TABLE 1

M1 coverage in nonclinical pivotal toxicity studies at the respective NOAEL

SpeciesDose at NOAEL
mg/kg/day
M1 Exposure at NOAEL [AUC0-24 in ng·h/ml]Animal vs. Human M1 Exposure Ratio*
MFMFMF
Monkeys1.51.52853140.430.47
Adult rats1379631951.194.78
Rats (PND31)1.51.54394060.660.61
RasH2 mice99169015802.532.37
RabbitsNA4NA303NA0.45
  • *The M1 AUC0-24,ss at the mean exposure guidance in patients with SMA (2000 ng·h/ml; parent AUC0-24,ss) was extrapolated by multiplying the parent AUC0-24,ss with the median M1/parent ratio (0.334) in patients with SMA at pivotal doses (i.e., M1 AUC0-24,ss = 2000 ng·h/ml × 0.334 = 668 ng·h/ml). The animal vs. human M1 exposure ratio is the ratio of the animal M1 AUC0-24,ss on the last day of dosing at the NOAEL dose divided by the extrapolated M1 AUC0-24,ss at the mean exposure guidance in patients with SMA (668 ng·h/ml).

  • Plasma samples taken before incorporation of M1-preservation measures into bioanalytical methods. The M1 exposure was estimated from a corresponding PK bridging study as follows: M1 AUC0-24 = (parent AUC0-24 on the last day of dosing at the NOAEL dose) × (M1/parent ratio from PK bridging study).

  • AUC0-24, AUC from time 0 to 24 h; AUC0-24,ss, steady-state AUC from time 0 to 24 h; F, females; M, males; NA, not applicable; NOAEL, no observed adverse effects level; PK, pharmacokinetics; PND, postnatal daySMA, spinal muscular atrophy.