Transcript From animal vaccines to human cancers

David Gray
There and back again
Eastbio June 2015
Caveat
This is a very personal view and does not
necessarily reflect the views of employers,
friends, colleagues or family members past
and present
My experience is
largely academia
and large pharma
From
‘Weasels’ – Elys Dolan
Overview
• Why I became a pharmacologist
– ‘There were two Scotsmen……’
• PhD – academia/industry
• Post-Doc – blue skies research
• Going ‘there’ - joining industry
• Back to academia?
• What I have learned along the way
Ritchie Calder
Peter Ritchie Calder
Baron Ritchie-Calder of Balmashanner
Born Forfar – died in Edinburgh
Scottish socialist, pacifist, journalist and
academic
First write up of structure of DNA in press
Wikipaedia
Iain Gray
Iain Allan Gray
Born Glasgow
Scottish anarchist, entrepreneur and
physicist
Severe childhood asthmatic
Why I became a pharmacologist
I wanted to involved in making a ‘lifesaver’
…and preferably in asthma
Pharmacology Undergraduate
University of Glasgow – Pharmacology honours
Research projects with
Dr Paul Skett on influence of diabetes on metabolism of drugs
Prof Graeme Milligan on intrinsic efficacy of nucleotide analogues on
activation of G proteins
Pharmacology PhD
University College London – Pharmacology
Research projects on
Mechanism of action of CGRP in cardiovascular system
Celltech were looking to achieve orphan drug status for CGRP for wound
healing
Pharmacology PhD
• 5 publications
• Exposure to trials and tribulations of drug discovery
• Amazing clinical effects on skin graft resurrection
• Never published
• Wow moment
• Totally unpredicted results of control molecules based on dogma
Wisskirchen FM. Gray DW. Marshall I. Receptors mediating CGRP-induced relaxation in the rat isolated thoracic aorta and porcine isolated
coronary artery differentiated by h alpha CGRP(8-37). British Journal of Pharmacology. 128(2):283-292, (1999)
Gray DW. Marshall I. Novel signal transduction pathway mediating endothelium-dependent beta-adrenoceptor vasorelaxation in rat thoracic
aorta. British Journal of Pharmacology. 107(3):684-90, (1992)
Gray DW. Marshall I. Human alpha-calcitonin gene-related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat
thoracic aorta by releasing nitric oxide. British Journal of Pharmacology. 107(3):691-6, (1992)
Gray DW. Marshall I. A pharmacological profile of the endothelium-derived relaxant factor released by calcitonin gene-related peptide in rat
aorta. Annals of the New York Academy of Sciences. 657:517-8, (1992)
Gray DW. Marshall I. Nitric oxide synthesis inhibitors attenuate calcitonin gene-related peptide endothelium-dependent vasorelaxation in rat
aorta. European Journal of Pharmacology. 212(1):37-42, (1992)
Post-doc
University of Leicester – Pharmacology
Research projects on
Interaction between ionotropic and metabotropic glutamate receptors
Post-doc
• 4 publications plus contribution to textbook
Gray DW. Whitham EM. Challiss RA. Nahorski SR. Muscarinic cholinoceptor-stimulated synthesis and degradation of inositol 1,4,5trisphosphate in the rat cerebellar granule cell. Journal of Neurochemistry. 64(3):1143-51, (1995)
Challiss RA. &. Gray DW. Vascular smooth muscle contraction; second messenger systems. Textbook of Hypertension (Ed. JD Swales)
Blackwell Scientific Publications, Oxford
Gray DW. Challiss RA. Nahorski SR. Differential effects of lithium on muscarinic cholinoceptor-stimulated CMP-phosphatidate accumulation in
cerebellar granule cells, CHO-M3 cells, and SH-SY5Y neuroblastoma cells. Journal of Neurochemistry. 63(4):1354-60, (1994)
Challiss RA. Mistry R. Gray DW. Nahorski SR. Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic
glutamate receptor agonist 1S,3R-ACPD in neonatal rat cerebral cortex. British Journal of Pharmacology. 112(1):231-9, (1994)
Challis RA. Mistry R. Gray DW. Nahorski SR. Modulation of muscarinic cholinoceptor-stimulated inositol 1,4,5-trisphosphate accumulation by
N-methyl-D-aspartate in neonatal rat cerebral cortex. Neuropharmacology. 33(1):15-25, (1994)
Academia – phase 1
• I greatly enjoyed working for my PhD
– Excellent supervisor
– Interaction with pharma
– Range of techniques
– Wow moments
– Direct relevance of research to patients
• I did not enjoy working as a postdoc nearly as
much
– Excellent supervisor
– Interaction with pharma
– Range of techniques
– Wow moments
– Direct relevance of research to patients
Going ‘There’ - Into Industry
Joined Wellcome in February 1995
Wellcome bought by Glaxo 1 week later…..
Worked in lab which Sir James Black had led – learned more in vitro
pharmacology as applied to drug discovery than at any other time
Initial contrasts
• Very few people cared whether you had a
PhD or not – what had you done in the last
2-3 years was most important
• The environment was fluid – scientists who
initiated or drove projects were recognised
• Working across disciplines was very
rewarding
• Most drug discovery projects fail – so
scientists generally critically assessed
datasets more rigorously
• I got to see projects from initiation all the
way to naming of drugs post clinical trials
• They paid a bit more
15 years in industry
Director – Screening & Compound Profiling
~1/3rd of GSK’s global hit discovery campaigns
Supported European lead optimisation campaigns
Multiple enzyme, receptor and phenotypic projects
Senior Biologist and Project Leader on asthma early
stage and late stage drug discovery projects
Achievements
• Breo ellipta in active use in
asthma and COPD patients
(worked on both components)
• Veramyst on the market for
allergic rhinitis
• GW559090 clinical candidate –
failed in phase 2 POC
• Firategrast in phase 2 for
multiple sclerosis
Changing contrasts
• Marked investment in people – managerial
training, coaching, legal framework
background, lean-sigma techniques etc
• Drug discovery became process obsessed
– Fragmentation and silos
– No overview (or understanding) of
where projects had come from or where
they went
– Loss of scientific thought
• Industry struggling to maintain an
investable way of working – lots of downsizing
And back again? – the DDU
• Joined Drug Discovery Unit in 2010 as
Head of Biology
The Drug Discovery Unit
• A “Biotech company” within a university
– But with better equipment and facilities
– Current funding streams - >£27 million
– Biopharma industry drug discovery experienced team
– >95 people with >600 years experience in BioPharma
– From companies including – AstraZeneca, Merck (MSD), GSK, Pfizer, Astex
• Combines excellence in basic science with biopharma industry expertise
• Complements the pharmaceutical industry
– Diseases of the Developing World (tropical & orphan)
– Identify new approaches for tackling major diseases
Drug Discovery Capabilities
Target Selection
Validation
Druggability
Assay Feasibility
Toxicity
Compound Sets
Resistance potential
Structural Information
DMPK
in vivo models
384 MTS/HTS Robotics
in vitro models
Structural Biology
Medicinal & Computational Chemistry
Target or cell screen
Data Management
DDU Major Goals
Discovering drugs
(Neglected Diseases
Developing World)
Developing tool
molecules to
understand
fundamental biology
Improving the
science of drug
discovery
Discovering drugs
(Neglected Diseases
Developed World)
Examples of Success
Lead
Optimisation
Leishmania
Late lead optimisation
2 hit optimisation series with
animal efficacy
Candidate
Selection
Malaria drug candidate
Undergoing FTIH
enabling studies with
MMV
Chagas’ disease
Early lead optimisation
2 series with efficacy in
acute animal model
Cystic Fibrosis project
partnered with Pfizer
Fexinidazole
Repurposed for
leishmania
Phase 2
NMT inhibitors
Animal trypanosomiasis
Field trials on-going
Huntington Disease project
partnered with GSK (DPAc)
Dermatology project
partnered with GSK (DPAc)
Clinical Trials
Oncology drug
candidate – partnered
with biopharma
What have I learned
• Academic and industrial organisations value
doers and shapers – there are always good
reasons for not starting something
• Money for research can be as difficult (or
easy) to come by in both arenas
• Ultimately the opportunities exist in both
arenas, both contribute to society and both
can be immensely satisfying
• Different people have different things that
are important to them – this shapes the
Wow! Moments that make a science career
so much fun
• The clear differences between academia and
industry that I saw at the start of my career
are now blurred
Roosevelt quotes
Thanks
Family, friends, colleagues, teachers (of all
forms), two excellent academic supervisors and
two excellent research organisations
Acknowledgement of Funders
Developmental Pathways
Funding Scheme