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Sökning: WFRF:(Vugts Danielle J.) > (2022) > Pharmacodynamic eva...

  • 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 ...

  • 2022-02-13
  • BioMed Central (BMC),2022
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-469207
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469207URI
  • https://doi.org/10.1186/s12872-021-02407-6DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 ...)

  • Antoni, GunnarUppsala universitet,Plattformen för Preklinisk PET-MRI,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)gunnarat (författare)
  • Al Azzam, WasfiGlaxoSmithKline, Philadelphia, PA USA.;Takeda, Lexington, MA USA. (författare)
  • Bergstrom, MatsGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Biswas, SwethajitGlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England. (författare)
  • Chen, ChaoGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Cheriyan, JosephCambridge Univ Hosp NHS Fdn Trust, Cambridge, England. (författare)
  • Cleveland, MatthewGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Cookson, LouiseGlaxoSmithKline, Cambridge, England. (författare)
  • Galette, PaulGlaxoSmithKline, Philadelphia, PA USA. (författare)
  • Janiczek, Robert L.GlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Kwong, Raymond Y.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. (författare)
  • Lukas, Mary AnnGlaxoSmithKline, Philadelphia, PA USA. (författare)
  • Millns, HelenGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Richards, DuncanGlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England. (författare)
  • Schneider, IanGlaxoSmithKline, Cambridge, England.;Consolidated Consulting LTD, Cambridge, England. (författare)
  • Solomon, Scott D.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. (författare)
  • Sörensen, JensUppsala universitet,Klinisk fysiologi,Radiologi(Swepub:uu)jenssore (författare)
  • Storey, JamesGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • Thompson, DouglasGlaxoSmithKline, Stevenage, Herts, England. (författare)
  • van Dongen, GuusVrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands. (författare)
  • Vugts, Danielle J.Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands. (författare)
  • Wall, AndersUppsala universitet,Radiologi(Swepub:uu)andewall (författare)
  • Wikström, GerhardUppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR),Klinisk epidemiologi,Uppsala Univ, Inst Med Vetenskaper, Uppsala, Sweden.(Swepub:uu)gewik021 (författare)
  • Falk, Rodney H.Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. (författare)
  • UCL, Gower St, London WC1E 6BT, England.Plattformen för Preklinisk PET-MRI (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:BMC Cardiovascular Disorders: BioMed Central (BMC)22:11471-22611471-2261

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