Treating systemic amyloidosis by removing amyloid deposits from the tissues and organs of the body: good news, bad news and hope for the future

by Professor Sir Mark Pepys FRS, Founder of the NAC and Director of the Wolfson Drug Discovery Unit in the Centre for Amyloidosis and Acute Phase Proteins


I have been doing research on amyloidosis since 1976 and started looking after patients with the disease soon afterwards.  In 1986 I invented SAP scintigraphy for diagnosis and monitoring of systemic amyloidosis.  The success of this procedure, the clinical implementation of which I assigned to Philip Hawkins for his PhD project, swiftly led to my unit, the Immunological Medicine Unit at the Royal Postgraduate Medical School, Hammersmith Hospital, becoming the de facto national referral centre for amyloidosis.  Increasing numbers of patients were referred and from 1990, I put Philip in charge of the clinical service we provided.  When I was invited to become the Professor and Head of Medicine at the Royal Free Campus of University College London, and to move there with my whole team on 1999, we applied successfully to the Department of Health for special funding as the National Amyloidosis Centre.  The Centre was borne, Philip was appointed to a personal chair in Medicine, as Professor Hawkins, and he became the Clinical Director of the NAC.

In 1984, I published my first paper suggesting a novel approach to treatment of amyloid: targeting SAP to promote the removal of the amyloid deposits from the body.  SAP is a normal protein, present in everybody, and it is also always present in all amyloid deposits.  In subsequent work we accumulated increasing evidence that validated SAP as a therapeutic target.  Eventually, following our design and development of new potential drugs, I invented a method to stimulate the body to remove amyloid.  The new method worked amazingly well in experimental models.  I patented it and, in 2009, I licensed it to GlaxoSmithKline for development and clinical testing in patients.

Good news

The first in human phase 1 clinical trial of the new treatment started in 2013 and ran until 2015.  It was spectacularly successful.  Despite some minor side effects, trivial by comparison with the side effects of many chemotherapy drugs, the treatment was well tolerated.  Furthermore it produced unprecedented removal of amyloid deposits from the liver, spleen and kidneys.  In the liver, where organ function can very easily be precisely monitored, amyloid removal was universally associated with improved function.  These very encouraging results were published in the major medical journals – see here and here.

Bad news

The single most common serious problem caused by systemic amyloidosis is involvement of the heart.  The initial series of patients tested with the new treatment were selected, for safety reasons, to be free of any heart amyloid.  Later some heart cases were treated and tolerated the drugs without any heart problems.

A phase 2 clinical trial was therefore designed and conducted by GSK, specifically to test efficacy of the amyloid removal approach in the heart.  Unfortunately, GSK’s assessment of the risk-benefit profile of the early cardiac results led them to stop the trial and to terminate all further work on the treatment.  My patents on the invention are being returned but it will be extremely challenging to try to develop it again.

GSK, who were conducting and funding all aspects of the development and testing of the treatment I invented, swiftly decided to terminate all further work on the treatment because of its risk-benefit profile.

This is a very common outcome in drug development, where at most 5% of all programmes that start actually make it all the way to becoming licensed medicines.  Nevertheless it is, of course, very disappointing for everybody, inventors and patients alike, who had high hopes for arrival of an effective new treatment for amyloidosis.  Interestingly, the termination decision came at almost the same time that GSK divested its whole drug development portfolio for all other rare diseases.  Such major strategic decisions and changes of priorities and direction are normal in the pharmaceutical industry.

Immunotherapy for amyloidosis – hope for the future

The treatment, the development of which has just been terminated, involved a humanised antibody.  Antibodies are part of the body’s immune system and using antibodies as drugs is called immunotherapy.  The phase 1 trial of our approach triumphantly established proof of the concept that immunotherapy can remove amyloid deposits from the body and thereby provide clinical benefit for the patient.  This crucial positive result remains valid and is completely unaffected in any way by the ending of the development programme.  We can confidently conclude that we understand how to use the antibody approach effectively.  We just need to be able to do so safely, without any significantly threatening adverse effects.

Fortunately, there is every reason to believe that this is indeed possible.  I have alternative inventions, involving use of antibodies to remove amyloid, which are ready for development and testing and which will almost certainly avoid the adverse effects seen with the previous approach.  The only problems we face are the years of time and the hundreds of millions of pounds that will be required to progress, again, through the nightmare process of drug development.  But I have every intention of pursuing this aim and have already started.