Amyloidosis and acute phase proteins: development of new drugs and a new approach to academia-industry collaboration
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Immunology, Neurosciences
Summary of the impact
The UCL Centre for Amyloidosis and Acute Phase Proteins has designed and
developed new chemical entities targeting serum amyloid P component (SAP),
C-reactive protein (CRP) and transthyretin, for novel therapeutic
approaches to amyloidosis, Alzheimer's disease, cardiovascular and
inflammatory diseases. The UCL spin out company, Pentraxin Therapeutics
Ltd, founded by Sir Mark Pepys to hold his intellectual property (IP), has
licensed two programmes to GlaxoSmithKline (GSK). These highly
synergistic, collaborative multi-million pound developments, strikingly
exemplify new working relationships between academia and the
Elucidation by Pepys of the role of SAP in amyloidosis (1977-95) led to
his invention, in collaboration with Roche, of the bis D-proline drug,
CPHPC, which produces sustained depletion of circulating SAP by a novel
pharmacological mechanism, first demonstrated at UCL in the early 2000's .
Patients with systemic amyloidosis are significantly stabilised while
being treated with CPHPC but the drug does not remove all SAP from their
amyloid deposits and the amyloid does not regress . These
observations led Pepys to invent the use of anti-SAP antibodies to target
residual SAP in the amyloid deposits of CPHPC treated subjects .
The antibodies trigger remarkable, clinically silent elimination of
visceral amyloid in experimental models, which has not previously been
achieved. GSK licensed the invention in 2009. They have conducted phase I
studies of CPHPC in healthy volunteers and amyloidosis patients, have
fully humanised Pepys's optimal mouse monoclonal anti-human SAP antibody,
and the first clinical trial of CPHPC plus antibody is currently in
progress, so far with no adverse effects.
SAP is universally present in human amyloid deposits, including the
cerebral and cerebrovascular amyloid deposits in Alzheimer's disease (AD).
SAP also binds to most neurofibrillary tangles. Brain content of SAP is
thus higher in AD than in normal subjects, and since SAP is directly
neurocytotoxic it likely contributes to neurodegeneration, in addition to
its role in amyloidogenesis. The complete removal of SAP from the
cerebrospinal fluid, by administration of CPHPC in Alzheimer's disease, is
thus an attractive therapeutic approach . Experimental work has
been supported by the MRC and preparatory work for a first clinical trial
in Alzheimer's disease is currently in progress funded by the NIHR through
the UCLH/UCL Biomedical Research Centre (BRC) and strongly supported by
Transthyretin causes both acquired senile cardiac amyloidosis, a hitherto
grossly under diagnosed condition, and hereditary systemic amyloidosis.
The Pepys team designed and patented novel small molecule compounds
targeting transthyretin , pursued possible development
supported by one of the first Wellcome Trust Seeding Drug Discovery
Initiative awards (£3.89 million), but then licensed the IP to GSK for a
close collaboration which has yielded new IP.
Human CRP potently activates complement when it binds to dead and damaged
cells and this exacerbates tissue damage after ischaemic injury in the
heart and brain, validating inhibition of CRP binding as a therapeutic
strategy . Development of Pepys's small molecule CRP inhibitor
approach has been funded by the first award (£4 million) made by the MRC
under their Developmental Clinical Studies scheme and latterly also by the
British Heart Foundation (BHF).
Pepys joined UCL in 1999, when he was appointed Professor and Head of the
Department of Medicine at the Royal Free Campus of University College
London, and is currently Principal Clinical Research Associate and
Emeritus Professor of Medicine. He was awarded a Knighthood in the 2012
New Year Honours list for services to biomedicine.
References to the research
 Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ,
Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T,
Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW,
Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN. Targeted
pharmacological depletion of serum amyloid P component for treatment of
human amyloidosis. Nature. 2002 May 16;417(6886):254-9. http://doi.org/fq58gj
 Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC,
Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV,
Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe
SE, Thompson D, Wood SP. Targeting C-reactive protein for the treatment of
cardiovascular disease. Nature. 2006 Apr 27;440(7088):1217-21.
 Kolstoe SE, Ridha BH, Bellotti V, Wang N, Robinson CV, Crutch SJ,
Keir G, Kukkastenvehmas R, Gallimore JR, Hutchinson WL, Hawkins PN, Wood
SP, Rossor MN, Pepys MB. Molecular dissection of Alzheimer's disease
neuropathology by depletion of serum amyloid P component. Proc Natl Acad
Sci U S A. 2009 May 5;106(18):7619-23.
 Gillmore JD, Tennent GA, Hutchinson WL, Gallimore JR, Lachmann HJ,
Goodman HJ, Offer M, Millar DJ, Petrie A, Hawkins PN, Pepys MB. Sustained
pharmacological depletion of serum amyloid P component in patients with
systemic amyloidosis. Br J Haematol. 2010 Mar;148(5):760-7. http://dx.doi.org/10.1111/j.1365-2141.2009.08036.x
 Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA,
Hutchinson WL, Mangione PP, Gallimore JR, Millar DJ, Minogue S, Dhillon
AP, Taylor GW, Bradwell AR, Petrie A, Gillmore JD, Bellotti V, Botto M,
Hawkins PN, Pepys MB. Antibodies to human serum amyloid P component
eliminate visceral amyloid deposits. Nature. 2010 Nov 4;468(7320):93-7.
 Kolstoe, S.E., Mangione, P.P., Bellotti, V., Taylor, G.W., Tennent,
G.A., Deroo, S., Morrison, A.J., Cobb, A.J.A., Coyne, A., McCammon, M.G.,
Warner, T.D., Mitchell, J., Gill, R., Smith, M.D., Ley, S.V., Robinson,
C.V., Wood, S.P. and Pepys, M.B. (2010) Trapping of palindromic ligands
within native transthyretin prevents amyloid formation. Proc. Natl.
Acad. Sci. USA, 107: 20483-20488. http://dx.doi.org/10.1073/pnas.1008255107
Details of the impact
Pepys's drug discovery intellectual property portfolio, comprising more
than 20 granted patents [a], is held by the UCL spin out company,
Pentraxin Therapeutics Ltd, which he founded in 2001 [b]. The
company, created as a vehicle for commercialisation of the IP, was
initially funded exclusively by loans from UCL totalling more than £1.5
million and has not sought external investment. It conducts its activities
entirely through its relationship with UCL and its external collaborations
and has no employees. In 2009 and 2010, Pentraxin licensed two of its drug
programmes to GlaxoSmithKline (GSK) in multi-million pound deals and is
developing them in close collaboration with GSK where several hundred
employees participate at various levels [c, d]. Pentraxin has
repaid all its loans from UCL and is now in profit with substantial
further milestone and royalty payments in prospect if programmes are
The most advanced programme, aiming to eliminate visceral amyloid
deposits, is the first in class obligate therapeutic partnership of CPHPC,
a small molecule drug, and a mouse monoclonal anti-human SAP antibody
which has been fully humanised by GSK. The first human patient studies are
now in progress and are progressing very well [d, e]. The
programme has been chosen by GSK as its flagship candidate for potential
adaptive licensing in the process being led by the MIT Centre for
Biomedical Innovation through its New Drug Development Paradigms (NEWDIGS)
initiative. There is a very strong movement towards streamlining and
improvement of the regulatory licensing pathway for new medicines so that
patients with unmet medical needs get access to novel treatments more
rapidly and more efficiently than at present. The UCL/Pentraxin/GSK
amyloidosis programme is in the vanguard.
GSK also licensed Pepys's IP covering compounds for treatment of
transthyretin amyloidosis and the programme has passed its initial
developability milestone. Typical industry costs for a drug development
programme to this stage are £6-8 million.
The discovery and development of CRP inhibitors for myocardial
infarction, stroke, cancer cachexia and inflammatory diseases has been
supported by the MRC and BHF and has received expert guidance from GSK.
Work on SAP depletion by CPHPC for Alzheimer's disease has been supported
at the experimental level by the MRC. Via the UCLH/UCL BRC, the NIHR is
now funding preparatory work for the first clinical trial of CPHPC in
Alzheimer's disease, with GSK as major participants contributing crucially
to project management, funding and provision of their existing CPHPC
results. Furthermore GSK have an option to licence CPHPC for this
The transmission of drug discovery directly from a university into big
pharma is a very rare achievement, particularly across such a broad range
of different programmes. In 2011, GSK named Professor Pepys as the first
"academic superstar" in its programme to develop long term ongoing
partnerships with academia as part of its drug discovery programme [d,
f]. GSK has changed its R&D model over the last 5 years,
including the creation of the Academic Discovery Partnership Unit and
Discovery Partnerships with Academia. The aim is to make the company more
productive, agile, and focussed on areas of scientific potential [g].
The Head of the Academic Discovery Partnership Unit at GSK confirmed the
ways in which close working with the UCL team has been important in
progress towards bringing a drug to market:
[Text removed for publication] [d].
Sources to corroborate the impact
[a] Major Patents
Pepys, M.B. CRP binding agents. US Patent No. 7,390,795, granted 24 June
Pepys, M.B. Treatment and prevention of tissue damage. European Patent No.
1 503 800, granted 28 October 2009.
Pepys, M.B. Treatment and prevention of tissue damage. US Patent No.
7,615,543, granted 10 November 2009.
Pepys, M.B. Therapeutic agent. US Patent No. 7,691,897, granted April
Pepys, M.B. and Hawkins, P.N. Compounds inhibiting the binding of SAP for
US Patent No. 7,659,299, granted 9 February 2010.
Pepys, M.B. Therapeutic agent for depletion of an unwanted protein
population from plasma.
European Patent No. 1 820 501, granted 14 September 2011.
Pepys, M.B. and Hawkins, P.N. Compounds inhibiting the binding of SAP for
European Patent No. 1 633 345, granted 21 September 2011.
Pepys, M.B. Therapeutic agent. US Patent No. 8,173,694, granted 8 May,
Pepys, M.B. Combinations of SAP depleting agents and anti-SAP antibodies.
US Patent No. 7,910,106, granted 22 March 2011.
[b] Pentraxin Therapeutics Ltd
Corroboration can be obtained from the Managing Director, UCL Business
[c] Commercial deals
[d] Engagement with GSK
Letter of support from the Head of the Academic Discovery Partnership
Available on request.
[e] Phase I Clinical trial of a combination of CPHPC and an anti-SAP
[f] Financial Times on Professor Pepys being chosen as an academic
[g] Details of GSK's R&D model is available in their evidence to
the Parliamentary Science and Technology Committee, March 2013