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Dompé R&D Pipeline

BioEurope 2012

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1880 1920 1940 1976

Onorato Dompé founded “Farmacie Inglesi”,

pharmacies adopting the English standard

Sergio Dompé joined his father and fostered the company’s fast growth

Franco Dompé established Dompé

farmaceutici in Milan

Gian Antonio Dompé opened the first

pharmacy in Milan

Dompé A name of great tradition within the Italian pharmaceutical industry

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Dompé A fully integrated biopharmaceutical company

Dompé Group at a glance: • 2011 revenues of $500 million • 10% of revenues invested in R&D • 600 employees • 100 dedicated to R&D

Successful partnership and joint ventures with leading biopharmaceutical companies

Committed to innovative therapies with deep&robust R&D pipeline • Rare diseases, oncology, personalized medicine and ophthalmology

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Dompé Focus on building a fast growing biotech company…

2012

2009

2004 Biotech Plant GMP

1993 Manufacturing and R&D site

set up in Italy

1998 Biotech Plant set up in Italy

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Innovation as a strategic imperative

Breakthrough innovation

Incremental innovation

• Innovative programs for high unmet medical need up to Marketing Authorization

• Highly innovative programs in Specialties, oncology field, feeded by scientific partnerships and business alliances

• Lyfe cycle management driven by Technological R&D:

– Primary Care business

– Specialties business

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Innovation forged by distinctive competences

Bio and Chemoinformatic Platform for Drug

Discovery

Biotech Development of therapeutic

recombinant proteins

• A proprietary technology for the rational design of novrl GPCR allosteric modulators

– GPCRBaseTM

– LigandBaseTM

– LigenTM

• Strong expertise in development of antibody fragments, fusion proteins and growth factors

• Distinctive skills in folding and characterization of complex 3D structures

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Source: R&D Department data

... with deep and robust pipeline...

Area Discovery Preclinical Phase I Phase II Phase III

Diabetes

Reparixin - Pancreatic islet b-cell transplant (Rare) – Allogenic setting

Reparixin - Pancreatic islet b-cell transplant (Rare) – Autologous setting (pilot trial)

Ladarixin - Onset Type 1 Diabetes (Rare)

Ophthalmology

rhNGF - Neurotrophic Keratitis (Rare)

rhNGF - Retinitis Pigmentosa

rhNGF - NAION (Rare)

Oncology

Lutathera - Gastro-pancreatic tumors (GEP-NETs)

Darleukin - Metastatic Melanoma

Reparixin - Breast cancer

CXCR1/2 Inhibitors - Bladder, prostate cancer

FabOvar - Ovarian cancer

Inflammation

Dekavil - Rheumatoid Arthritis

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...forged by growing investment in R&D

Source: R&D Department data

R&

D K

ey M

ilesto

nes

Compoun

d Condition 2012 2013 2014 2015 2016 2017 2018 2019

Dia

bete

s

Reparixin Pancreatic

islet Tx

• Phase 3

• Allogenic

• ODD

EU/US

• IND FDA

• Phase 3

• Autologous

start

• EMA

Approval

• Allogenic

• FDA

Approval

• Auto-

logous

Ladarixin Onset T1D • Phase 2

start

• Phase 3 start

• FDA/EM

A

approval

Op

hth

alm

olo

gy

rhNGF

NK • SA EMA • VHP Phase 2

approval • Phase 1

• Phase 2

start

• IND (US

sites

extension)

• Phase 3

start

• FDA/EM

A

approval

RP • Phase 2

start

• Phase 3

start

• FDA/EM

A

approval

On

co

log

y Reparixin Breast

cancer

• IND

• Phase 1b

Metastatic

• Phase 2

Preoperativ

e (Q4)

• Phase2

preoperativ

e

completion

(PoC)

• Phase 2

Neoa-

djuvant

• Start

• Phase 2

comple-

tion

(clinical

PoC)

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Dompé at a glance

Global supplier

Internationalization

Partnership

R&D Driven Company

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Neurotrophic Keratitis

Glaucoma Dry Eye

Molecule

Projects

Optical Neuropathies

Retinitis Pigmentosa

Anterior Segment

Innovative approaches to Ophthalmology Nerve Growth Factor roadmap

Nerve Growth Factor

Posterior Segment

rhNGF represents a breakthrough in ophthalmology: • Fast market access in the treatment of high medical need disease of the anterior segment • Unique disease modifying mechanism of action in treatment of severe posterior segment

pathologies

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Ladarixin prevents Type1 Diabetes Onset acting on the inflammatory

signal

Reparixin treatment dramatically improves graft function after transplant leading to a

rapid insulin-independence

Islet Tx Allogeneic

Type 2 Diabetes Islet Tx

Autologous

Molecule

Projects

Type 1 Diabetes Onset

Pancreas Tx

Islet Transplant

Innovative approaches to Diabetes treatment IL-8 inhibitors roadmap

Reparixin/Ladarixin

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Innovative approaches to Tumor targeting An Overall Picture

Intralesional Melanoma

Prostate Cancer Metastatic Melanoma

Molecule

Projects

Preoperative Breast Cancer

Metastatic Breast Cancer

Vascular Targeting (DarLeukin)

L19, a novel fully human Ab Fragment, selectively targets tumor vessel vehiculating cytotoxic agents

Cancer Stem Cells (Reparixin)

Reparixin selectively targets Cancer Stem Cell population in triple negative breast

cancer

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Discovery Pipeline

Hit-to-Lead Lead-to-Candidate

Pre Discovery Feasibility Hit Finding

Milestones

C5aR Antagonists (NAM) Pain Proof of Principle: mid 2010

GPR120 Agonists Diabetes Preclinical PoM: 1Q 2012

BKB1R Antagonists Neuropathic Pain

Preclinical PoC: 3Q 2011

CNR2 Agonists Neuropathic Pain Preclinical PoC: 3Q 2011

TRPV4 Ligands Pain

TGR5 Ligands Diabetes, Obesity

Validated Hit Series : 4Q 2011

Validated Hit Series : 4Q 2011

TRPM8 Blockers Pain, Urology

Proof of Principle: mid 2011

Candidate Drug

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Drug Discovery

R&D Pipeline for out licensing

R&D Pipeline for internal development

in Rare Disease Area

Dompé Drug Discovery

Platform o Pipeline valorisation in other indications

o Network extension

o Partnerships

o Sustainability

o Feeding of Q-Rare product portfolio

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• The Dompé Discovery is focused on the identification of novel drug candidates targeting high-value, validated G-Protein Coupled Receptors (GPCR) and ion channels in several areas with a specific focus on rare diseases

• Based on a proprietary Drug Discovery Platform, Dompé has built an integrated discovery tool aimed to progress promising candidates internally and through strategic alliances

• This technological approach is expected to:

design new chemical libraries targeting specific receptors;

improve the chances of finding novel drug candidates (small molecules)

for difficult targets;

enable the development of safer and more selective therapeutic agents

Drug Discovery

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Drug Discovery: The Technological Platform

GPCRBase™ • A knowledge-based system for drug discovery

• Tool for the identification of druggable GPCRs based on local homologies

LigandBase™ • An integrated framework for drug discovery

• ChemoInformatic and data mining tool for library assembly and HTS data analysis

LiGen™ • De novo design workflows of high synthetically accessible drug-like chemical libraries

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CXCR1 Binding Site Characterization

Photochemical Cross linking

Alanine Scanning

Molecular Modeling CXCR2

C5aR

Binding Site Characterization

Photochemical Cross linking

Alanine Scanning

Molecular Modeling

0

10

20

30

40

50

60

70

80

90

100

0 10-9 10-8 10-7 10-6

Reparixin (M)

Cell

mig

rati

on

(%

of

co

ntr

ol)

wt-CXCR1 V41A-CXCR1 V42A-CXCR1 I43A-CXCR1 V113A -CXCR1 Y46A -CXCR1 K99A-CXCR1 E291A-CXCR1 Endogenous CXCR4 (CXCL12)

GPCRBase™: CXCR1 - A prototype for allosteric modulation

• Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2 (PNAS 2004) • Structure-Activity Relationship of novel phenylacetic CXCR1 inhibitors (Bioorg Med Chem Lett 2009) • Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2 (J Med Chem 2007) • DF 2156A, a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor [Brit J Pharm (submitted)] • Targeting C5a: recent advances in drug discovery (Curr Med Chem 2005) •

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GPCRBase™: A common mechanism of negative modulation

Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls. Trends Pharm. Sci. 2008 Jun;29(6):280-6.

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• Identification of a subset of proteins that share the allosteric site and can be potential novel targets for the rational design

• Studies extended to the whole GPCR family

• Reliability of the results limited to the class A receptors

GPCRBase™: GPCR Allosteric Inhibition: Druggable Targets

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GPCRBase™: A Tool to Identify Homologue Binding Sites

Similarity between GPCRs even if not belonging to the same family

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Compounds Confirmed Hits Qualified Hit

Rate % Library

Focused

Targeted

Pharmacophore

based

560

810

1376

67

81

9

12.0

10.0

0.7

GPCRBase™: A Case Study - Novel BKB1R Antagonists

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Virtual Compounds (1 billion)*

Vendor Catalogues (70 millions)

Corporate Library

(250 000)

LigandBase™

Knowledge-Based Systems

HTS Data Database

Chemoinformatic tool

Virtual Screening

Targeted Libraries

LigandBase™: An Integrated Framework for Drug Discovery

* Tangible compounds by de novo design

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LigandBase™: Case Studies

TRPM8 Blockers

• 1 active chemotype (IC50 < 10 nM; first round HTS)

• 3 active chemotypes (IC50 < 100 nM; first round HTS)

• IP novelty

• High Qualified Hit Rate (first round > 7%)

• Low number of singletons (SAR embedded in the library design)

• Homology Modeling and binding site characterization (mutagenesis studies ongoing)

GPR120 Agonists

• 3 chemotypes (IC50 < 500 nM; first round HTS) with IP novelty

• High Qualified Hit Rate (second round > 20%)

• Homology Modeling and binding site characterization confirmed by mutagenesis studies

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Business Model

• Dompé strategy:

• Development of innovative solutions for unmet medical need diseases from Discovery to Market

• Strong commitment to partnerships or strategic collaborations on proprietary products/programs

in specific geographic territories

• Increasing innovation in R&D

• External growth opportunities for Development programs (emerging countries)

• Out-licensing or strategic collaborations for Discovery programs in order to leverage the potential

of the technology platform

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For any inquiries or information:

Maria Candida Cesta

R&D Project Planning & Management

Dompé S.p.A.

Via Campo di Pile - 67100 L'Aquila (Italy)

phone +39 0862 338422 | fax +39 0862 338219

email candida.cesta@dompe.it