Improving Neuroscience Drug Discovery through the Application of Human Molecular Imaging
Submitting Institution
Imperial College LondonUnit of Assessment
Psychology, Psychiatry and NeuroscienceSummary Impact Type
TechnologicalResearch Subject Area(s)
Physical Sciences: Other Physical Sciences
Information and Computing Sciences: Artificial Intelligence and Image Processing
Medical and Health Sciences: Neurosciences
Summary of the impact
Scientists in the MRC Cyclotron Unit within Imperial College pioneered
quantitative Molecular Imaging methods for neuroscience drug development
that have since been expanded through collaboration between Imperial and
GlaxoSmithKline (GSK) scientists. Human Molecular Imaging has had
significant commercial impact with adoption by the major pharmaceutical
companies to reduce the risks and costs associated with early drug
development. This led directly to the selection of the Imperial
Hammersmith Hospital site for the world's first clinical imaging centre
embedded in a pharmaceutical company. New GSK investment created new and
highly skilled UK employment opportunities first at this GSK Clinical
Imaging Centre (CIC) and then Imanova, Ltd., a specialised imaging CRO
that was "spun out" from the CIC. Outcomes from studies commissioned by
GSK in the CIC and later in Imanova have directly influenced GSK clinical
development planning, strategy and drug candidate progression. More
recently, outcomes from Imanova are influencing clinical development
decisions of other pharmaceutical organisations in similar ways.
Underpinning research
Key Imperial College London researchers:
Professor Paul Matthews, Professor of Clinical Neuroscience (2006-
present)
Professor David Brooks, Professor of Neurology (1993-present)
Professor Adriaan Lammertsma, Professor of Medical Physics (1993-1996)
Professor Vin Cunningham, Professor of Imaging (1993-2004)
Professor Terry Jones, Professor of Medical Physics (1993-2001)
Professor Roger Gunn, Professor of Molecular NeuroImaging (1996-present)
Professor Karl Friston, Professor of Neuroscience (1993-1994)
The Medical Research Council Cyclotron Unit (MRC CU, 1955-2011) situated
at Hammersmith Hospital, London, enjoyed sustained MRC funding for its
continued, pioneering contributions to positron emission tomography (PET)
radiochemistry and methodology and became one of the largest and most
comprehensive research PET centres in the world (1). It was one of the
limited number of centres globally that developed a general [11C]
labelling capacity for small molecules generated as part of medicinal
chemistry efforts. With the use of appropriate analytical approaches,
imaging of such [11C]-labelled molecules could be used to assess their
blood brain barrier (BBB) penetration to test whether they can reach
pharmacological targets in the brain. This information allows confident
decision-making about a major risk to later failure in clinical
development of drugs for central nervous system disease. These studies
were further enhanced by the development at Imperial of specific
radioligands which allowed for the assessment, not simply of BBB
penetration, but also of level of drug-target engagement at differing
doses and administration regimes through PET occupancy studies (2) (e.g.
the first 5HT1A receptor imaging agent, which was later applied to
evaluation of GSK163090.
Advances in quantitative image and tracer kinetic analyses by Professors
Cunningham, Lammertsma and Gunn with reference tissue approaches enabled
quantification of drug-target interactions in the brain without the need
to arterial cannulate subjects. This contributes substantially to their
feasibility of use in clinical applications. Tissue reference-based image
quantitation (3) has become routinely applied in pharmacological studies
since then. Professor Friston's pioneering development of Statistical
Parametric Mapping techniques during his years at the Hammersmith (4)
supports anatomically accurate regional assessment of radioligand signal
in the brain, a critical step in accurate signal quantitation for any
regionally variable target. These analytical advances have all been
combined into a standard molecular imaging analysis workflow that is
applied routinely for the analysis of drug development molecular imaging
studies across most centres conducting this work world-wide.
Professor Brooks and his colleagues have been international leaders for
the validation of the use of dopaminergic and amyloid molecular imaging
agents to support the diagnosis of Parkinson's Disease and Alzheimer's
disease, molecular imaging supported tests of efficacy of putative
neuroprotective agents in industry and international academic led clinical
trials, and rational approaches to clinical management based on them (5,
6). This science has provided a foundation for commercialisation of
DaTSCAN™, which is now licenced for differentiating benign tremor from
Parkinson's Disease, and for Amyvid™ for detecting beta amyloid, a risk
factor for Alzheimer's disease.
Professor Matthews jointly lead imaging investigative medicine research
and training at Imperial while directly supporting GlaxoSmithKline's
research as founding Head of their Clinical Imaging Centre (CIC). During
the period that he led the CIC before its "spin out", Professor Matthews
and Professor Gunn, with their teams involving both Imperial and GSK
staff, validated several novel tracers (e.g. 5HT4, 5HT6, Histamine H3,
GlyT1, PDE10) that were subsequently applied to therapeutics development
decision-making in the neurosciences in GSK and, in some cases, in other
contexts since.
References to the research
(1) T Jones and E A Rabiner (2012) The development, past achievements and
future directions of brain PET. A. J Cereb Blood Flow and Metab
32, 1426-1454. DOI
(Background review)
(2) Rabiner, E.A., Beaver, J., Makwana, A., Searle, G., Long, C., Nathan,
P.J., Newbould, R.D., Howard, J., Miller, S.R., Bush, M.A., Hill, S.,
Reiley, R., Passchier, J., Gunn, R.N., Matthews, P.M., Bullmore, E.T.
(2011). Molecular and functional neuroimaging of human opioid receptor
pharmacology. Molecular Psychiatry, 16, 785. DOI.
Journal Impact Factor: 14.89
(3) Gunn, R.N., Lammertsma, A.A., Hume, S.P., Cunningham, V.J. (1997).
Parametric imaging of ligand-receptor binding in PET using a simplified
reference region model. Neuroimage, 6 (4), 279-287. DOI.
Times cited: 492 (as at 7th November 2013 on ISI Web of
Science). Journal Impact Factor: 6.25
(4) Friston, K.J., Holmes, A.P., Worsley, K.J., Poline, J.-P., Frith,
C.D., Frackowiak, R.S.J. (1994). Statistical parametric maps in functional
imaging: A general linear approach. Human Brain Mapping, 2 (4),
189-210. DOI. Times
cited: 6929 (as at 7th November 2013). Journal Impact Factor:
6.87
(5) Rinne, J.O., Brooks, D.J., Rossor, M.N., Fox, N.C., Bullock, R.,
Klunk, W.E., Mathis, C.A., Blennow, K., Barakos, J., Okello, A.A.,
Rodriguez Martinez de Liano, S., Liu, E., Koller, M., Gregg, K.M., Schenk,
D., Black, R., Grundman, M. (2010). 11C-PiB PET assessment of change in
fibrillar amyloid-beta load in patients with Alzheimer's disease treated
with bapineuzumab: a phase 2, double-blind, placebo-controlled,
ascending-dose study. Lancet Neurol, 9 (4), 363-372. DOI.
Times cited: 199 (as at 7th November 2013 on ISI Web of
Science). Journal Impact Factor: 23.91
(6) Piccini, P., Brooks, D.J., Björklund, A., Gunn, R.N., Grasby, P.M.,
Rimoldi, O., Brundin, P., Hagell, P., Rehncrona, S., Widner, H., Lindvall,
O. (1999). Dopamine release from nigral transplants visualized in vivo in
a Parkinson's patient. Nat Neurosci, 2 (12),1137-1140. DOI.
Times cited: 386 (as at 7th November 2013 on ISI Web of
Science). Journal Impact Factor: 15.25
Details of the impact
Impacts include: commercial
Main beneficiaries include: industry
Research undertaken at Imperial's Hammersmith Hospital site in PET
radiochemistry and imaging analysis that enabled radiolabelling,
quantitative analysis and interpretation of the behaviour of small
molecules in man was a major contributor to making applications of PET
imaging to drug development possible. Quantitative in vivo
assessment in man of whether a putative central nervous system (CNS) drug
penetrates the blood brain barrier and interacts with its intended target
at the right concentration has been uniquely important for neuroscience
drug development because it removes a major risk of failure for molecules
progressed. Pharmaceutical companies have extended applications to
preclinical studies for early candidate molecule selection, limiting the
need to take molecules without likely efficacy into human experiments. The
high impact of the approach arises because a single study can provide
fundamental "Go/No Go" criteria for an entire development effort. For
example, if CNS penetration is needed for target access and a PET study
fails to demonstrate significant entry of the radiotagged drug candidate
and/or significant engagement of the CNS target, development can be
discontinued without further investment, saving costs and time from what
would otherwise be a failure in Phase II and limiting exposure of subjects
to a molecule that cannot be expected to have any of the desired
pharmacological benefit [1]. If target engagement can be assessed, it
enables rationale selection of potentially effective doses by defining its
relationship to plasma concentration of the drug directly. This, in turn,
reduces the range of doses that need to be explored in Phase II studies,
limiting exposure of patients to doses without efficacy and trial costs
and duration. For example, a single, small Phase I imaging study with the
histamine H3 antagonist GSK239512 (using a novel H3 receptor tracer
developed by GSK and Imperial scientists in the CIC) confirmed that the
compound entered the brain and bound to its target histamine H3 receptor.
Unexpectedly, it also demonstrated that the compound had an order of
magnitude higher affinity (and therefore target occupancy) in man
then predicted from preclinical data (ClinicalTrials.gov
Identifier: NCT00474513), enabling lower dosing in subsequent Phase
II trials that avoided adverse events while achieving the desired
pharmacological effect (ClinicalTrials.gov Identifier:NCT01009255
& NCT01772199).
Over 14 CNS assets under commercial development were characterised in
humans with biodistribution and target-occupancy studies during the period
2007-2013 at the GSK Clinical Imaging Centre/Imanova in conjunction with
Imperial [2]. This work has influenced the global drug development of
international pharmaceutical companies such as GSK [2]. The Senior
Director and Head, Global Imaging Unit GSK, confirmed that "The
quantitative molecular imaging data derived for these assets early in
Phase I/II studies has had significant impact on identifying the right
molecules and designing later phase studies at the right clinical doses
with the inevitable reduction in development timelines and costs...only a
few sites in the world have the capabilities to do these. The GSK Imaging
Centre and now Imanova with the backup of key Imperial staff ... provide a
"partner of choice" for GSK..." [2].
Reach has extended beyond GSK and the Imperial site. Other major
pharmaceutical companies in the UK and abroad have adopted the
methodologies for "in house" or outsourced programmes. They also have been
used for quantitative pharmacodynamics outcomes in several Phase II
studies, e.g., for bapineuzimab (see reseach reference 5), a beta-amyloid
sequestering antibody, and other Alzheimer's disease agents in early
evaluation [3], as a pharmacological proof of principle test for a mu
opioid antagonist in the treatment of addictive disorders (see research
reference 2], in evaluation of a novel D3 antagonist and for other
neuropsychiatric drug candidates [4].
Direct commercial impact and new job creation came first with a
GSK-Imperial partnership to develop the £50M GSK Clinical Imaging Centre
on the Hammersmith Hospital site. By 2011 this centre employed over 70
scientists and support staff in development work with Imperial College,
leading to an annual direct GSK R&D spend of over £11M in the UK [5].
Work led by Professor Matthews from his joint appointment between Imperial
and GSK led the GSK Clinical Imaging Centre in decision-making studies (as
noted above, for over 14 molecules in early development) [2]. Additional
experimental medicine studies (e.g., pharmacokinetic characterisation of a
novel GSK SIRT1 activator [6]) were additionally underpinned by the
clinical pharmacology expertise, broader imaging capabilities of the CIC
and resources of the Sir John McMichael Centre, which has been supported
recently by a £73 million investment from the College, NIHR and the
Wellcome Trust. The GSK Clinical Imaging Centre was "spun out" as Imanova
in 2011. Imanova continues to employ 70 scientists and staff working on
Molecular Imaging studies not just for GSK, but an even broader range of
international Pharma companies involved in CNS drug development. Since its
formation, it has secured over £1.5M in commercial revenue from other
companies in addition to GSK's continued investments [7]. Imanova Ltd has
been identified by the new National Institute for Health Research Dementia
Translational Research Collaboration as a UK centre of excellence [8].
Sources to corroborate the impact
[1] Drug Development for CNS disorders:
D. D. Schoepp (2011) Where will new neuroscience therapies come from? Nature
Reviews Drug Discovery, 10, 715-716. DOI.
[2] Letter from the Head of Global Imaging Unit GlaxoSmithKline detailing
impact on drug discovery (available upon request).
[3] Evaluation of a novel Alzheimer's disease agent:
Tzimopoulou, S., Cunningham, V.J., Nichols, T.E., Searle, G., Bird, N.P.,
Mistry, P., Dixon, I.J., Hallett, W.A., Whitcher, B., Brown, A.P.,
Zvartau-Hind, M., Lotay, N., Lai, R.Y., Castiglia, M., Jeter, B.,
Matthews, J.C., Chen, K., Bandy, D., Reiman, E.M., Gold, M., Rabiner,
E.A., Matthews, P.M. (2010). A multi-center randomized proof-of-concept
clinical trial applying [18F]FDG-PET
for evaluation of metabolic therapy with rosiglitazone XR in mild to
moderate Alzheimer's disease. J Alzheimers Dis, 22 (4),
1241-1256. DOI.
[4] Evaluation of a novel D3 antagonist and other neuropsychiatric drug
candidates:
Searle, G., Beaver, J.D., Comley, R.A., Bani, M., Tziortzi, A., Slifstein,
M., Mugnaini, M., Griffante, C., Wilson, A.A., Merlo-Pich, E., Houle, S.,
Gunn, R., Rabiner, E.A., Laruelle, M. (2010). Imaging dopamine D3
receptors in the human brain with positron emission tomography, [11C]PHNO,
and a selective D3 receptor antagonist. Biol Psychiatry,
68(4):392-399. DOI.
[5] http://cic.gsk.com/downloads/CIC_Information.pdf
(archived
on 8th November 2013)
[6] Example of pharmacokinetic characterisation:
Libri, V., Brown, A.P., Gambarota, G., Haddad, J., Shields, G.S., Dawes,
H., Pinato, D.J., Hoffman, E., Elliot, P.J., Vlasuk, G.P., Jacobson, E.,
Wilkins, M.R., Matthews, P.M. (2012) A pilot randomized, placebo
controlled, double blind phase I trial of the novel SIRT1 activator
SRT2104 in elderly volunteers. PLoS One, 7 (12): e51395. DOI
[7] Expansion of collaborative base of the Clinical Sciences Centre &
Creation and spin out of Imanova Ltd:
[8] The UK government has established the new National Institute for
Health Research Dementia Translational Research Collaboration:
http://www.nocri.nihr.ac.uk/research-expertise/dementia-translational-research-collaboration/
Archived on 8th
November 2013