary pipeline against validated molecular targets
• Overcoming limitations of long-acting and larger biologics
January 2015
10
Introduction
Product Pipeline
Product (Target)
Indication
DLX105
(TNFα)
Psoriasis (intradermal)
Psoriasis (topical)
Hidradenitis suppurativa
Ophthalmology¹
DLX2751
(TNFα)
Psoriasis (topical)
Hidradenitis suppurativa
DLX2323/DLX2681
(IL-1β)
Acne
Acute gout
DLX2882/3003
(IL-17A)
Psoriasis
DLX1008
(VEGF-A)
Kaposi Sarcoma, Rosacea
Oncology (glioblastoma)
Ophthalmology*
DLX2201
(IL-12/23)
Lead
Preclinic
1b/2a
2
completed
completed
ESBA105
ESBA1008/RTH258
Psoriasis, Inflammatory
Bowel Disease
* Rights to ophthalmology indications owned by Novartis, through ESBATech/Alcon acquisition in 2009
January 2015
11
Agenda
Summary
Introduction
PENTRA®Body Platform
Dermatology
Oncology
January 2015
12
PENTRA®Body Platform
Modular Platform
Bispecific
PENTRA®Bodies
PENTRA®
PENTRA®ADC
gr
gr
Toxin, cytokine,
radionuclide
Other…
IgG & Fab based
on PENTRA®
VL
VL
VH
CH1
CL
CL
CH1
VH
VH VL
CH1 CL
S-S
1.-3. generation CAR
January 2015
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PENTRA®Body Platform
Unique Characteristics
• Low picomolar neutralizing potency
• Anti-IL-1β PENTRA®Body with IC50 of 600 fM
 best-in-class
• Rapid identification of potent development
candidate (6 mo)
 no affinity maturation
2400
Inhibition of IL1β induced IL6 release
2000
rhIL-1RA
2800
1600
1200
Canakinu
mab
800
DLX2323
400
0
0.1
10
1000 100000
Antibody, pM
• Readily penetrates into skin and other surfaces
In vitro model
of skin:
• Three times higher volume of distribution (Vdss =
12-16 liters) compared to IgGs
Tailored for specific local and systemic applications
January 2015
Distribution of
labelled
DLX105
around
epidermal
cells
DLX105
Keratin
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PENTRA®Body Platform
Differentiation
PENTRA®Bodies
Standard mAb
Other Antibody
Fragments/Scaffolds
25 kDa
150 kDa
< 20 kDa
~1 day
~3 weeks
~ minutes to hours
high
very low
likely high
Potency
pM
pM
nM
Affinity maturation
no
no
required
Molecular weight
Pharmacokinetics
Plasma half-life
Tissue penetration
Pharmacodynamics
January 2015
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PENTRA®Body Platform
Humanized, Highly Stable and Modular
• Sequence of human origin
• 93% identical / 96% similar to closest human germline
genes
VL
VH
• Highly stable (Tm of up to 92°C)
• Protease resistant
• Highly soluble (up to at least 90 mg/ml)
• Modular system allows rapid switching of format: scFv,
Fab, IgG, bispecifics
January 2015
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PENTRA®Body Platform
High Solubility and Stability of PENTRA®Bodies
• Optimizing the hydrophilicity increases solubility
• Optimizing the VL-VH interface increases stability
January 2015
VL blue
VH green
17
PENTRA®Body Platform
Homogenous and Monomeric
• Convenient, reliable expression in E.coli (GMP-validated)
• Well scalable
• Monomeric, homogeneous
No impurities after DSP
Monomeric in size-exclusion
Single peak in mass-spec
SDS-Page
January 2015
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PENTRA®Body Platform
Effective Tissue Penetration (Cartilage)
DLX105
Surface
Cartilage tissue
Four hours of diffusion of FITC-labeled DLX105 (26 kDa)
200 μm
or infliximab IgG (145 kDa) into ex vivo bovine cartilage at
physiological pH
Infliximab
Surface
X
Cartilage tissue
200 μm
January 2015
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PENTRA®Body Platform
Rapid Grafting of CDRs from Various Sources
VL
VH
+
PENTRA® scaffold
=
CH2
CH2
CH3
CH3
Potent binding loops (CDRs)
from novel or existing antibody
VL
VH
PENTRA®Body
The PENTRA® scaffold: flexible to design novel single-chain antibodies with
CDRs from known IgG, synthetic libraries, public sequences or other sources
January 2015
20
PENTRA®Body Platform
Platform Delivers Highest Potency in Short Time
• Recent screenings yielded monovalent, 25 kDa small PENTRA®Bodies with
very high potency in very short time, i.e., within 6-10 months:
 IL-1β: antibodies with IC50 of ≤ 0.6 - 3 pM obtained within 10 months
 TNFα: IC50 of 20 - 30 pM within 8 months
 IL-17A: IC50 of ≤ 5 pM within 6 months
• The timeline is rather dependent on the availability and robustness of a
specific cell-based assay required for screening
• Many, very different, highly potent PENTRA®Bodies against a chosen target
are obtained offering choices re. epitope-specificity
January 2015
21
PENTRA®Body Platform
Modular Platform
Bispecific
PENTRA®Bodies
PENTRA®
PENTRA®ADC
gr
gr
Toxin, cytokine,
radionuclide
Other…
IgG & Fab based
on PENTRA®
VL
VL
VH
CH1
CL
CL
CH1
VH
VH VL
CH1 CL
S-S
1.-3. generation CAR
January 2015
22
PENTRA®Body Platform
Antibody Drug Conjugates (ADCs)
• Trend to novel, smaller ADC formats with enhanced tumor penetration, e.g.:
- ADCs based on DARPins (Molecular Partners/Roche)
- ADCs based on nanobodies (Ablynx/Bayer)
• Coming: ADCs based on PENTRA®Bodies
-
Tunable potency/affinity
Small size for superior tumor penetration
Highly stable
Bivalent PENTRA®Bodies feasible, if receptor cross-linking is required for
intracellular toxin delivery
- Cloning of anti-cancer target PENTRA®Bodies started
January 2015
23
PENTRA®Body Platform
ADC Formats
Bispecific PENTRA®ADC
gr
scFv PENTRA®ADC
PENTRA®
Toxin, cytokine,
radionuclide
gr
IgG & Fab based PENTRA®ADC
= drug, toxin
enzyme, cytokine
or radioisotope
VL
VL
VH
CH1
CL
CL
CH1
VH
VH VL
CH1 CL
S-S
January 2015
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PENTRA®Body Platform
Key Asset: Delenex Site Specific Functionalization
VL
VH
HS
SH
ScFv functionalization enjoys granted US patent, with Delenex as exclusive
licensee for all fields outside ophthalmology  strongly supports ADC development
January 2015
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PENTRA®Body Platform
ADC: Summary
• ADC is an attractive area within oncology with two recent market
approvals, and pharma/large biotech companies filling their pipeline
accordingly
• Delenex PENTRA®Bodies are well-suited for ADC development
because of inherent favorable characteristics
• Site-specific functionalization of scFv antibodies recently received US
patent grant with Delenex as exclusive licensee
• Delenex has started cloning anti-cancer target PENTRA®Bodies for
ADC purposes
January 2015
26
PENTRA®Body Platform
Modular Platform
Bispecific
PENTRA®Bodies
PENTRA®
PENTRA®ADC
gr
gr
Toxin, cytokine,
radionuclide
Other…
IgG & Fab based
on PENTRA®
VL
VL
VH
CH1
CL
CL
CH1
VH
VH VL
CH1 CL
S-S
1.-3. generation CAR
January 2015
27
PENTRA®Body Platform
Bispecific Antibodies
• Allow blockade of multiple targets or multiple sites
• Alternative for combinational therapy of mAbs
 Development and approval of only one bispecific antibody compared to two individual
antibodies
• Small bispecific antibodies
 More rapid distribution and tissue penetration due to lower molecular mass (~50 kDa) has
several advantages especially in dermatology, oncology, inflammation
→ High performing PENTRA®Bodies (potency & stability) are an ideal starting
point for construction of small bispecific antibodies
Byrne, H. et al. A tale of two specificities: bispecific antibodies for therapeutic and diagnostic applications (2013)
Trends Biotechnol. 31(11):621-32
Kontermann, R. Dual targeting strategies with bispecific antibodies (2012) mABs 4(2):182-197
January 2015
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PENTRA®Body Platform
Bispecific Antibodies: Formats
Diabodies (DB)
scDB
tandem scFvs
Simple & small
Well known1,2,3
1 Robinson
et al. Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and
induces a therapeutic effect in vitro (2008) Br J Cancer 99:1415-1425
2 Hudson and Kortt. High avidity scFv multimers; diabodies and triabodies (1999) J Immunol Methods 10;231(12):177-89
3 Kipriyanov. Generation of bispecific and tandem diabodies (2009) Methods Mol Biol. 562:177-93
January 2015
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PENTRA®Body Platform
Bispecifics: Potency
Cell assays with human fibroblasts (IL-1β) and NK92 cells (IL-12)
BiPENTRA®Body
IC50 /
IC50 (parent)*
IC50 /
IC50 (parent)*
DLX2959
2.3
2.2
DLX2960
1.7
1.1
DLX2961
1.4
1.5
DLX2962
1.8
1.5
DLX2963
1.2
4.4
DLX2964
2.8
1.3
* Normalization to potency of parent scFv
→ All constructs basically preserve potency of the parental scFvs. It remains to be seen whether
the partially reduced potency in one arm of DLX2963 is a general phenomenon
January 2015
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PENTRA®Body Platform
Anti-IL-17A x Anti-TNFα
January 2015
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PENTRA®Body Platform
Anti-IL-17A x Anti-TNFα Biologics
• ABT-122 (AbbVie)
Phase II study ongoing for RA
190-200 kDa
• COVA322 (Covagen)
Entered phase Ib/IIa in 04/2014
160-170 kDa
• Eli Lilly
Pre-clinical
IgG-scFv, ~180 kDa
• DLX2907/DLX2909 (Delenex)
Pre-clinical
52 kDa
IC50: 5/33 pM (DLX2907/2909) for IL-17A and 20-30 pM for TNFa, i.e., the
potencies of the original monovalent PENTRA®Bodies are fully preserved
January 2015
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PENTRA®Body Platform
Bispecifics: Summary/Outlook
• Bispecific PENTRA®Bodies demonstrate
- lab scale expression & purification (non-optimized)
- simultaneous binding to both antigens
- about the same potency as the parent scFv (which is not trivial)
• Various bispecific PENTRA®Bodies are currently being cloned and tested
• E.g., Delenex’ anti-IL-17A x anti-TNFa bispecific PENTRA®Bodies DLX2907
/DLX2909 show the same high potency as the parental monospecific scFv
modules, i.e., about 5/33 pM and 20-30 pM, resp., neutralizing potency IC50
• Next
- animal model(s)
- nomination of targets in oncology
January 2015
33
Agenda
Summary
Introduction
PENTRA®Body Platform
Dermatology
Oncology
January 2015
34
Dermatology - DLX105 as a Proof of Concept Antibody
DLX105: the Anti-TNFa Frontrunner Drug
• DLX105 is the clinical frontrunner with an IC50 similar to infliximab and patent protection until 2028
• DLX2751 is a 10x more potent follow on drug in preclinical stage with patent protection until 2035
DLX105 tolerability and exploratory efficacy profile was tested in 3 clinical trials:
Psoriasis trial 1 - intradermal Psoriasis trial 2 - topical
• Intradermal injection of
• Topical application of
DLX105
DLX105
• Placebo-controlled,
• Placebo-controlled,
randomized intra-individual
randomized parallel group
trial with a total of 20 patients
trial with 59 patients
January 2015
Behçet disease - systemic
• Intravenous administration of
DLX105 to healthy and
Behçet disease subjects
• To explore PK and healing of
mucosal and skin signs after
a single i.v. dose of DLX105
35
Dermatology - DLX105 as a Proof of Concept Antibody
DLX105 Delivered Positive Clinical Results
Psoriasis trial 1 - intradermal Psoriasis trial 2 - topical
Behçet disease - systemic
• Intradermal injection
• Topical application of
• Intravenous
induced healing of
DLX105 induced cytokine
administration of DLX105
psoriatic plaques
mRNA improvements in
has a profound and fast
the skin, but no clinical
effect on mucosal and
• In the range of what
improvement over
skin eruptions over 2
infliximab or ustekinumab
placebo
weeks
delivered within 2 weeks
(30 to 40% PASI
improvement over
baseline)
Erythemata nodosa
in a Behçet patient
Clinical improvement of psoriasis
after intradermal DLX105
January 2015
X-fold skin mRNA changes
after topical DLX105
Substantial improvement
within 2 weeks after a
single dose of DLX105 i.v.
36
Dermatology Assets
Excellent Pipeline: Addressing Big Indications
Priority
Product (Target)
Indication (route of administration)
Core projects
DLX105 (anti-TNFα)
Hidradenitis suppurativa (s.c./topical/patch device),
Behçet disease
DLX2323/DLX2681 (anti-IL-1β)
Acne (s.c./topical)
DLX2882/3003 (anti-IL-17A)
Psoriasis (topical)
Anti-IL-4/13 bispecific
Atopic dermatitis (s.c./topical)
Anti-IL-17A/TNFα bispecific
Psoriasis (s.c./topical)
DLX1008 (anti-VEGF-A)
Kaposi sarcoma, rosacea, keloid, portwine stain
(intralesional, topical)
DLX2201 (anti-IL-12/23)
Psoriasis (topical)
DLX2751 (anti-TNFα)
Psoriasis, pyoderma gangraenosum, (s.c./topical)
Upside projects
Delenex explores devices to increase dermal exposure, in particular for hidradenitis suppurativa, and needle-free self injectors in
particular for children and adolescents with atopic dermatitis
January 2015
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Dermatology - Hidradenitis Suppurativa (HS) - DLX105 (anti-TNFα)
HS: a High Unmet Medical Need Condition
• Chronic inflammatory disease that affects apocrine-glandbearing body areas such as the axilla or the ano-genital region
• No effective treatment is available, medical need is high
• Hurley Stages I and II most often require oral antibiotic therapy
for up to 12 weeks, stage III requires surgery
• A phase 3 study with adalimumab 40 mg weekly achieved a
significantly greater response versus placebo at week 12
(41.8% versus 26%, p = 0.003) where response was defined
as an at least 50% improvement over baseline of abscesses
and inflammatory nodules (44th European Society for Dermatological Research
(ESDR) Meeting in Copenhagen, Denmark, 2014)
• DLX105 highly likely to be superior due to excellent tissue
distribution
January 2015
38
Dermatology - Psoriasis – DLX2882/3003 (anti-IL-17A)
Psoriasis: IL-17A Most Promising New Target
• Systemic use of anti-IL-17A mAbs has demonstrated extraordinary efficacy in phase 3 trials in
psoriasis
• IL-17A is produced predominantly by dermal T cells, but has its major activity on epidermal
keratinocytes
• Topical DLX2882/3003 (IC50 < 10 pM) is likely to inhibit IL-17A bioactivity in the epidermis
N Engl J Med 2014;371:326-38.
January 2015
39
Dermatology - Acne - DLX2323 (anti-IL-1β)
Acne: Femtomolar Antibody To IL-1β
biological activity
• Prevalence for severe acne is 1%
• Very little innovation in acne over
decades
• IL-1β has been validated as the
inflammatory marker in acne
• PENTRA®Bodies targeting IL-1β are
best in class with femtomolar
neutralizing activity
January 2015
Antibody
IC50 (pM)
Ilaris®
37.5 ± 11.0
DLX2323
3.0 ± 1.05
DLX2681
0.6 ± 0.42
Patient with PAPAlike syndrome
(pyogenic sterile
arthritis, pyoderma
gangrenosum and
acne) before (left)
and after 3 injections
of canakinumab
(Day 90); from JAMA
Dermatol 2013; 149:
209
Mouse P.acnesinduced ear swelling
is inhibited by IL-1β
but not by TNFα
inhibition (Kistowska
et al., JID 2014,
134:677)
40
Dermatology
Summary and Outlook
• Delenex has a unique, proprietary and validated platform to generate
PENTRA®Bodies which
-
are highly variable in CDR sequences targeting different epitopes
are highly stable and soluble
have excellent affinity/potency in the low picomolar to high femtomolar range
• Delenex is a clinical stage company
- DLX105 (anti-TNFα) in phase 1/2 by Delenex in psoriasis and Behçet disease
• These PENTRA®Bodies are particularly suited for conditions where
-
a flaring condition requires quick systemic medical intervention
a chronic condition requires long topical/local exposure
• Delenex is currently focusing on the further development of
-
DLX105 for hidradenitis suppurativa and DLX2323 for acne
anti-IL-17A for psoriasis and anti-IL-4/13 for atopic dermatitis
January 2015
41
Agenda
Summary
Introduction
PENTRA®Body Platform
Dermatology
Oncology
January 2015
42
Oncology
Advancing the Standard of Care (1/2)
Why PENTRA®Bodies in oncology?
• 25 kDa PENTRA®Bodies efficiently penetrate and distribute into tissues
• The PENTRA®Body technology offers a tool box with:
- a wide range of potencies (down to femtomolar IC50)
- high antibody sequence variability, enabling choice of epitope
- diverse formats attractive for cancer immunotherapy (multispecific, ADC,
immunoconjugates)
• PENTRA®Bodies allow flexible and controllable patient exposure to the therapy
• PENTRA®Bodies are clinically validated
January 2015
43
Oncology
Advancing the Standard of Care (2/2)
Inhibiting angiogenesis with 27 pM DLX1008
• The monovalent scFv DLX1008 displays very high affinities to human (27 pM) and mouse
VEGF-A (21 pM) facilitating more rapid drug development
• GMP production of DLX1008 is initiated, the Master Cell Bank is available
• Delenex is developing DLX1008 for oncology, with a focus on Kaposi's sarcoma and
glioblastoma
Expanding our oncology portfolio
• Targeting cytokine and immune check-points with bispecific PENTRA®Bodies
• Overcome drug resistance with bispecific PENTRA®Bodies
• Cell-based therapy with PENTRA®Body guided subsets of T cells
January 2015
44
Oncology
Summary and Outlook
• Our proprietary and clinically validated PENTRA®Bodies offer novel therapy options
in oncology
• DLX1008, a highly potent 25 kDa anti-VEGF-A PENTRA®Body, is in pre-clinical
oncology studies
• Master Cell Bank for GMP production of DLX1008 is available
• We plan to expand our oncology pipeline with several innovative programs applying
DLX1008, new bispecific antibody fusions as well as T cell-based approaches,
profiting from the clearly differentiating characteristics of our PENTRA®Bodies
January 2015
45