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  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1836-1836
    Abstract: In systemic amyloidosis, disease is caused by the extracellular accumulation of amyloid fibrils which do not elicit the normally efficient mechanisms of clearance of interstitial debris, and which progressively disrupt tissue architecture and function. Diagnosis is often late, with advanced organ dysfunction and major morbidity. The condition is usually fatal despite organ support and efforts to reduce production of the fibril precursor protein. In the most common type, AL, caused by monoclonal gammopathy, treatment with cytotoxic chemotherapy can slow or arrest amyloid deposition in some patients, and amyloid deposits may sometimes slowly regress but about 20% of patients still die within 6 months of diagnosis. No specific interventions exist for many of the rarer forms of systemic amyloidosis. Directly targeted measures are required to specifically remove amyloid deposits in order to preserve and possibly restore organ function. We have identified the normal plasma protein, serum amyloid P component (SAP), as a therapeutic target for this purpose. SAP binds to amyloid fibrils of all types and is thus always present in human amyloid deposits. Acute administration of (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC), swiftly depletes circulating SAP but leaves some SAP in amyloid deposits as an amyloid-specific antigen target. In patients with systemic AL, AA and AApoAI amyloidosis, we have lately reported that, following depletion of circulating SAP by CPHPC, a single dose of humanized monoclonal anti-SAP antibody substantially reduced the amyloid load, especially from the liver (D.B. Richards et al, New England Journal of Medicine, July 15, 2015; DOI: 10.1056/NEJMoa1504942). Here we show that repeated administration of the obligate therapeutic partnership of CPHPC with appropriate doses of anti-SAP antibody, progressively removed amyloid from the liver and other organs, including the kidney. Up to three antibody doses were given at intervals to patients, mostly with AL or AFib amyloidosis, in this second part of a phase I dose-ascending study. Treatments were generally well tolerated. Infusion reactions were largely mitigated by hydrocortisone and antihistamine premedication. Pharmacodynamic responses were associated with an early transient inflammatory cytokine response and increased CRP and SAA production, followed by substantial depletion of plasma C3 and a less marked fall in C4 and CH50. Pharmacodynamic responses were sometimes associated with self-limiting cutaneous rashes, especially in subjects without hepatic amyloidosis. Reduced amyloid load was demonstrated by radiolabelled SAP scintigraphy (liver, spleen, kidneys), extracellular volume measurement by equilibrium MRI (liver, spleen) and liver stiffness determined by transient elastography. Amyloid removal was not associated with detectable additional organ dysfunction. Abnormal liver function tests improved following clearance of hepatic amyloid. Renal parameters were stable but follow up is still too short to ascertain long term renal effects. In the preclinical mouse model, amyloid clearance mediated by anti-SAP antibody requires complement and macrophages and is effected by multinucleated giant cells. Consistent with this mechanism, the extent of amyloid clearance in patients depended on the dose of anti-SAP antibody in relation to the whole body amyloid load. In patients with hepatic and splenic amyloid, the anti-SAP antibody rapidly disappeared from the circulation, consistent with its easy access to these organs via their sinusoidal endothelium. Liver and spleen amyloid were cleared first but, after major reduction of liver and spleen load, renal amyloid was cleared by subsequent antibody doses. These preliminary observations demonstrate that progressive amyloid removal can probably be achieved in all types of systemic amyloidosis by repeated courses of CPHPC and anti-SAP antibody. A phase II study is now planned. This program is funded by GlaxoSmithKline. Figure 1. Figure 1. Disclosures Pepys: Pentraxin Therapeutics Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UK NIHR: Research Funding; UK MRC: Research Funding. Cookson:GlaxoSmithKline: Employment, Equity Ownership. Barton:GlaxoSmithKline: Employment, Equity Ownership. Berges:GlaxoSmithKline: Employment, Equity Ownership. Moon:GlaxoSmithKline: Consultancy, Research Funding. Richards:GlaxoSmithKline: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 373, No. 12 ( 2015-09-17), p. 1106-1114
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
    RVK:
    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2015
    detail.hit.zdb_id: 1468837-2
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  • 3
    In: The Journal of Clinical Pharmacology, Wiley, Vol. 61, No. 8 ( 2021-08), p. 1106-1117
    Abstract: The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question‐and‐answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small‐molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT‐related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration‐QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT‐related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit‐to‐risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.
    Type of Medium: Online Resource
    ISSN: 0091-2700 , 1552-4604
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2010253-7
    SSG: 15,3
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  • 4
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2019
    In:  Pharmaceutical Research Vol. 36, No. 9 ( 2019-9)
    In: Pharmaceutical Research, Springer Science and Business Media LLC, Vol. 36, No. 9 ( 2019-9)
    Type of Medium: Online Resource
    ISSN: 0724-8741 , 1573-904X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2036232-8
    SSG: 15,3
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