story cohort. The Motor domain of a CLN2 Clinical Rating Scale was used to assess disease progression. Scores ranged from 3 (grossly normal) to 0 (profoundly impaired) with unit decrements representing milestone events in the loss of motor function (ability to walk or crawl). Due to the inability to establish comparability for the CLN2 Language domain ratings between the clinical study with extension and the natural history cohort, efficacy of Brineura for the Language domain cannot be established.
Twenty-four patients, aged 3 to 8 years were enrolled in the Brineura single-arm clinical study. Sixty-three percent of patients were female and 37% were male. Ninety-six percent of patients were Caucasian and 4% were Asian. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with Brineura 300 mg every other week for 48 weeks, and continued treatment during the extension period.
In the clinical study with extension, patients were assessed for decline in the Motor domain of the CLN2 Clinical Rating Scale at 48, 72 and 96 weeks. Decline was defined as having an unreversed (sustained) 2-category decline or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale. Patients’ responses to Brineura treatment were eva luated if at screening a combined Motor plus Language CLN2 score of less than 6 was recorded. Two patients with a combined Motor plus Language CLN2 score of 6 were excluded from the analyses; they maintained that score throughout the study period. The patient who terminated early was analyzed as having a decline at the time of termination. Data used in the analyses from the natural history cohort began at 36 months of age or greater and at the first time a Motor plus Language CLN2 score less than 6 was recorded.
Motor scores of the 22 Brineura-treated patients in the clinical study with extension were compared to scores of the independent natural history cohort that included 42 untreated patients who satisfied inclusion criteria for the clinical study. The results of logistic modeling with covariates (screening age, screening motor score, genotype: 0 key mutations (yes/no)), demonstrated the odds of Brineura-treated patients not having a decline by 96 weeks were 13 times the odds of natural history cohort patients not having a decline (Odds Ratio (95% CI): 13.1 (1.2, 146.9)).
Descriptive non-randomized comparison
In an unadjusted non-randomized comparison, of the 22 patients treated with Brineura and eva luated for efficacy at week 96, 21 (95%) did not decline, and only the patient who terminated early was deemed to have a decline in the Motor domain of the CLN2 Clinical Rating Scale. Results from the natural history cohort demonstrated progressive decline in motor function; of the 42 patients in the natural history cohort, 21 (50%) experienced an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale over 96 weeks.
Given the non-randomized study design, a Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to eva luate time to unreversed 2-category decline or unreversed score of 0 in the Motor domain. This model showed a lesser decrease in motor function in the Brineura-treated patients when compared to the natural history cohort (see Figure 7).
Figure 7. Estimated Time to Unreversed (Sustained) 2-Category Decline or Unreversed Score of Zero in Motor Domain for Symptomatic Pediatric |
