The efficacy of BRINEURA was assessed over 96 weeks in a non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, confirmed by TPP1 deficiency. BRINEURA-treated patients were compared to untreated patients from a natural history 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 (Trial 1, NCT01907087). Sixty-three percent of patients were female and 37% were male. Ninety-six percent of patients were White and 4% were Asian; for ethnicity, 4% identified as Hispanic/Latino, 96% as non-Hispanic/Latino. 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 by intraventricular infusion for 48 weeks, and continued treatment during the 240-week extension period, Trial 2 (NCT02485899), for a total duration of 288 weeks, plus a 24-week safety follow-up.

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 evaluated 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 evaluated 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 evaluate 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).

Motor Domain Scores: Matched Patients Only

To further assess efficacy, the 22 patients from the BRINEURA clinical study with a baseline combined Motor plus Language CLN2 score less than 6 were matched to 42 patients in the natural history cohort. Patients were matched based on the following covariates: baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening.

Using the Motor domain of the CLN2 Clinical Rating Scale, decline was defined as having an unreversed 2-category decline or an unreversed score of 0. At 96 weeks, the matched analysis based on 17 pairs demonstrated fewer declines in the Motor domain for BRINEURA-treated patients compared to untreated patients in the natural history cohort (see Table 6).

Trial 3 (NCT02678689) was a Phase 2, open label clinical study designed to enroll symptomatic and presymptomatic CLN2 patients less than 18 years of age. The trial enrolled 14 patients ranging in age from 1 to 6 years at baseline, including 8 patients less than 3 years of age, the median age was 2.7 years. Patients received BRINEURA at the recommended dose every 2 weeks by intraventricular infusion for 144 weeks (1 patient withdrew to receive treatment commercially). Fifty-seven percent of patients were female and 43% were male. All patients were White; for ethnicity, 14% identified as Hispanic/Latino, 86% as non-Hispanic/Latino. The mean baseline CLN2 Motor score was 2.3 (standard deviation (SD) 0.83) with a range from 1 to 3.

Thirteen of the 14 BRINEURA treated patients were matched with up to 3 natural history comparators on the basis of age within 3 months, equal CLN2 Motor score, and genotype (0, 1, or 2 key mutations). None of the BRINEURA treated patients (N=14) had a 2-point decline or score of zero in the Motor scale by Week 169. Among the matched natural history comparators (N=31), 20 subjects (65%) had an unreversed 2-point decline or score of zero by last assessment.

The median time to an unreversed 2-point decline in Motor score or score of 0 was 133 weeks among the natural history comparators and was not reached by last assessment (Week 169) in patients treated with BRINEURA.

In patients below 3 years of age, none (0%) of the BRINEURA treated patients (N=8) had a 2-point decline or score of zero in the Motor score by Week 169. Among the 8 treated patients, 7 were matched to 18 untreated patients from the natural history cohort. Among the matched natural history comparators (N=18), 11 subjects (61%) had an unreversed 2-point decline or score of zero in the Motor score by last assessment. All seven of the treated patients below 3 years of age with a motor score of 3 at baseline remained at a motor score of 3 at the last measured timepoint, which represents grossly normal gait. In this population BRINEURA treated patients showed a delay in disease onset.