mrct's centre for therapeutics discovery
Post on 09-Jan-2017
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MRCT’s Centre for Therapeutics Discovery
Dr Andy MerrittHead of Chemistry
andy.merritt@tech.mrc.ac.uk
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Forming partnershipsto drive early stagescientific research
to the patient
ACADEMIC ANDNON PROFITInstitutions
PHARMACEUTICAL BIOTECHNOLOGY
Markets
MRCheritage
established2000
CHARITYstatus 140+
staff
DRUGDISCOVERY
4 DRUGSOn market
7drugs
in clinic SM and Abresearch
DIAGNOSTICS
NEWTechnology
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Early drug discovery Partner point
• Main role is to “de-risk” novel targets• Prove assays can be developed• Show starting molecules (Ab or SM) can be identified• Demonstrate target is “drug-able”• Deliver potent and selective molecules with IP
• Take to PoC in cells and/or relevant animal models• Show relevant effects in human tissues where possible• Give confidence in disease association
• Deliver quality data package supporting target validation• Reduce risks of clinical failures
MISSION - To progress promising early stage scientific discoveries and inventions into marketable products with a healthcare benefit.
UNMETHEALTHCARE
NEEDS
Forming partnerships
PHARMA / BIOTECH
MRCTPATIENT
RESEARCH
UNMETHEALTHCARE
NEEDS
PATIENT COLLABORATION
RESEARCH
MRCT
PHARMA / BIOTECH
Forming partnerships
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Centre for Therapeutics Discovery (CTD)• Small Molecule
Drug Discovery• Antibody Engineering• Antibody drug conjugates• Structural biology
Adding value Scientific development
Based in “The Accelerator Building”
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Disease focus Strategy
Balanced portfolio across disease areasMix of Ab and SM targetsWide academic network including cliniciansHighly collaborative with Academia, Pharma and BiotechExcellent project management
• High unmet medical need• Poorly served patients• Niche/orphan indications• Diseases of poverty
• Early stage, novel but high risk targets
• Focus on Target Validation• Take “validated” targets into
early stage drug discovery• Use synergies between SM
and Ab expertise
MRCT’s CTD is a centre of excellence in target validation and early drug discovery
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Resources Capability
Biology – 27 scientistsAssay Development & ScreeningCompound ProfilingCellular Pharmacology
Medicinal Chemistry – 23 scientistsComputational ChemistryMedicinal/Synthetic ChemistryADME
Biotherapeutics – 16 scientistsAntibody generationAntibody humanisationAffinity MaturationBiophysical optimisation
CRO Support Specialist screening (eg. Ion
Channels)Additional chemistry
synthesisIn vitro and in vivo ADME/PK
Structural Biology SupportProtein NMR and Crystallography
Embedded in Leicester University
(Mark Carr group)
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Early drug discovery Screening capabilities
• Mix of Academic and Pharma
• Extensive experience and wide choice of assay platforms
• 384-well format• Capacity up to 250k cpds• In-house 120k cpds• Can screen libraries from
partners
Identify high quality tools and start points for medicinal chemistry
Thousands of compounds
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Early drug discovery Medicinal chemistry
• Significant ex-Pharma experience• Over 150 years and 15+ clinical
candidates• Access to latest synthesis technology
• Additional synthesis capacity in Asia and UK (10 FTE)
• In house in vitro ADME/DMPK support• State of the art in silico design
• Supported by structural biology at Leicester University
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Early drug discovery Antibody expertise
• Over 20 years experience• Seen as a world leader in humanisation• Built on MRC’s CDR grafting technology
• Now expanding to other techniques• Can raise antibodies• Optimisation of affinity and biophysical
characteristics• Using expertise to create antibody drug
conjugates (ADCs)• Using antibodies to direct small molecule
design (A2D2)
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Drug discovery Delivering success
• 4 drugs on market
• 7 in clinical development in Pharma• 4 in pre-clinical development in Pharma
• MRCT Sustained by income stream
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Pipeline Sustaining Success
• Roughly 20 projects at any time
• 12 small molecule• 6 antibody• 2 Antibody-drug
conjugates• Overall 5-7 at late stage• Remainder at validation
stage
Examples of disease areas• Cancer• Fibrosis• Pain• Infectious diseases• Alzheimer’s Disease and CNS• Autoimmune Diseases • Cushing’s disease • Inflammation
Drug discovery Sustaining success
• Oncology– PAICS (small molecule target)– MNK1 (small molecule target)– ALK (Antibody drug conjugate)
• Inflammation and autoimmune disease– IL17BR (Antibody)– IL16 (Antibody)
• Alzheimer’s Disease– TAPAS (Antibody)
• Osteolysis and Osteoarthritis– Netrin 1 (Antibody)– Matriptase (Small molecule)
• Pain– GalR2 (Biological)
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PAICS: Potent Inhibitors of a Novel Cancer Metabolic Target
• PAICS (phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase) is a bifunctional enzyme involved in the de novo purine biosynthesis pathway
• Potential therapeutic window for targeting PAICS: rapidly dividing cancer cells are more dependent on de novo purine biosynthesis than normal cells
• PAICS mRNA is upregulated in breast and other cancers
•PAICS shRNA or CRISPR KD inhibits breast cancer cell proliferation and migration10% FBS
Time (hrs)
% C
onflu
ency
0 20 40 60 80 100 1200
20
40
60
80
100LM2 WTLM2 CR3LM2 CR14
Increasing stage of disease Normal Breast tissue
PAICS Gene Expression: Breast Cancer
CRISPR knockdown of PAICS
Proliferation (72h)
De novo Purine Biosynthesis
PAICS
ADENINE
GUANINE
Biochemical IC50 (nM)
Cell IC50 (nM)
Average LogD
Kin Sol (mM)
Mouse t1/2 (po)
Mouse Clint (mL/min/kg)
Mouse Bioavailability
(%F)
Compound 1 11.5 180 1.3 218 3.2 35.0 97*Compound 2 3.4 75 1.6 224 3.1 15.0 73
Mean plasma exposure (ng/mL) v time for po dosing (10mg/kg) in miceRed: compound 1Blue: compound 2
PAICS: Potent Inhibitors of a Novel Cancer Metabolic Target
• Compounds show good potency and good PK properties in vivo
• Key compounds are tolerated very well in mice (14 day study)
• Murine In Vivo xenograft study underway
Biochemical Biophysical Cellular
Mouse Pharmacokinetics
• Fragment screening & medicinal chemistry generated highly potent, bioactive PAICS inhibitors
Chronic nerve damage/injury induces alterations in primary sensory neurons in the dorsal root ganglion (DRG) and connections
Galanin and receptors have been implicated in pain
Peripheral GalR2 Neuropathic pain
• The galanin system (GalR2) is well validated with the regulation of nociception;– A 10-fold up-regulation in the levels of galanin in the DRG
after nerve injury– Use of GalR2 specific agonists in animal models and in
transgenic mice
GalR2-induced analgesia with MRCT molecules
• MRCT have developed a non-small molecule asset, with a preferred pharmacological profile and shown it to be active in a rodent model of Neuropathic Pain (reversal of mechanical hyperalgesia).
Baseli
ne 1
Baseli
ne 2
Baseli
ne 3 NP 2h
r4h
r24
hr0.0
0.2
0.4
0.6
0.8
1.0
Effect of MRCT-1 in mouse model CCI model(10mg/kg i.p. n=12)
Time post-dose (h)
Paw
With
draw
l Thr
esho
ld (g
)
*** P<0.05 c.f. Basline+ P<0.05 c.f. NP
***
+ +
Activity in a functional in vitro GalR2 assay
log[Compound] (M)
% A
ctiv
ity (G
alan
in)
-12 -10 -8 -6 -40
20
40
60
80
100
120
MRCT-1Galanin
Pharmacological optimisation
% A
ctiv
ity (G
alan
in)
-12 -10 -8 -6 -4
0
20
40
60
80
100
120 GalaninMRCT-AMRCT-BMRCT-CMRCT-DMRCT-EMRCT-FMRCT-GMRCT-H
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Projects Call for Targets
Alzheimer’s Research (Dementia Consortium)Arthritis Research UKMS SocietyParkinson’s UKDiabetes UK
• Access to worldwide network of academics
• Calls can be fine tuned to match Pharma interests• Disease relevance• Target class relevance
• Pharma can also propose targets they are interested in• De-risking at limited risk and
resource exposure• Links to disease focussed
charities
http://www.callfortargets.org/
Project Structure Academics
• MRCT Resources provided free of charge• PI always included in project team• Agreement provides revenue share back to PI• Sliding scale• Takes into account background IP• IP jointly owned• PI allowed to publish if project team agree• MRCT can defer publication if conflict with
commercial strategy• MRCT normally has commercialisation rights
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Benefits to Academics
• Access to drug discovery capability free of charge• No loss of control of own work• Potential to access tool compounds and Abs for
publications• Share of upside post-partnering• Possible access to industry funding downstream
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Project Structure Pharma/Biotech
Collaborations• Milestones and target profile defined up front• Partner joins project team• Partner may provide compounds and/or resources• Defined points for transfer of project to partner
Partnering• Risk sharing• Upfront, milestones and royalty
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Benefits to Pharma/Biotech
• Access to huge network of academic research• Potential to trawl network for specific solutions• Early sight of cutting edge science• De-risking early stage targets at limited risk and
resource exposure• Ability to shape project selection and direction• Access to academic expertise• Flexible deal terms
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Dementia Consortium
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Patient needDisease experts
Funding
Early stage drug discovery
PoC
Late stage DDDevelopment
Clinical
New potential AD treatments
£3m
PI
Project Selection Triage
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Project Proposals
Approved Projects
Initial TriageLimited data
Yes/No answer
Full ReviewDue diligence
Scientific rationaleFTO, IP, Competition
Patient need/populationRoute to market
External Expert Review
Disease experts
ExperimentalDue diligenceRepeat PI data
Additional studiesAnalysis of reagents
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Pharma Alliances
•Efficiencies in research, eg:• Target know-how• Assay build• Selectivity assays• Compound sets• 2o assays• In vivo models
• “Mini-portfolios” (3-5 targets)• Centred on Pharma’s interests• Focussed on a specific target
class or disease area• Find targets from MRCT
Network, Pharma suggestions and relevant experts
• Pharma engaged throughout process• Opportunity to shape
target selection and portfolio direction
Center for Theraputics DiscoveryWhy us?
COLLABORATIONPI/Pharma
De-risking the targetRelevance to human diseaseCompound library, diversity sets and pharma links
Constructing a pharma quality data packageProfile of compounds and antibodiesWork in collaboration
Assay DevelopmentScreeningMedicinal chemistryAntibody Engineering
Melanocortin small molecule programmeLRRK2 small molecule programmeAnti IL25 ligand antibodyFibrosis antibody project
Academic research translationHigh risk drug discovery
Commercialising healthcare discoveries
Dr Andy MerrittHead of Chemistry
andy.merritt@tech.mrc.ac.uk
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Questions?MRCT’s Centre for Therapeutics Discovery
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