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Pharmacodynamic eva...
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Wechalekar, AshutoshUCL, Gower St, London WC1E 6BT, England.
(författare)
Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis : an open-label Phase 2 study and an adjunctive immuno-PET imaging study
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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2022-02-13
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BioMed Central (BMC),2022
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-469207
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469207URI
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https://doi.org/10.1186/s12872-021-02407-6DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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Background In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. Methods Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received <= 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), <= 2 doses of non-radiolabelled dezamizumab plus [Zr-89]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [Zr-89]Zr-dezamizumab cardiac uptake assessed via PET. Results Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [Zr-89]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. Conclusions Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Antoni, GunnarUppsala universitet,Plattformen för Preklinisk PET-MRI,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)gunnarat
(författare)
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Al Azzam, WasfiGlaxoSmithKline, Philadelphia, PA USA.;Takeda, Lexington, MA USA.
(författare)
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Bergstrom, MatsGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Biswas, SwethajitGlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England.
(författare)
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Chen, ChaoGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Cheriyan, JosephCambridge Univ Hosp NHS Fdn Trust, Cambridge, England.
(författare)
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Cleveland, MatthewGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Cookson, LouiseGlaxoSmithKline, Cambridge, England.
(författare)
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Galette, PaulGlaxoSmithKline, Philadelphia, PA USA.
(författare)
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Janiczek, Robert L.GlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Kwong, Raymond Y.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
(författare)
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Lukas, Mary AnnGlaxoSmithKline, Philadelphia, PA USA.
(författare)
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Millns, HelenGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Richards, DuncanGlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England.
(författare)
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Schneider, IanGlaxoSmithKline, Cambridge, England.;Consolidated Consulting LTD, Cambridge, England.
(författare)
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Solomon, Scott D.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
(författare)
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Sörensen, JensUppsala universitet,Klinisk fysiologi,Radiologi(Swepub:uu)jenssore
(författare)
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Storey, JamesGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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Thompson, DouglasGlaxoSmithKline, Stevenage, Herts, England.
(författare)
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van Dongen, GuusVrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
(författare)
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Vugts, Danielle J.Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
(författare)
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Wall, AndersUppsala universitet,Radiologi(Swepub:uu)andewall
(författare)
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Wikström, GerhardUppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR),Klinisk epidemiologi,Uppsala Univ, Inst Med Vetenskaper, Uppsala, Sweden.(Swepub:uu)gewik021
(författare)
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Falk, Rodney H.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
(författare)
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UCL, Gower St, London WC1E 6BT, England.Plattformen för Preklinisk PET-MRI
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:BMC Cardiovascular Disorders: BioMed Central (BMC)22:11471-22611471-2261
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Wechalekar, Ashu ...
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Antoni, Gunnar
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Al Azzam, Wasfi
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Bergstrom, Mats
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Biswas, Swethaji ...
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Chen, Chao
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visa fler...
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Cheriyan, Joseph
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Cleveland, Matth ...
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Cookson, Louise
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Galette, Paul
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Janiczek, Robert ...
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Kwong, Raymond Y ...
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Lukas, Mary Ann
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Millns, Helen
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Richards, Duncan
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Schneider, Ian
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Solomon, Scott D ...
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Sörensen, Jens
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Storey, James
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Thompson, Dougla ...
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van Dongen, Guus
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Vugts, Danielle ...
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Wall, Anders
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Wikström, Gerhar ...
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Falk, Rodney H.
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