In 2002 the National Amyloidosis Centre in London announced that they had developed a new drug in conjunction with Roche Pharmaceuticals that would dissolve amyloid. Unfortunately the drug did not work well in humans.
Nature 417, 254-259 (16 May 2002)
Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis
M. B. Pepys et al..Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, UK and others.
Abstract: The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.
(We can provide a copy of the complete article. ER)
Fortunately the NAC continued research with this drug, and found that a combination of it with an antibody resulted in rapid breakdown of deposited amyloid in humans.
In March 2009 University College of London (associated with the National Amyloidosis Centre) and another pharmaceutical company, Glaxo Smith Klinejoined forces to develop combined small molecule-antibody treatment for rare disease
Collaboration to develop a world first drug-antibody dual treatment for the rare and often fatal condition amyloidosis has been formed between the University College London spinout company Pentraxin Therapeutics Ltd and GlaxoSmithKline (GSK).
Amyloidosis is a disease caused by build up of abnormal proteins (amyloid) in body tissues, leading to organ failure. The heart, kidneys, liver and almost any other organ can be affected. Around 500 new cases are diagnosed each year in the UK. Despite the best available therapy, the prognosis for patients with amyloidosis is poor and new treatments are urgently needed.
"We initially developed the small molecule drug, CPHPC, and while we had promising early results, they were not enough to benefit patients with advanced disease. Something more dramatic is needed," explained Professor Mark Pepys FRS, the head of Pentraxin and the UCL Centre for Amyloidosis and Acute Phase Proteins which includes the UK National Amyloidosis Centre.
"We then combined CPHPC treatment with an antibody that seeks out the amyloid deposits in the organs in mice. This combination triggered a rapid clearance of the deposits."
With this new agreement, the research teams from UCL and GSK will work together to convert the mouse antibody into one that can be used in humans in combination with CPHPC. The aim is to find out if the benefits seen in the animal model can be replicated in patients with amyloidosis.
The collaboration brings together UCL's clinical and science expertise and the development expertise of GSK's Academic Discovery Performance and Biopharm Units.
"We are delighted to enter into this alliance," said Mike Owen, Senior Vice President, Biopharmaceutical Research, GSK. "Our biopharmaceutical and clinical development capabilities and Prof Pepys's team's knowledge of the disease provide a synergistic collaboration that will greatly enhance our chances of success."
Under the terms of the agreement, Pentraxin will receive undisclosed early stage success-based milestones plus drug development milestones and royalties.
Because of discussion on the ACOR Amyloidosis forum we contacted Prof. Sir Mark Pepys about the drug combination, and he replied:, 28 Apr 2009
"The combination of CPHPC and anti-SAP antibody, which we are now developing in collaboration with GSK (Glaxo Smith Kline), should effectively clear the amyloid deposits in all forms of the disease, regardless of the amyloid fibril protein.
The treatment targets only SAP with great specificity and SAP is present in all types of amyloid.
The CPHPC clears SAP from the blood so that the anti-SAP antibody can be given safely and can effectively reach the SAP in the amyloid deposits where it then triggers the body's normal highly potent clearance mechanisms to remove the amyloid without adverse side effects.
We hope to be ready for the first patient studies in 2 years from now."
Professor MB Pepys FRS FMedSci
Head, Division of Medicine, Royal Free Campus
Director, Centre for Amyloidosis & Acute Phase Proteins
University College London Medical School
To us this was the most wonderful news about Amyloidosis we had heard in the past 8 years!
We later asked Dr Pepys about the availability and dosage of CPHPC and he replied:
"CPHPC is not available to anyone anywhere at present regardless of route of administration. But I'm working hard on the regulatory obstructions and hope to have it available in the future.All our studies after the original ones were done by subcutaneous injection once to three times daily depending on the patient, disease, etc.The drug does work by mouth and we are working now on making the routine route."
We also asked about the possibilities of the new drug combination for use in other conditions where Amyloid is a factor, and he replied:
"Although amyloid deposits are present in CJD, they almost certainly do not cause the neuronal loss. In Down's (sic) the position is less clear and if CPHPC helps in Alzheimer's disease it might also help to prevent or control the dementia in Down's. The amyloid in type 2 diabetes probably makes the diabetes worse and we are working hard on approaches to that. In particular the anti-SAP antibody might be helpful. Watch this space."
In March 2010 there was an article on the results of the first new trial of CPHPC in the British Journal of Haematology:
Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis.
Gillmore, Hawkins, Pepys et al, NAC, London.
Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence.
We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexa-noyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis.
CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available.
There were no significant adverse effects of either SAP depletion or CPHPC itself.
No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug.
In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group.
These promising clinical observations merit further study.
An audio interview from 2009 with Dr Pepys is available at the website below:
More news (2014) on how Dr Pepys is trialling removal of Alzheimer Beta Amyloid deposits with CPHPC:
Clinical trials on human patients with Amyloidosis have finally started on this promising drug: