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Prof Sir Mark Pepys
Director, Wolfson Drug Discovery Unit
Centre for Amyloidosis & Acute Phase Proteins
UCL Division of Medicine, Royal Free Campus
London
NW3 2PF
Tel: 020 7433 2801
Fax: 020 7433 2803
Appointment
  • Principal Clinical Research Associate
  • Inflammation
  • Div of Medicine
  • Faculty of Medical Sciences
  • Emeritus Professor of Medicine
  • Div of Medicine
  • Faculty of Medical Sciences
Biography

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 for his PhD in immunology and 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 in 1984.  In 1999 he was invited to become Professor and Head of the Department of Medicine at the Royal Free Campus of University College London, and he moved his whole Department there to establish the UCL Centre for Amyloidosis and Acute Phase Proteins.  He also established the UK National Health Service National Amyloidosis Centre, funded by the UK Department of Health, to provide diagnostic and management advisory services for the whole national caseload, and which also sees many patients from abroad.  There are more than 4,000 patient visits per year.  His research has been continuously supported by the Medical Research Council, with more than £18 million since 1969, and he has also received generous support from the Wolfson Foundation, the Wellcome Trust and other medical charities.  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.  In 2007 he was the Harveian Orator of the Royal College of Physicians and also received the Royal Society GlaxoSmithKline Prize.  In 2008 he received the Ernst Chain Prize for medical discovery.  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.  Core funding of the Unit, lately renewed until 2022, is from the National Institute for Health Research via the UCLH/UCL Biomedical Research Centre, which is also funding the DESPIAD clinical trial of his drug for Alzheimer’s disease.  He was created Knight Bachelor for Services to Biomedicine in the 2012 New Year Honours and in 2014 was elected to Honorary Fellowship of his alma mater, Trinity College, Cambridge.

Research Summary

After his seminal discovery, in 1972, of the role of complement in the induction of antibody production, and subsequent related studies, 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 first identified these proteins as therapeutic targets, and has designed and is 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, and has guided radical therapeutic developments, especially by focusing attention on the crucial importance of reducing the abundance of the protein precursors of amyloid fibrils.  Pepys has discovered many of the mutations responsible for hereditary amyloidosis, including the first mutations in the human lysozyme gene, leading to the demonstration that the amyloidogenic lysozyme variants are less stable than wild type lysozyme and the construction of a widely accepted general model of amyloid fibrillogenesis.

Pepys first suggested a small molecule therapy for amyloidosis in 1984.  His novel SAP targeting drug, CPHPC, hexanoyl bis(D-proline), reported in Nature in 2002, was an American Chemical Society medicinal chemistry highlight of that year.  CPHPC depletes circulating SAP almost completely, reduces the SAP content of systemic amyloid deposits and completely removes SAP from the brain.  His invention of the obligate partnership of CPHPC with anti-SAP antibody for treatment of systemic amyloidosis is being developed with GlaxoSmithKline.  Unprecedented clinically beneficial clearance of visceral amyloid deposits was reported in the New England Journal of Medicine in 2015 and Science Translational Medicine in 2018.  The WHO International Non-proprietary Names, miridesap (CPHPC) and dezamizumab (humanised monoclonal anti-SAP antibody), were assigned in 2017.  GSK’s phase 2 study of the intervention in cardiac amyloidosis is in progress.  SAP depletion for Alzheimer’s disease is being tested in the NIHR funded DESPIAD phase 2b clinical trial.

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 rational design of bis-phosphocholine-hexane as the first specific inhibitor of CRP was reported in Nature in 2006.  Work continues on creation of more medicinal CRP inhibitors.  Pepys identified innate host defence against pneumococcal infection as the first definite in vivo function of autologous CRP.  He has also shown that human CRP is not pro-inflammatory or pathogenic in healthy individuals.  He previously played a leading role in establishing the routine use of CRP testing in clinical practice.  He produced the World Health Organization’s International Immunoassay Reference Standard for CRP, and also those for serum amyloid A protein, and thyroxine binding globulin.

Appointments
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
Academic Background
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
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