Regulatory Decision Summary for Dysport Therapeutic

Authorization was based on a double-blind, low-dose controlled, multicenter study in patients 2 to 17 years of age treated for upper limb spasticity due to cerebral palsy. A total of 60% of the patients were male and 75% of the patients were white. The muscle tone in affected parts in limb spasticity was measured by Modified Ashworth Scale (MAS), which is a six-point scale (0, 1, +1, 2, 3 and 4) ranging from no increase in muscle tone (score 0) to affected part rigid in flexion or extension (score 4). All patients in the study had a baseline MAS score ≥2 (with the majority of patients (89%) having a MAS score of 2 and no one having a MAS score of 4) in primary targeted muscle group (PTMG) in elbow flexors or wrist flexors in the study upper limb, indicating that the degree of spasticity in the studied patients was generally moderate. A total of 208 toxin naive or non-naive patients were randomised and received Dysport Therapeutic in a single dose of 2U/kg as the low-dose control (n = 69), 8 U/kg (n = 69) or 16 U/kg (n = 70) injected into primary targeted muscle group (PTMG) in the initial treatment (Treatment 1). After Treatment 1, up to 3 further treatments of Dysport Therapeutic could be administered in PTMG in the study upper limb and muscles in other limbs at doses of either 8 U/kg or 16 U/kg, or titrated up or down according to the investigator judgement with a treatment interval of at least 16 weeks. The majority of the patients had physical therapies such as occupational therapy at least 30 days prior to Treatment 1 and, at minimum, up to 16 weeks following Treatment 1. The primary efficacy endpoint was the mean change from baseline in MAS in the PTMG at Week 6 after Treatment 1. Mean Physician Global Assessment (PGA) score at Week 6 after Treatment 1 was a key secondary efficacy point. PGA is a nine-point rating scale in answering the question: How would you rate the response to treatment in the subjects upper limb since the start of the study?

A significant reduction in mean change from baseline in MAS in PTMG at Week 6 after Treatment 1 in the 8 U/kg group and the 16 U/kg group was observed compared to that in the low-dose control group (2 U/kg). PGA scores at Week 6 after Treatment 1 in the 8 U/kg group and the 16 U/kg group were numerically higher than that in the 2 U/kg group with no statistical significance.

Overall, the safety data of Dysport Therapeutic in the treatment of PUL spasticity in this study were consistent with the observed safety profile of the product in children in the approved indication of lower limb spasticity. Repeat administrations of Dysport Therapeutic at doses of 8 U/kg or 16 U/kg in the upper limb muscles and up to the total body dose of 30 U/kg or a maximum of 1,000 U (whichever was lower) were well tolerated in this population. No new safety concern was identified.

Due to the limited number of patients exposed to Dysport at 8 U/kg or 16 U/kg, this study has limitations in identifying rare drug reactions in the paediatric population.

In order to mitigate the risk of serious adverse events, especially remote spread of treatment effects, 1) the treatment interval for PUL spasticity is recommended to be at least 16 weeks in repeated treatment and 2) when combining indications, the maximum cumulative body dose in a 16-week interval should not exceed 30 Units/kg or 1,000 Units, whichever is lower, in pediatric patients.

In conclusion, the benefit/risk ratio of Dysport Therapeutic in treatment of upper limb spasticity in patients 2 to 17 years of age is considered favorable.