Centre for Amyloidosis and Acute Phase Proteins



Publication in Science Translational Medicine of the full results of the phase 1 clinical trial of miridesap (formerly known as CPHPC) followed by dezamizumab (fully humanised monoclonal anti-human SAP antibody) in patients with systemic amyloidosis

The first in human study of SAP depletion by CPHPC followed by humanised monoclonal anti-SAP antibody, to remove systemic amyloid deposits, started with antibody dose escalation and a single dose per patient. The very promising initial results, showing dramatic reduction in visceral amyloid load following administration of an adequate dose of antibody in relation to the amount of residual SAP in the patient's amyloid deposits, were published in 2015 in the New England Journal of Medicine.  Patients with cardiac amyloidosis were originally excluded on safety grounds but, following acceptable safety and tolerability of the intervention, some patients with definite cardiac amyloid were included and a number of subjects received a total of 2 or 3 courses of SAP depletion followed by anti-SAP antibody. The trial ended in 2016 and in early 2017 the WHO International Nonproprietary Names were assigned for CPHPC, miridesap, and for GSK's fully humanised monoclonal IgG1 version of our anti-human SAP antibody, dezamizumab.

The final results of the phase 1 trial are summarised in the abstract of the Science Translational Medicine paper.

Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, CPHPC] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. Here, we report the safety, pharmacokinetics and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (Clinicaltrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid‑specific radioligand binding of 123I‑SAP or of 99mTc‑3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. Organ extracellular volume was measured by equilibrium magnetic resonance imaging, and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses in relation to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I‑SAP scintigraphy confirmed amyloid removal from spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by this targeted therapy has the potential to improve management and outcome in systemic amyloidosis.

Repeat cycles of miridesap followed by dezamizumab progressively removed amyloid from the liver, spleen and kidneys of the patients. Evidence of clinical benefit suggests that this new approach has potential to improve management and outcome for patients with systemic amyloidosis.

First reports on the phase I clinical trial of the obligate therapeutic partnership of CPHPC and anti-SAP antibodies in patients with systemic amyloidosis

Our novel approach to direct targeting of systemic amyloid deposits for accelerated clearance from the tissues was invented in 2005.  Early successful preclinical experiments led to patents owned by Pentraxin Therapeutics Ltd, the UCL spin out company founded by Sir Mark Pepys in 2001 to hold and commercialise his intellectual property (IP). 

The amyloid treatment IP was licensed to GlaxoSmithKline (GSK) in 2009 and they have developed the unique small molecule and antibody partnership for clinical testing with recent successful completion of the first in human clinical trial.  The whole process has involved very close collaboration between GSK, Pentraxin, the Wolfson Drug Discovery Unit and the National Amyloidosis Centre. It is a paradigm for collaboration in drug discovery and development between academic science and a major pharmaceutical company.

The treatment has been well tolerated so far and, encouragingly, it has demonstrated notable efficacy in removing amyloid deposits from the tissues, leading to clinical benefit.  The initial results were reported at the annual meeting of the Association of Physicians of Great Britain and Ireland, held in Sheffield in March 2015.  The first formal publication was posted online in the New England Journal of Medicine on 15 July 2015 and appeared in print in September 2015.  The article was the subject of a report in the Financial Times on 16 July 2015. A phase 2 trial, focussed on cardiac amyloidosis, is planned to start in 2016.

Creation of a new dedicated cardiac magnetic resonance imaging facility in the National Amyloidosis Centre

Radiolabelled SAP scintigraphy, invented by Sir Mark Pepys in 1986, was developed for routine clinical use by him and Professor Philip Hawkins in Hawkins's PhD project in 1987-1990.  It has long been a crucial component of the unique clinical research and practice of the National Amyloidosis Centre.  SAP scanning is not suitable for imaging cardiac amyloidosis, for technical reasons.  Fortunately, cardiac magnetic resonance (CMR) methods, developed in the past 10 years, now provide very sensitive and specific information about amyloid in the heart and its effects on cardiac function. 

The National Amyloidosis Centre has been funded to obtain CMR tests on our patients but these have been limited by shortage of NHS CMR facilities.  Professor Hawkins therefore effectively raised NHS funds for installation of a dedicated CMR facility within the Centre for Amyloidosis and Acute Phase Proteins and it opened for patients in December 2015. 

Magnificent additional fundraising for the UCL Amyloidosis Research Fund, largely through the sponsored bike ride from Land's End to John O'Groats by Thirusha Lane and David Hutt, together with many friends and supporters, contributed significantly towards the cost. 

The new scanner is, and will continue to be, tremendously helpful for diagnosis and patient management, and also of critical important for clinical development of our own and other novel treatments for amyloidosis.