Workshop on Clinical Outcome Measures and endpoints for efficacy assessment in spinal muscular atrop

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Workshop on Clinical Outcome Measures and
endpoints for efficacy assessment in spinal
muscular atrophy13th October European Medicines
Agency, London

• Electrophysiologic Outcomes
• Kathryn J. Swoboda, MD (PCSMA)

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Definitions

• Maximum Compound Muscle Action Potential
  Amplitude
• The maximum electrical response as recorded from
  a given muscle in response to incremental
  increases in stimulation intensity and/or
  duration of a motor nerve
• A combined measure of nerve and muscle function
• Motor Unit Number Estimation
• Use of one of a variety of techniques to estimate
  the number of motor units in a given nerve-muscle
  group
• Provides an estimate of the number of motor axons
  innervating the muscle group of interest
• Amplitude and area of a given motor unit varies
  with territory and number of muscle fibers
  innervated
• Average single motor unit potential (SMUP) may
  provide information about the ability of axons to
  reinnervate as an additional measure of nerve
  function

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Relevance of Electrophysiologic Outcomes to
Disease Pathogenesis

• Improvement in motor function in response to a
  given therapy limited by
• Muscle and joint contractures, scoliosis, hip
  dislocation
• Reliable assessments of strength and function in
  the youngest infants and children who have
  potentially the most to gain
• Independent measures of nerve and muscle function
  provide a more direct measure of potential
  benefit of a given therapy on motor nerve and
  muscle function
• It is important to be able to evaluate potential
  therapies that could provide benefit when
  administered early (ie in infants), especially
• Neuroprotective agents
• Agents directed at up-regulating SMN2 function

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Protocol for ulnar mCMAP amplitude and MUNE
studies in SMA subjects

• Surface electrodes
• Ulnar nerve
• Hypothenar eminence
• CMAP
• Supramaximal
• minimum 3 - 5 placements

Swoboda KJ, Prior TW, Scott CE et al. Ann Neurol
200557704-712
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Experience in Clinical Studies and Trials

• Natural History Data (single center)
• 21 subjects ICC CMAP Npamp 0.958, CMAP Nparea
  0.958, MUNE Npamp 0.993, MUNE Nparea 0.958
• Open label Phase I/II VPA trial (single center)
• Subjects recruited from those enrolled in natural
  history study, baseline data 3-6 months each
  subject
• SMA type II subjects with 3 and 6 point increases
  in mHFMS values had higher CMAP values
• AmSMART Riluzole Trial in Type I Infants
• Of data available from six patients, ICCs for the
  2 significant measures (CMAP Npamp and CMAP
  Nparea) ranged from 0.98 to 0.99 and were all
  found to be significant (p lt 0.0001 and p
  .0004)
• Experience with MUNE confounded by low
  enrollment, software issues, limited experience
  of investigators with MUNE

Swoboda KJ, Prior TW, Scott CE et al. Ann Neurol
200557704-712 Data courtesy of AmSMART
statistical consultant Lynda Hynan
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Max CMAP vs MHFMS-Extend (CARNI-VAL TRIAL)
Cohorts 1 (type II) and 2 (type III) Scatterplot
matrix N68 subjects Correlation0.767
Also, increased CMAP amplitudes compared to
baseline after 6 (p0.0022) and 12 (p0.0012)
months treatment, cohort 2
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SMA types I and II Ulnar CMAP vs Age natural
history data SMA type I (n46) and type II
(n34)
Black circles type II presymptomatic Black
triangles type I presymptomatic Clear triangles
type I symptomatic Clear circles type II
presymptomatic Green normal controls
Updated April 07
Ulnar CMAP refers to the maximum amplitude
obtained from 3-5 G1 electrode placements
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Ulnar CMAP vs Age SMA type II, N 57, natural
history data Note Overall decline in CMAP
with age for the cohort
Green squares control - SMN1 del carrier Black
circles presymptomatic SMA II Open circles
symptomatic SMA II
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Implications for Clinical Trials

• SMA II and III subjects demonstrate widely
  differing levels of denervation which correlate
  with motor function using MHFMS and differing
  extend modules
• (independent data acquired by Utah (single site),
  PCSMA (multi-center clinical trial) and PNCR
  networks (multi-center natural history )
• SMA I subjects show severe and rapidly
  progressive denervation very early in the disease
  course, with most catastrophic loss within the
  first 2 months data correlating motor function
  (TIMPSI or INTEND) with CMAP still in progress
• there is little capacity for collateral
  reinnervation in SMA type I, while there is great
  capacity in SMA type III, so looking for change
  in CMAP may be reasonable in SMA III but not SMA
  I
• time to reach certain level of denervation (ie lt
  0.2 mV) could be further explored as potential
  outcome for clinical trials
• Increased SMN2 copy correlates with better
  distal innervation and motor function
  electrophysiologic data strongly supports
  rationale for the earliest possible intervention
  in the disease course
• Use of MUNE techniques would further validation,
  but would be of potential value in distinguishing
  mechanism of a given therapy.

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Acknowledgements

• Project Cure SMA Investigators Network
• PNCR Investigators Network
• AmSMART Investigators Network
• TREATNMD
• Families of SMA
• Muscular Dystrophy Association USA
• FightSMA