David GrayThere 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

From‘Weasels’ – Elys Dolan

My experience is largely academia and large pharma

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 CalderBaron 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 withDr Paul Skett on influence of diabetes on metabolism of drugsProf Graeme Milligan on intrinsic efficacy of nucleotide analogues on activation of G proteins

Pharmacology PhD

University College London – Pharmacology

Research projects onMechanism 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 onInteraction 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 1,4,5-trisphosphate 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 1995Wellcome 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 campaignsSupported European lead optimisation campaignsMultiple 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 down-sizing

And back again? – the DDU

• Joined Drug Discovery Unit in 2010 as Head of Biology

• 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

The Drug Discovery Unit

Drug Discovery CapabilitiesTarget Selection

Validation

Druggability

Assay Feasibility

Toxicity

Resistance potential

Structural Information

in vivo models Medicinal & Computational Chemistry

Structural Biologyin vitro models

Data Management

384 MTS/HTS RoboticsCompound Sets

DMPK Target or cell screen

DDU Major Goals

Discovering drugs

(Neglected Diseases

Developing World)

Developing tool molecules to understand

fundamental biology

Discovering drugs

(Neglected Diseases

Developed World)

Improving the science of drug

discovery

Examples of Success

Clinical TrialsLead Optimisation

Candidate Selection

Fexinidazole Repurposed for leishmaniaPhase 2

NMT inhibitorsAnimal trypanosomiasisField trials on-going

Malaria drug candidate

Undergoing FTIH enabling studies with MMV

Oncology drug candidate – partnered with biopharma

LeishmaniaLate lead optimisation2 hit optimisation series with animal efficacy

Chagas’ diseaseEarly lead optimisation2 series with efficacy in acute animal model

Huntington Disease project partnered with GSK (DPAc)

Dermatology project partnered with GSK (DPAc)

Cystic Fibrosis project partnered with Pfizer

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

Developmental Pathways Funding Scheme

Acknowledgement of Funders