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- Principal Clinical Research Associate
- Div of Medicine
- Faculty of Medical Sciences
- Emeritus Professor of Medicine
- Div of Medicine
- Faculty of Medical Sciences
Mark Pepys was born in Cape Town, South Africa and came to the UK in 1948. He was educated at Trinity College, Cambridge, where he was a Senior Scholar, and took a double first in the Natural Sciences Tripos. After qualifying in medicine at University College Hospital Medical School, he returned to Cambridge as a Research Scholar at Trinity for his PhD in immunology. He was elected to a Fellowship at Trinity in 1973 for his discovery of the role of complement in induction of antibody production. After training in clinical medicine and continued immunology research at the Royal Postgraduate Medical School he was appointed Head of the Department of Immunology at the Royal Free Hospital School of Medicine in 1976. In 1977 he returned to the Royal Postgraduate Medical School as Senior Lecturer/Consultant Physician and established the Immunological Medicine Unit, which became one of the world’s leading centres for basic and clinical research on the acute phase response and amyloidosis. He was appointed Professor of Immunological Medicine at the RPMS in 1984. In 1999 he was appointed Professor and Head of the Department of Medicine at the Royal Free Campus of University College London, and moved his whole Department there to establish the UCL Centre for Amyloidosis and Acute Phase Proteins. He also created the UK National Health Service National Amyloidosis Centre, funded by the UK Department of Health to provide diagnostic and management advisory services to the whole national caseload, and which also sees many patients from abroad. His research has been continuously supported by the Medical Research Council since 1969, including a Programme Grant from 1979 to 2009 followed by a Research Grant and the first award under the MRC Developmental Clinical Studies Scheme from 2010-2013 and a second DCS award from 2012-2015. He has also received generous support from the Wolfson Foundation and the Wellcome Trust, including one of the first Seeding Drug Discovery awards from 2007-2010. He is a Fellow of the Royal Society, a Founder Fellow of the Academy of Medical Sciences, and has been a member of the Councils of both academies. He was the Harveian Orator of the Royal College of Physicians for 2007 and winner of the Royal Society GlaxoSmithKline Prize in 2007. In 2008 he received the Ernst Chain Prize for medical discovery and in 2009 gave the Annual Keynote Lecture at the Academy of Medical Sciences. In 2011 he retired as Head of Medicine at the Royal Free Campus of UCL in order to become the first Director of the new UCL Wolfson Drug Discovery Unit, created with Wolfson Foundation support and core funding from the NIHR via the UCLH/UCL Biomedical Research Centre. He was created Knight Bachelor for Services to Biomedicine in the 2012 New Year Honours and was elected to an Honorary Fellowship of Trinity College, Cambridge in 2014.
After his seminal discovery in 1972 of the role of complement in the induction of antibody production Pepys has mostly worked on amyloid and acute phase proteins. He has illuminated the pathogenesis and natural history of systemic amyloidosis, transforming diagnosis of this fatal disease, and improving management and survival. He has also elucidated the structural properties, function and clinical significance of serum amyloid P component (SAP) and C-reactive protein (CRP). He was the first to identify these proteins as therapeutic targets, and has designed and worked on developing new drugs aimed at them.
His invention of in vivo scintigraphy with radiolabelled SAP enabled systemic amyloidosis for the first time to be safely, non invasively diagnosed and quantitatively monitored. This revolutionised understanding of the natural history of amyloidosis and its response to therapy, guiding radical therapeutic developments, especially regarding the crucial importance of reducing the abundance of amyloid fibril protein precursors. Pepys has discovered many of the mutations responsible for hereditary amyloidosis, including the first mutations in the human lysozyme gene. He showed that amyloidogenic lysozyme variants are less stable than wild type lysozyme and developed a widely accepted general model of amyloid fibrillogenesis. His detailed phenotypic characterisation of hereditary amyloidoses improved investigation and management of systemic amyloidosis in general.
Pepys’s first suggestion of small molecule therapy for amyloidosis (1984) led eventually to his novel SAP targeting drug, CPHPC, bis(D-proline)hexane, reported in Nature in 2002, and recognised by the American Chemical Society as a medicinal chemistry annual highlight. This small molecule palindromic ligand cross links pairs of circulating SAP molecules, triggering their immediate clearance from the circulation, a novel pharmacological mechanism. Sustained plasma SAP depletion removes some but not all SAP from systemic amyloid deposits, leading Pepys to the invention in 2005 of a partnership between CPHPC and antibodies to SAP, to directly target the deposits. In 2009 the IP was licensed for development by GlaxoSmithKline and the dramatic amyloid clearance seen in patients in the first clinical trial is reported in the New England Journal of Medicine on 15 July 2015. In contrast to systemic amyloid, CPHPC removes all SAP from the brain and cerebral amyloid deposits, offering a potential new therapeutic prospect for Alzheimer's and some other neurodegenerative diseases. The first clinical trial of CPHPC in Alzheimer's disease, DESPIAD, is fully funded and will start in 2016.
Pepys’s demonstration that CRP increases ischaemic myocardial and cerebral damage in vivo, was the first validation of CRP as a potential therapeutic target. His rationally designed bis(phosphocholine)hexane compound, the first specific inhibitor of CRP, reported in Nature in 2006, has proved challenging to develop as a drug. Pepys previously played a leading role in establishing the routine use of CRP testing in clinical practice, and produced the WHO International Immunoassay Reference Standards for CRP, serum amyloid A protein, and thyroxine binding globulin.
|1999 – 2011||Professor of Medicine and Head||Medicine||University College London, United Kingdom|
|1999 – 2011||Director, Centre for Amyloidosis & Acute Phase Proteins||Medicine||University College London, United Kingdom|
|1984 – 1999||Professor||Immunological Medicine||RPMS/ICSM, Hammersmith Hospital, United Kingdom|
|1980 – 1984||Reader||Immunological Medicine||RPMS, Hammersmith Hospital, United Kingdom|
|1977 – 1999||Consultant Physician||Hammersmith Hospital, United Kingdom|
|1977 – 1980||Senior Lecturer||Medicine||RPMS, Hammersmith Hospital, United Kingdom|
|1976 – 1977||Senior Lecturer and Head||Immunology||Royal Free Hospital School of Medicine, United Kingdom|
|1974 – 1976||Assistant Lecturer/Honorary Senior Registrar||RPMS, Hammersmith Hospital, United Kingdom|
|1973 – 1974||Medical Registrar||RPMS, Hammersmith Hospital, United Kingdom|
|1973 – 1979||Fellow||Trinity College, Cambridge, United Kingdom|
|1970 – 1970||Research Assistant/Honorary Registrar||RPMS, Hammersmith Hospital, United Kingdom|
|1970 – 1973||Research Scholar||Trinity College, Cambridge, United Kingdom|
|1970 – 1973||MRC Junior Research Fellow||University of Cambridge, United Kingdom|
|1969 – 1970||Senior House Officer||RPMS, Hammersmith Hospital, United Kingdom|
|1969 – 1969||House Surgeon||University College Hospital, United Kingdom|
|1968 – 1969||House Physician||University College London, United Kingdom|
|1998||FMedSci||Fellow of the Academy of Medical Sciences||Academy of Medical Sciences|
|1998||FRS||Fellow of the Royal Society||Royal Society|
|1991||FRCPath||Fellow of the Royal College of Pathologists – Pathology||Royal College of Pathologists, UK|
|1982||MD||Doctor of Medicine – Medicine||University of Cambridge|
|1981||FRCP||Fellow of the Royal College of Physicians – Clinical Medicine||Royal College of Physicians|
|1981||MRCPath||Member of the Royal College of Pathologists||Royal College of Pathologists, UK|
|1974||PhD||Doctor of Philosophy||University of Cambridge|
|1970||MA||Master of Arts||University of Cambridge|
|1970||MRCP||Member of the Royal College of Physicians – Clinical Medicine||Royal College of Physicians|
|1968||MB BChir||Bachelor of Medicine/ Bachelor of Surgery – Medicine/Surgery||University of Cambridge|
|1965||BA Hons||Bachelor of Arts (Honours) – Natural Sciences Tripos Part I||University of Cambridge|