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MRCT's Centre for Therapeutics Discovery
- 1. MRCT’s Centre for Therapeutics Discovery Dr Andy Merritt Head of Chemistry andy.merritt@tech.mrc.ac.uk 1
- 2. Forming partnerships to drive early stage scientific research to the patient ACADEMIC AND NON PROFIT Institutions PHARMACEUTICAL BIOTECHNOLOGY Markets MRC heritage established 2000 CHARITY status 140+ staff DRUG DISCOVERY 4 DRUGS On market 7 drugs in clinic SM and Ab research DIAGNOSTICS NEW Technology
- 3. 3 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.
- 4. UNMET HEALTHCARE NEEDS Forming partnerships PHARMA / BIOTECH MRCTPATIENT RESEARCH
- 5. UNMET HEALTHCARE NEEDS PATIENT COLLABORATION RESEARCH MRCT PHARMA / BIOTECH Forming partnerships
- 6. 6 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”
- 7. 7 Disease focus Strategy Balanced portfolio across disease areas Mix of Ab and SM targets Wide academic network including clinicians Highly collaborative with Academia, Pharma and Biotech Excellent 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
- 8. 8 Resources Capability Biology – 27 scientists Assay Development & Screening Compound Profiling Cellular Pharmacology Medicinal Chemistry – 23 scientists Computational Chemistry Medicinal/Synthetic Chemistry ADME Biotherapeutics – 16 scientists Antibody generation Antibody humanisation Affinity Maturation Biophysical optimisation CRO Support Specialist screening (eg. Ion Channels) Additional chemistry synthesis In vitro and in vivo ADME/PK Structural Biology Support Protein NMR and Crystallography Embedded in Leicester University (Mark Carr group)
- 9. 9 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
- 10. 10 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
- 11. 11 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)
- 12. 12 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
- 13. 13 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
- 14. 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) 14
- 15. 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 migration 10% FBS Time (hrs) %Confluency 0 20 40 60 80 100 120 0 20 40 60 80 100 LM2 WT LM2 CR3 LM2 CR14 Increasing stage of diseaseNormal Breast tissue PAICS Gene Expression: Breast Cancer CRISPR knockdown of PAICS Proliferation (72h) De novo Purine Biosynthesis PAICS ADENINE GUANINE
- 16. 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 mice Red: compound 1 Blue: 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
- 17. 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
- 18. 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). B a se lin e 1B a se lin e 2B a se lin e 3 N P 2 h r 4 h r 2 4 h r 0 .0 0 .2 0 .4 0 .6 0 .8 1 .0 E ffe c t o f M R C T -1 in m o u s e m o d e l C C I m o d e l (1 0 m g /kg i.p . n = 1 2 ) T im e p o s t-d o s e (h ) PawWithdrawlThreshold(g) ** * P < 0 .0 5 c .f. B a s lin e + P < 0 .0 5 c .f. N P ** * + + Activity in a functional in vitro GalR2 assay lo g [C o m p o u n d ] (M ) %Activity(Galanin) -1 2 -1 0 -8 -6 -4 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 M R C T -1 G a la n in Pharmacological optimisation %Activity(Galanin) -1 2 -1 0 -8 -6 -4 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 G a la n in M R C T -A M R C T -B M R C T -C M R C T -D M R C T -E M R C T -F M R C T-G M R C T-H
- 19. 19 Projects Call for Targets Alzheimer’s Research (Dementia Consortium) Arthritis Research UK MS Society Parkinson’s UK Diabetes 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/
- 20. 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 20
- 21. 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 21
- 22. 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 22
- 23. 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 23
- 24. Dementia Consortium 24 Patient need Disease experts Funding Early stage drug discovery PoC Late stage DD Development Clinical New potential AD treatments £3m PI
- 25. Project Selection Triage 25 Project Proposals Approved Projects Initial Triage Limited data Yes/No answer Full Review Due diligence Scientific rationale FTO, IP, Competition Patient need/population Route to market External Expert Review Disease experts Experimental Due diligence Repeat PI data Additional studies Analysis of reagents
- 26. 26 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
- 27. Center for Theraputics Discovery Why us? COLLABORATION PI/Pharma De-risking the target Relevance to human disease Compound library, diversity sets and pharma links Constructing a pharma quality data package Profile of compounds and antibodies Work in collaboration Assay Development Screening Medicinal chemistry Antibody Engineering Melanocortin small molecule programme LRRK2 small molecule programme Anti IL25 ligand antibody Fibrosis antibody project Academic research translation High risk drug discovery Commercialising healthcare discoveries
- 28. Dr Andy Merritt Head of Chemistry andy.merritt@tech.mrc.ac.uk 28 Questions? MRCT’s Centre for Therapeutics Discovery