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 (Sci Transl Med 2018).
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.
Strong experimental support for the DESPIAD trial of CPHPC in patients with Alzheimer’s disease
Al-Shawi, R., Tennent, G.A., Millar, D.J., Richard-Londt, A., Brandner, S., Werring, D.J., Simons, J.P. and Pepys, M.B. (2016). Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo. Open Biol., 6: 150202.
Crucial experimental studies confirming that CPHPC treatment can remove all SAP from the brain have been published in the Royal Society journal Open Biology. The paper includes a comprehensive review of the scientific evidence supporting the concept of CPHPC treatment in Alzheimer’s disease and also in cerebral amyloid angiopathy (CAA). CAA is the most common form of localised amyloidosis and is a very important cause of cerebral haemorrhage (stroke) and dementia. There is no effective treatment for it but Pentraxin is enthusiastically working towards a clinical trial of CPHPC in this condition.
The new paper was heralded by a piece in The Times newspaper of London on 3 February 2016 by Science Correspondent, Oliver Moody:
Alzheimer’s drug ready for patient trials
A drug for Alzheimer’s disease is ready to be tested on British patients after it showed promising results in mice.
Scientists in London have developed a compound that roots out a fundamental cause of the clumps blamed for the brain damage linked to the disease.
Its effect on the physical precursors of Alzheimer’s in mice is so strong that the researchers are preparing for a clinical trial later this year. There are no drugs for treating the disease, which affects 800,000 people in Britain.
Sir Mark Pepys, the director of the Wolfson Drug Discovery Unit at University College London, led the development of the new drug, CPHPC, which attacks an important ingredient in the protein that builds up in the brain and gradually chokes its cells.
Its target is serum amyloid P component protein (SAP), which starts in the bloodstream and is thought to find its way into the brain, where it binds together the plaques that are the main physical signs of Alzheimer’s.
Sir Mark and his colleagues genetically engineered mice so that they could develop the disease and harbour SAP in their blood. In a study published in the journal Royal Society Open Biology, they said that the drug had cleared all the protein from the mice’s brain.
Following the print publication of Richards et al in the New England Journal of Medicine (2015, 373: 1106-1114), the further results of the phase I clinical trial of CPHPC plus anti-SAP antibody were reported at the 2015 Annual Meeting of the American Society of Hematology, as shown here:
Landmark New England Journal of Medicine publication online 15 July 2015
Richards, D.B., Cookson, L.M., Berges, A.C., Barton, S.V., Lane, T., Ritter, J.M., Fontana, M., Moon, J.C., Pinzani, M., Gillmore, J.D., Hawkins, P.N. and Pepys, M.B. (2015). Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N. Engl. J. Med., 373: 1106-1114.
The first in human clinical trial of our novel investigational drug intervention for patients with systemic amyloidosis has reported the initial results in the first 15 patients treated with a therapeutic partnership of a small chemical molecule and a large biological molecule (an antibody). Further clinical testing is in progress and a phase II trial to explore efficacy and safety is planned.
Amyloid is an abnormal protein material that accumulates in the tissues, damaging their structure and function and causing a serious and usually fatal disease called systemic amyloidosis. It is a rare disease but an important unmet medical need. Present treatments can stabilise some patients and substantially prolong life but about 20% of patients still die within 6 months of diagnosis.
The body is normally very efficient in clearing abnormal debris from the tissues but, mysteriously, this does not happen with amyloid deposits. Even when amyloid formation is controlled, the deposits are cleared very slowly if at all.
No approved treatments exist to accelerate amyloid removal. New approaches are thus urgently needed.
The results of the phase I study now published online showed that the antibody was generally well tolerated and produced swift clearance of amyloid from various organs. Removal of amyloid from the liver was associated with improved function. More extended follow up is required to establish functional improvement in other organs.
Professor Sir Mark Pepys FRS, Director of the UCL Wolfson Drug Discovery Unit, said: “Amyloidosis is a very challenging clinical condition. It causes serious ill health and is usually fatal, despite best efforts to support the patients and to control the underlying conditions responsible for amyloid formation. Furthermore amyloidosis can present in so many different ways that, coupled with its relative rarity, the diagnosis is often long delayed. As a result patients frequently have advanced disease before they receive any treatment. We have long recognised that measures to remove amyloid from the tissues are required and have been working on this problem for over 30 years. We were finally successful for the first time in experimental models 10 years ago. The collaboration with GSK started in 2009 and it has been a privilege to work with their expertise and resources to bring our approach into clinical testing. Seeing clearance of amyloid deposits from patients’ tissues has been thrilling. It is a crucial first step on the long path towards having a medicine that could transform the outlook for people suffering from this terrible disease.”
Dr Duncan Richards, Head of GSK’s Academic Discovery Performance Unit, said: “Establishing proof of mechanism is a vital milestone that needs to be determined early in the path of developing a medicine so we are pleased to have this confirmed for the first time in patients. The initial results of the therapeutic intervention of CPHPC and the anti-SAP antibody are encouraging and we are now actively planning the next stages of development to better understand its potential benefits and safety in patients.”
Professor Sir Mark Pepys FRS and his team in the Wolfson Drug Discovery Unit at the Royal Free Campus of UCL, have been working on amyloidosis since 1974. Their innovations in diagnosis and monitoring of amyloidosis led to establishment of the UK NHS National Amyloidosis Centre at the Royal Free Hospital in 1999. The Centre is funded directly by the Department of Health to provide diagnostic and management advice services for all patients with this disease in the UK. Some 4,000 patients visit the Centre annually, including about 1,000 newly diagnosed patients. This is probably about half the total number of amyloidosis patients in the UK.
In 2005 Pepys devised a novel strategy for amyloid removal comprising the partnership between a small chemical molecule drug and a large biological molecule. He originally developed the small molecule drug, called CPHPC, to remove a normal blood protein, called serum amyloid P component (SAP), from amyloid deposits. SAP is always present in amyloid and Pepys thought that removing it completely would help the body to get rid of the deposits. Although CPHPC treatment efficiently removes almost all the SAP from the blood it does not remove all the SAP from amyloid. Patients on CPHPC remained clinically stable but their amyloid deposits did not disappear. However, the prior administration of CPHPC uniquely enables subsequent administration of antibody to SAP that specifically targets the amyloid deposits. This approach worked well in experimental models. It successfully triggers normal mechanisms of debris clearance to efficiently remove amyloid from the tissues and restore their structure and function.
The invention was patented by Pentraxin Therapeutics Ltd, the UCL spin out company created to hold Pepys’s intellectual property. The patents on CPHPC and anti-SAP antibody treatment were licensed to GSK in February 2009 within a collaborative development agreement framed to optimise the synergistic interaction of the scientific research and clinical expertise of UCL and the drug development expertise of GSK. GSK conducted all the essential development work required for clinical testing and the first in human, phase I, clinical trial in amyloidosis patients started on 1 June 2013.
The study proceeded very cautiously for safety reasons since nothing comparable had previously been attempted in humans. CPHPC has long been known to be safe and well tolerated in patients and, starting with very small doses and increasing progressively, the antibody has also been generally well tolerated so far.
CPHPC and the anti-SAP antibody have received Orphan Drug designation for the treatment of light chain (AL) amyloidosis from both the US Food and Drug Administration and the European Medicines Agency.
Proof of clinical mechanism milestone achieved for systemic amyloidosis treatment
The ongoing clinical trial of the unique, first in class, obligate therapeutic partnership of CPHPC and anti-SAP antibody, has provided compelling evidence of unequivocal removal of systemic amyloid deposits. This meets the criteria for the proof of clinical mechanism milestone under the collaborative development agreement between Pentraxin and GSK and the undisclosed milestone payment has accordingly been confirmed. The clinical trial is proceeding very satisfactorily.
Prof Mark Pepys hailed as “academic superstar” by GlaxoSmithKline
As reported in the Financial Times, GlaxoSmithKline (GSK) has announced it aims to sign up 10 academic ‘superstars’ for long term partnerships to develop medicines more cost effectively.
UCL Business is delighted to announce that the first academic ‘superstar’ to be chosen is Professor Mark Pepys, head of medicine at the Royal Free and University College Medical School in London.
Professor Pepys started up the UCL-spin out Pentraxin Therapeutics, which is developing a treatment for a rare form of amyloidosis.
Professor Pepys said: “It’s a wonderful idea and we are delighted to be working with GSK to develop new medicines for patients”.
GSK aims to work closely with leading external medical researchers until the launch of a new drug. This will allow GSK to tap their expertise while providing them with facilities, funding and incentives to be paid if a treatment proves successful.
Treatment for amyloidosis a step closer
UCL spin out company, Pentraxin Therapeutics Ltd, has hit the first milestone in its collaboration with pharmaceutical giant GlaxoSmithKline.
Pentraxin owns the IP and proprietary knowledge of Professor Mark Pepys FRS, including his invention of a new therapy for systemic amyloidosis. Systemic amyloidosis is a serious and usually fatal disease that can affect virtually any organ in the body. It is the cause of death in one per thousand of the population in developed countries and effective treatments are urgently needed.
In 2009 GSK licensed Professor Pepys’s new therapy and is developing it in collaboration with Pentraxin for early clinical trials.
The first published description of the underlying research appeared online last week and will be in print in the prestigious scientific journal Nature on 4 November 2010 (Nature 2010). The paper demonstrates efficacy of this first in class, dual small molecule antibody therapy in an experimental model.
Amyloid is composed of abnormal protein fibres that are deposited in the body’s tissues, damaging their structure and function. Diagnosis is often difficult and delayed so that, by the time the disease is recognised, most patients already have irreversible organ damage. The SAP protein from the blood accumulates in amyloid deposits and contributes to their formation and persistence. In work supported by the MRC spanning 30 years, Professor Pepys and his team from UCL discovered the role of SAP in amyloidosis and have been developing new treatments aimed at it. Initially they partnered with Roche to develop a small molecule drug, called CPHPC, which removes SAP from the blood but only partly clears it from amyloid deposits. This treatment stopped the accumulation of new amyloid but did not clear the existing deposits.
The latest development uses CPHPC to first remove SAP from the blood so that antibodies to SAP can then be safely given to target the residual SAP in the amyloid deposits. In experimental models closely resembling human disease, this treatment swiftly eliminated all the amyloid. The next stage will be to test the treatment in patients and, as mentioned above, work towards clinical trials is proceeding well in collaboration with GlaxoSmithKline.
Professor Pepys, Director of the UCL Centre for Amyloidosis and Acute Phase Proteins, said: “Our findings open up the prospect of a successful treatment for patients with amyloidosis and we are looking forward to continuing the development of the drugs for testing in the first human studies with our commercial partner GSK”.
UCL and GSK join forces to develop combined small molecule-antibody treatment for rare disease
A 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.