ReportSYSTEMIC AMYLOIDOSIS

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

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Science Translational Medicine  03 Jan 2018:
Vol. 10, Issue 422, eaan3128
DOI: 10.1126/scitranslmed.aan3128
  • Fig. 1 Pharmacokinetics of dezamizumab in patients with systemic amyloidosis.

    The pharmacokinetics of dezamizumab are shown here in two subjects, illustrating how plasma clearance of the antibody changes with progressive reduction of hepatic amyloid load. Subject 013 received 650 mg of dezamizumab in part A (Embedded Image) and 600 mg in part B (Embedded Image). Subject 016 received an ineffective first antibody dose in part A but then received an effective second dose of 2000 mg in part B (Embedded Image) followed by a further 2000-mg third dose in part B (Embedded Image).

  • Fig. 2 Effect on amyloid load of miridesap followed by dezamizumab.

    (A) Anterior views of radiolabelled serum amyloid P component (SAP) scintigraphy scans for amyloid in subject 014 with systemic immunoglobulin light chain (AL) amyloidosis. Images shown are for before treatment (left), 42 days after first dezamizumab dose (center), and 42 days after second dezamizumab dose (right). (B) Posterior views of radiolabelled SAP scintigraphy scans for amyloid in subject 017 with hereditary systemic fibrinogen A α-chain (AFib) amyloidosis. Images shown are before treatment (left) and 42 days after dezamizumab treatment (right).

  • Fig. 3 Liver stiffness and NT-proBNP concentration after treatment with miridesap followed by dezamizumab.

    (A and B) Serial measurements of liver stiffness using transient elastography after the start of dezamizumab infusion on day 1 in subjects with hepatic amyloidosis. Predose measurements before each dezamizumab infusion are indicated by PD. Median normal liver stiffness, 5.3 kPa (90% of individuals are <7.0 kPa). (A) Graph shows subjects with initial baseline liver stiffness ≤15kPa. Subject 007 (Embedded Image) received sequential doses of 152, 600, and 2000 mg of dezamizumab. Subject 008 (Embedded Image) received sequential doses of 246 and 600 mg. Subject 013 (Embedded Image) received sequential doses of 650 and 600 mg. Subject 014 (Embedded Image) received sequential doses of 600, 1000, and 500 mg. Subject 015 (Embedded Image) received sequential doses of 600 and 2000 mg. (B) Graph shows subjects with initial baseline liver stiffness >15kPa. Subject 009 (Embedded Image) received sequential doses of 637, 1000, and 2000 mg. Subject 010 (Embedded Image) received sequential doses of 400, 1200, and 2000 mg. Subject 011 (Embedded Image) received sequential doses of 650, 1000, and 2000 mg. Subject 016 (Embedded Image) received sequential doses of 600, 2000, and 2000 mg. Subject 019 (Embedded Image) received a single dose of 2000 mg. The interval between doses was variable: range, 3 to 12 months. (C) Serial measurements of the concentration of circulating NT-proBNP after dezamizumab treatment in subjects with proven cardiac amyloidosis. All available results are shown. S, value at screening before study; PD, predose value before each dezamizumab infusion; NT-proBNP, N-terminal pro–B-type natriuretic peptide. Results after first dose are shown on an expanded scale. Subject 018 (AL type) (Embedded Image) received sequential doses of 600, 1200, and 1200 mg of dezamizumab. Subject 020 (AL) (Embedded Image) received a single dose of 600 mg. Subject 021 (AL) (Embedded Image) received sequential doses of 600, 1200, and 1200 mg. Subject 023 [transthyretin amyloidosis (ATTR)] (Embedded Image) received a single dose of 1200 mg. Subject 024 (ATTR) (Embedded Image) received a single dose of 1000 mg. Subject 025 (ATTR) (Embedded Image) received a single dose of 600 mg. The interval between doses was variable: range, 2 to 3 months.

  • Table 1 Effect of serial dezamizumab doses in subjects with hepatic amyloidosis.

    Median normal extracellular volume (ECV), 0.29; liver stiffness, 5.3 kPa (90% <7.0 kPa); GGT, γ-glutamyl transpeptidase, 5 to 45 IU/liter. These 10 subjects were those who had definite detectable hepatic amyloidosis. Subjects 011 and 013 entered clonal relapse after first dosing session. Subject 014 suffered clonal relapse after second dose and developed rash in session 3, thus receiving only half of the planned 1000-mg dose.

    SubjectAmyloid typeDezamizumab
    dose (mg)*
    Amyloid load
    by SAP scan
    Liver ECV
    predose
    Liver ECV
    day 42
    Liver
    stiffness
    (kPa)
    predose
    Liver
    stiffness
    (kPa) day
    42
    GGT
    (IU/liter)
    predose
    GGT
    (IU/liter)
    day 42
    007AL152No change0.450.5010.49.89396
    600No change0.400.438.45.97479
    2000Liver and
    spleen reduced
    0.400.376.34.96667
    008AL246Liver reduced0.370.3314.48.913598
    600Spleen
    reduced
    0.300.245.78.94443
    009AApoAI650Liver reduced0.480.4224.211.9714331
    1000No change0.460.4417.88.9264278
    2000Liver and
    spleen reduced
    0.400.4012.56.6283211
    010AL400No change0.580.6146.525.7181158
    1200No change0.610.6648.028.0166125
    2000Liver reduced0.530.5627.316.912988
    011AL650Liver reduced0.540.5327.015.7466411
    1000No change0.580.6328.023.9401465
    2000No change0.650.6335.327.0526751
    013AL650Liver reduced0.360.295.72.82016
    600Kidney
    reduced
    0.330.353.33.71418
    Adrenal
    reduced
    014AL600Liver reduced0.350.348.94.414896
    1000Liver reduced0.340.324.37.56044
    500Liver increased0.310.324.84.83233
    015AL600No change0.420.384.95.22719
    2000Spleen
    reduced
    0.430.376.34.22418
    016AL600No change0.450.4327.727.0274240
    2000No change0.430.4035.317.3161126
    2000Liver reduced0.360.3314.813.310677
    019AL2000No change0.420.4326.632.06970

    *Doses shown are as planned unless administered doses differed greatly.

    • Table 2 Effect of dezamizumab on measures of cardiac amyloid.

      DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; N/A, not applicable.

      Subject numberAmyloid typeDose of dezamizumab (mg)*LV mass
      Predose (g)
      LV mass
      Day 42 (g)
      Cardiac DPD scan
      018AL600258246N/A
      1200248249
      1200254243
      020AL600213211N/A
      021AL600264244N/A
      1200251228
      1200225220
      023ATTR1200248255Perugini grade 2
      cardiac uptake. No
      change
      024ATTR1000255260Perugini grade 2
      cardiac uptake. No
      change
      025ATTR600196205Perugini grade 2
      cardiac uptake. No
      change

      *Dezamizumab was administered in two equal infusions, each lasting about 6 hours, on days 1 and 2.

      Supplementary Materials

      • Supplementary Material for:

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

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

        *Corresponding author. Email: m.pepys{at}ucl.ac.uk

        Published 3 January 2018, Sci. Transl. Med. 10, eaan3128 (2018)
        DOI: 10.1126/scitranslmed.aan3128

        This PDF file includes:

        • Table S1. Demographic features of participants, amyloid type and load, dezamizumab doses administered, and dosing rationale.

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