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

• Max Compound Muscle Action Potential Amplitude
  (mCMAP)
• 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 (MUNE)
• 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 from Natural History Studies

• Natural History Data, 89 subjects
• Test-retest ICC CMAP 0.958, MUNE 0.993 (21
  subjects)
• CMAP values across SMA subtypes are distinct and
  correlate with motor function (plt0.05)
• SMN2 copy lt3 associated with worse functional
  outcome (plt0.0001)
• CMAP values stable over six - twelve month
  periods in SMA I and III slight decline over
  this time frame in SMA II (-0.007 mV/month,
  p0.047)
• Age dependent declines in CMAP for SMA type I
  (plt0.0001) and SMA type II subjects (plt0.0001)
• CMAP at initial assessment predicts functional
  outcome (plt0.0001)

Swoboda KJ, Prior TW, Scott CE et al. Ann Neurol
200557704-712 Data courtesy of AmSMART
statistical consultant Lynda Hynan
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Experience in Clinical Trials

• Open label Phase I/II VPA trial (single center)
• Non-ambulatory (SMA type II/III subjects with at
  least 3 point increases in HFMS scores had higher
  CMAP values after 3 months treatment (p0.03)
• Increased CMAP values in type II (n29) after 6
  and 12 months treatment (p lt 0.004), and in type
  III (n11) at 3, 6 and 12 months treatment (p lt
  0.0127)
• AmSMART Riluzole Trial in Type I Infants
• ICC for maximum CMAP was 0.98 (p lt 0.0001)
• Experience with MUNE confounded by low
  enrollment, software issues, limited experience
  of investigators

Data courtesy of AmSMART statistical consultant
Lynda Hynan
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CMAP vs Motor Function, Natural History Study
Scatterplot Matrix SMA II, n71 Pairwise
correlation CMAP vs HFMS score
0.6291 plt0.0001 As CMAP increases, so does
motor function
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Max CMAP vs MHFMS-Extend (CARNI-VAL TRIAL)
Scatterplot matrix N68 subjects (types II and
III) As CMAP increases, so does motor
function Correlation0.767
Increased CMAP after 6 (p0.0022) and 12
(p0.0012) months treatment in the ambulatory
cohort indicate potential value as surrogate
outcome measure (data not shown)
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CMAP vs motor function in SMA type I
Scatterplot Matrix SMA type I, n43 Pairwise
correlation CMAP vs TIMPSI 0.4639 p0.0195
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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 subjects demonstrate variable denervation
  which can be reliably measured in a multi-center
  trial format
• CMAP values are stable in a given individual over
  a 6-12 month time period, and correlate with
  motor function
• SMA I subjects show rapidly progressive
  denervation early, with most catastrophic loss
  within the first 2 months
• Differential approach needed infants with SMA
  type I have little capacity for reinnervation,
  but SMA type III much greater capacity
• time to reach certain level of denervation (ie lt
  0.2 mV) could be explored as surrogate outcome
  for clinical trials

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Implications for Clinical Trials

• Increased SMN2 copy correlates with better distal
  innervation and motor function
• Cross-sectional population CMAP and MUNE data
  strongly supports rationale for the earliest
  possible intervention in the disease course given
  age-dependent decline
• Use of MUNE techniques would require further
  validation in multi-center context
• Would be of potential value in distinguishing
  mechanism of a given therapy