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@ARTICLE{Hutchison:267500,
      author       = {Hutchison, R Matthew and Fraser, Kyle and Yang, Minhua and
                      Fox, Tara and Hirschhorn, Elizabeth and Njingti, Edwin and
                      Scott, David and Bedell, Barry J and Kistner, Kristi M and
                      Cedarbaum, Jesse M and Evans, Karleyton C and Graham,
                      Danielle and Martarello, Laurent and Mollenhauer, Brit and
                      Lang, Anthony E and Dam, Tien and Beaver, John},
      title        = {{C}inpanemab in {E}arly {P}arkinson {D}isease: {E}valuation
                      of {B}iomarker {R}esults {F}rom the {P}hase 2 {SPARK}
                      {C}linical {T}rial.},
      journal      = {Neurology},
      volume       = {102},
      number       = {5},
      issn         = {0028-3878},
      address      = {[Erscheinungsort nicht ermittelbar]},
      publisher    = {Ovid},
      reportid     = {DZNE-2024-00146},
      pages        = {e209137},
      year         = {2024},
      abstract     = {Sensitive, reliable, and scalable biomarkers are needed to
                      accelerate the development of therapies for Parkinson
                      disease (PD). In this study, we evaluate the biomarkers of
                      early PD diagnosis, disease progression, and treatment
                      effect collected in the SPARK.Cinpanemab is a human-derived
                      monoclonal antibody binding preferentially to aggregated
                      forms of extracellular α-synuclein. SPARK was a randomized,
                      double-blind, placebo-controlled, phase 2 multicenter trial
                      evaluating 3 cinpanemab doses administered intravenously
                      every 4 weeks for 52 weeks with an active treatment
                      dose-blind extension period for up to 112 weeks. SPARK
                      enrolled 357 participants diagnosed with PD within 3 years,
                      aged 40-80 years, ≤2.5 on the modified Hoehn and Yahr
                      scale, and with evidence of striatal dopaminergic deficit.
                      The primary outcome was change from baseline in the Movement
                      Disorder Society-Sponsored Revision of the Unified
                      Parkinson's Disease Rating Scale total score. Secondary and
                      exploratory biomarker outcomes evaluated change from
                      baseline at week 52 relative to placebo. Dopamine
                      transporter SPECT and MRI were used to quantify changes in
                      the nigrostriatal dopamine pathway and regional atrophy. CSF
                      and plasma samples were used to assess change in total
                      α-synuclein levels, α-synuclein seeding, and neurofilament
                      light chain levels. SPARK was conducted from January 2018 to
                      April 2021 and terminated due to lack of
                      efficacy.Approximately $3.8\%$ (15/398) of SPECT-imaged
                      participants did not have evidence of dopaminergic deficit
                      and were screen-failed. Binary classification of
                      α-synuclein seeding designated $93\%$ (110/118) of the
                      enrolled CSF subgroup as positive for α-synuclein seeds at
                      baseline. Clinical disease progression was observed, with no
                      statistically significant difference in cinpanemab groups
                      compared with that in placebo. Ninety-nine percent of
                      participants with positive α-synuclein seeding remained
                      positive through week 52. No statistically significant
                      changes from baseline were observed between treatment groups
                      and placebo across biomarker measures. Broadly, there was
                      minimal annual change with high interindividual variability
                      across biomarkers-with striatal binding ratios of the
                      ipsilateral putamen showing the greatest mean change/SD over
                      time.Biomarker results indicated enrollment of the intended
                      population with early PD, but there was no significant
                      correlation with disease progression or clear evidence of a
                      cinpanemab treatment effect on biomarker measures. Suitable
                      biomarkers for evaluating disease severity and progression
                      in early PD trials are still needed.NCT03318523
                      (clinicaltrials.gov/ct2/show/NCT03318523); Submitted October
                      24, 2017; First patient enrolled January 2018.},
      keywords     = {Humans / Parkinson Disease: diagnostic imaging / Parkinson
                      Disease: drug therapy / alpha-Synuclein / Antiparkinson
                      Agents: therapeutic use / Antibodies, Monoclonal:
                      therapeutic use / Dopamine: metabolism / Biomarkers /
                      Disease Progression / Double-Blind Method / alpha-Synuclein
                      (NLM Chemicals) / Antiparkinson Agents (NLM Chemicals) /
                      Antibodies, Monoclonal (NLM Chemicals) / Dopamine (NLM
                      Chemicals) / Biomarkers (NLM Chemicals)},
      cin          = {AG Fischer},
      ddc          = {610},
      cid          = {I:(DE-2719)1410002},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38315945},
      doi          = {10.1212/WNL.0000000000209137},
      url          = {https://pub.dzne.de/record/267500},
}