mercachem - eelco ebbers 22092011
TRANSCRIPT
From Chemistry
to Drug Candidates
Agenda
1
• Introduction of Mercachem
• Drug Discovery & trends
• Development of services of Mercachem
• Project examples
Facts and figures
Innovative Netherlands-based chemistry service provider in
discovery chemistry, medicinal chemistry and process research
One of the leading CRO’s in Europe
110 employees (45% Ph.D. and 55% M.Sc./B.Sc.)
Spin-out of University of Nijmegen
Founded in 1997
Facts and figures
4,000 m2 modern research facilities with 10 synthesis
laboratories (120 fume hoods)
Moved to a new state-of-the-art laboratory facility in 2006
Located in Nijmegen (2 sites)
Independent, privately owned
Services
Exclusive
- Discovery chemistry services
- Medicinal chemistry services
- Process research & development services
to support research and development programs of companies and research institutes worldwide
Regions:
- Europe
- US
- Japan
Markets
Pharmaceuticals (~70%)
Agrochemicals (~10 %)
Animal Health (~5%)
Flavors and fragrances (~5%)
Speciality chemicals (~5%)
• cosmetics
• monomers
• diagnostics
Research organizations (~5%)
Drug Discovery
Definition: process by which drugs are discovered and/or designed Process: • Identification & validation of target & candidates • Synthesis, optimization & characterization • Screening and assays for therapeutic efficacy • Drug development • Clinical trials Despite advances in technology and understanding of biology drug discovery is still: • Lengthy, expensive, difficult, and inefficient process • Low rate of new therapeutic discovery Currently: Research and development cost of each NME: ~ US$1.8 billion
Drug Discovery pipeline
8
Costs (m$) (Out of pocket)
Costs (m$) (capitalized)
Drug Discovery pipeline
Mercachem
UMC UMC
Synthon
Former Organon
Trends in pharmaceutical research
10
Mergers and acquisitions at big pharma (Organon, Schering-Plough, MSD) R&D is moving from big to medium to small specialized companies Outsourcing of R&D is increasing - Total value: 15-24 billion$ - Increase: 10-20% per year Increasing parts of drug discovery are being outsourced Virtual pharma Open innovation
Outsourcing
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Reasons:
• Focus on primary activities
• Expertise
• New methodologies / technologies
• Cost effective
• Fasten product development (time to market)
• Capacity & Quality
Development of Services Phase 0: Start
12
Start of Mercachem • Two founders with PhD in Organic Chemistry
• Market trend for outsourcing and specialized companies
• Market niche for chemistry outsourcing
• Business plan, financing
• Start (1997)
Characteristics:
• Independent
• Professional
• Pragmatic
• Product & services according to market needs
• Compete on quality and innovation
Development of Services Phase 1: discovery chemistry
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Market trends (1996-2001):
• Outsourcing of small parts of drug discovery
• Outsourcing of non-IP projects
• Limited outsourcing of biology
• Pharma company in charge & initiates projects
Development of Services Phase 1: discovery chemistry
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Discovery Chemistry Services:
Lab-scale synthesis of:
• Research compounds
• Scaffolds and building blocks
• Reference compounds and metabolites
• Synthesis of compound libraries
• Development of novel chemistries
Project Goals:
• Preparation of (new) molecules for testing
• Method of preparation is not important
Drug Discovery pipeline
Discovery chemistry
Development of Services Phase 2: Process R&D services
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Market trends (2002-2005):
• Outsourcing of bigger parts of drug discovery
• Outsourcing of more IP sensitive projects
• Increasing outsourcing of biology
• Pharma company in charge & initiates projects
• Upcoming competition from low-cost countries
• Decreasing nr of new drugs entering the market
• Patent cliffs
• Mergers & acquisitions (M&A)
• Increasing need for innovation
Development of Services Phase 2: Process R&D services
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Process Research Services:
• Route development and route scouting
• Process optimization and catalyst screening
• Scale-up and small bulk supply
(~1 kg, non-GMP)
Project Goals:
• Candidate or lead molecule is known
• Development and optimization of
method of preparation
• Method development & Scale-up for
material supply regarding clinical studies (GMP)
Drug Discovery pipeline
Discovery chemistry
Process R&D
Development of Services Phase 3: Medicinal Chemistry services
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Market trends (2006-2011):
• Outsourcing of complete drug discovery projects
• Outsourcing of IP sensitive projects
• Both pharma company and CRO in charge
• Both pharma company and CRO initiates projects
• Increasing competition from low-cost countries
• Increasing M&A
Development of Services Phase 3: Medicinal Chemistry services
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Medicinal Chemistry Services:
• Hit Finding , Hit optimization
• Hit-to-Lead
• Lead Optimization
• ADME
Project Goals:
• Design of molecules based on target information
• Preparation and optimization of molecules with the right
properties
• Screening compounds against their properties
• Combination of chemistry and biology
Drug Discovery pipeline
Discovery chemistry
Medicinal chemistry
Process R&D
Integrated services
Target
identification
Assay
development
Hit
finding
Lead
optimization
Preclinical
development
IND filing Phase 1
Knowledge
management
• Discovery Chemistry
Skilled chemists
Facilities/Equipment
• Medicinal Chemistry
• Process chemistry
Mercachem’s strengths
Unprecedented knowledge solving synthetic challenges by
team of experienced chemists and knowledge management
Creative and independent thinking complimentary to customer
knowhow
Strong communication skills and proactive attitude when
project requires
Reliability reaching success with respect to quality and time
High impact and high productivity due to combination of
creativity, proactivity and effective infrastructure
Performance in 2010
Number of active customers : > 60
Number of projects : 205
Number of compounds synthesized : ~ 4,500
Delivery rate : 98%
Patents and publications
Patents and publications:
• WO2009007098 (Syngenta)
• WO2009003650 (Bayer CropScience)
• WO2005019208 (Grünenthal)
• WO2004016581, WO2004074266 and WO2005028479 (Janssen)
• WO2003171374 (Johnson & Johnson)
• Synth. Comm., 2011, 41, 3246 (Janssen)
• Biorg. Med. Chem. Lett., 2010, 20, 4350 (MSD Newhouse)
• Eur. J. Org. Chem, 2010, 15, 2852 (Janssen)
• Tet. Lett., 2010, 51, 543 (Janssen)
• Synth. Comm., 2006, 36, 365 (Esperion)
• Biorg. Med. Chem., 2005, 13, 223 (Esperion)
Multidisciplinary Integration
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Partnerships: ZoBio Leiden FBLG, NMR, Biacore Proqinase Freiburg Cancer pharmacology Vichem Budapest Kinase Inhibitor Library Life Science Park Oss Screening Facilities (HTS, uHTS) 100.000 Library
Project Example: Reverse Transcriptase inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s) anti HIV-drugs Collaboration between Janssen Research Foundation and Mercachem In silico design New molecules designed by molecular modeling. X-ray crystallography of HIV reversed transcriptase complexed with key analogues Result: DAPY (DiArylPYrimidine) compounds
Project Example: Reverse Transcriptase inhibitors
Project Development & synthesis of 2nd generation DAPY compounds Results • 2 years of synthesis with a team of 3 chemists • 280 compounds synthesized • Several patents and publications (novel routes & compounds)
References
1. R. Leenders et al. Tetrahedron Lett. 2010, 51, 543 (patent: U.S. 7276510, 2007)
2. R. Leenders et al. Synth. Comm. 2010, accepted for publication (patent: WO 2005/028479)
3. R. Leenders et al. Eur. J. Org. Chem. 2010, 2852 (patent: WO2004/074266)
4. P. Janssen et al. J. Med. Chem. 2005, 48, 1901 (review)
Project Example: Dr. August Wolff – Mercachem collaboration in Medicinal chemistry
Dr. August Wolff Arzneimittel GmbH & Co. KG and Mercachem BV start two drug development collaborations
Bielefeld, Germany & Nijmegen, the Netherlands – August 26, 2010. Dr. August Wolff GmbH & Co. KG Arzneimittel and Mercachem have started two multi-year drug development collaborations.
Dr. August Wolff GmbH & Co. KG Arzneimittel have licensed a number of patents from universities that cover novel classes of molecules with potential use in dermatology. Mercachem is responsible for medicinal chemistry and project management with the goal to further improve the properties of these molecules and to develop them into clinical candidates.
Project Example: PDE inhibitors for Neglected Tropical Diseases
Project T4-302: PDE inhibitors for Neglected Tropical Diseases
Focus: African Sleeping Sickness Parasitic Disease (Trypanosome brucei) 100% fatal if untreated 50 million people at risk Present Medication: A disgrace of modern pharmaceutical sciences old and toxic (~10% patients die from side effects), painful, resistance
Aim of T4-302: A PDE (PhosphoDiEsterase) inhibitor as novel and well tolerated medication for the African sleeping sickness
Lead compound
PDE
Project Example: PDE inhibitors for Neglected Tropical Diseases
Project T4-302: PDE inhibitors for Neglected Tropical Diseases
Mercachem: • participates in TIPharma (Top Institute Pharma) • project management, synthesis, SAR, medicinal chemistry
PARTNERS IN CONSORTIUM • Mercachem, Nijmegen NL • Nycomed Pharma, Zurich CH • Top Institute Pharma • Vrije Universiteit, Amsterdam NL • University of Berne, CH • IOTA pharmaceuticals, Cambridge UK • Drugs for Neglected Disease initiative, Geneva CH • Koninklijk instituut van de Tropen, Amsterdam NL
Project Example: PDE inhibitors for Neglected Tropical Diseases Volkskrant 13-09-2011
