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Pharmacodynamic eva...
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
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- Wechalekar, Ashutosh (author)
- UCL, Gower St, London WC1E 6BT, England.
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- Antoni, Gunnar (author)
- Uppsala universitet,Plattformen för Preklinisk PET-MRI,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Al Azzam, Wasfi (author)
- GlaxoSmithKline, Philadelphia, PA USA.;Takeda, Lexington, MA USA.
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- Bergstrom, Mats (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Biswas, Swethajit (author)
- GlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England.
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- Chen, Chao (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Cheriyan, Joseph (author)
- Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England.
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- Cleveland, Matthew (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Cookson, Louise (author)
- GlaxoSmithKline, Cambridge, England.
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- Galette, Paul (author)
- GlaxoSmithKline, Philadelphia, PA USA.
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- Janiczek, Robert L. (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Kwong, Raymond Y. (author)
- Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
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- Lukas, Mary Ann (author)
- GlaxoSmithKline, Philadelphia, PA USA.
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- Millns, Helen (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Richards, Duncan (author)
- GlaxoSmithKline, Stevenage, Herts, England.;Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England.
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- Schneider, Ian (author)
- GlaxoSmithKline, Cambridge, England.;Consolidated Consulting LTD, Cambridge, England.
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- Solomon, Scott D. (author)
- Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
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- Sörensen, Jens (author)
- Uppsala universitet,Klinisk fysiologi,Radiologi
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- Storey, James (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- Thompson, Douglas (author)
- GlaxoSmithKline, Stevenage, Herts, England.
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- van Dongen, Guus (author)
- Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
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- Vugts, Danielle J. (author)
- Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
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- Wall, Anders (author)
- Uppsala universitet,Radiologi
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- Wikström, Gerhard (author)
- Uppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR),Klinisk epidemiologi,Uppsala Univ, Inst Med Vetenskaper, Uppsala, Sweden.
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- Falk, Rodney H. (author)
- Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
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UCL, Gower St, London WC1E 6BT, England Plattformen för Preklinisk PET-MRI (creator_code:org_t)
- 2022-02-13
- 2022
- English.
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In: BMC Cardiovascular Disorders. - : BioMed Central (BMC). - 1471-2261 .- 1471-2261. ; 22:1
- Related links:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://bmccardiovas...
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Abstract
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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).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Keyword
- Cardiac amyloidosis
- Miridesap
- Dezamizumab
- Positron emission tomography
- Immuno-PET
- Serum amyloid P component
- Systemic amyloidosis
Publication and Content Type
- ref (subject category)
- art (subject category)
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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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show more...
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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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