Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis

Richards, Duncan; Cookson, Louise; Barton, Sharon V.; Liefaard, Lia; Lane, Thirusha; Hutt, David F.; Ritter, James M.; Fontana, Marianna; Moon, James; Gillmore, Julian D.; Wechalekar, Ashutosh; Hawkins, Philip N.; Pepys, Mark B.

doi:10.1126/scitranslmed.aan3128

Cited by 109 publications

(96 citation statements)

References 25 publications

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“…It is administered after depletion of circulating serum SAP by miridesap /CPHPC, which allows dezamizumab to specifically target and degrade SAP‐containing amyloid deposits via complement activation and a macrophage‐dependent phagocytic clearance mechanism, similar to the one described above . Following promising results in murine models, an open‐label multi‐dose phase 1 trial, administering serial doses of dezamizumab, was conducted on 38 patients with systemic amyloidosis, three of which suffered from ATTR . Herein, dezamizumab reduced amyloid deposits in the kidney (especially at >1200 mg) and liver (especially at >2000 mg), as assessed by SAP scintigraphy and liver stiffness, in a dose‐dependent fashion .…”

Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

“…Following promising results in murine models, an open‐label multi‐dose phase 1 trial, administering serial doses of dezamizumab, was conducted on 38 patients with systemic amyloidosis, three of which suffered from ATTR . Herein, dezamizumab reduced amyloid deposits in the kidney (especially at >1200 mg) and liver (especially at >2000 mg), as assessed by SAP scintigraphy and liver stiffness, in a dose‐dependent fashion . An effect on cardiac amyloid deposits could not be shown, although transient increases in N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) were interpreted as the initiation of a mechanism for potential cardiac amyloid clearance …”

Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

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Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild‐type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin‐3‐gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided.

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Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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“…Plasma SAP levels lower than 3 mg·L −1 were achieved from 24 hr post‐dose onwards (see Figure ). Although a defined target degree of SAP depletion has not been formally established, these concentrations allowed administration of anti‐SAP antibodies in clinical studies in systemic amyloidosis (Richards et al, ; Richards et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Follow‐up exercise testing, echocardiogram, and 48‐hr Holter recording were normal. Miridesap has not been associated with arrhythmias in clinical studies to date, including patients with cardiac amyloidosis (Gillmore et al, ; Richards et al, ; Richards et al, ). Preclinical profiling against a wide range of ion channels and in vivo pharmacology studies did not identify a pro‐arrhythmic potential for GSK294 or miridesap.…”

Section: Resultsmentioning

confidence: 99%

“…In systemic amyloidosis, a clinical disorder that is caused by a progressive accumulation of insoluble, misfolded deposits of normally soluble precursor proteins (amyloid) in the extracellular matrix of target organs, SAP universally decorates amyloid deposits and contributes to their persistence. Professor Pepys identified SAP as a drug target in systemic amyloidosis, which led to the development of miridesap (Pepys et al, ) and subsequently dezamizumab (anti‐SAP monoclonal antibody) for clinical testing (Bodin et al, ; Richards et al, ; Richards et al, ). Miridesap is a small molecule depleter of circulating SAP with a unique mechanism of action; it non‐covalently crosslinks pentameric SAP molecules to form a decameric complex that is rapidly removed from the circulation (Pepys et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

Richards

Bamford

Liefaard

et al. 2020

British J Pharmacology

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Background and Purpose Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro‐drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability. Experimental Approach We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing. Key Results GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro‐drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear. Conclusion and Implications Using a preclinical screening cascade, we identified a pro‐drug for a palindromic molecule with unique pharmacology (miridesap). The pro‐drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap.

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Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment

Gertz

2018

American J Hematol

109

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Upon completion of this educational activity, participants will be better able to: Master recognition of clinical presentations that should raise suspicion of amyloidosis. Understand simple techniques for confirming the diagnosis and providing material to classify the protein subunit. Recognize that a tissue diagnosis of amyloidosis does not indicate whether the amyloid is systemic or of immunoglobulin light chain origin. Understand the roles of the newly introduced chemotherapeutic and investigational antibody regimens for the therapy of light chain amyloidosis.

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Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis

Cited by 109 publications

References 25 publications

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment

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