Schulz et al. (2018) conducted a nonrandomized, single-arm, dose-escalation study with extension consisting of 24 pediatric individuals with symptomatic CLN2, confirmed by TPP1 deficiency, treated with cerliponase alfa (Brineura) studied over 96 weeks. The efficacy population analysis consisted of 23 individuals with a mean age of 5 years at enrollment, excluding one individual who discontinued treatment due to an unwillingness to continue study visits, though will be included in the safety analysis. Results of the cerliponase alfa (Brineura)-treated group were compared to the scores of untreated individuals from an independent natural history cohort (n=42). The matched efficacy population consisted of 21 treated individuals matched to an untreated individual. A matched comparison was also conducted using natural historical controls (NHC), which resulted in 17 match pairs for analysis based on baseline age, genotype, and motor CLN2 score. Assessments for decline in the motor domain of the CLN2 Clinical Rating Scale were done at 48, 72, and 96 weeks. Primary outcome of interest was time until the first unreversed two-point decline measured using the combined CLN2 Clinic Rating Scale Motor-Language Domain. Each functional area is scored on a scale of 3 (normal function) to 0 (total loss of function), with the highest possible score being 6. The treatment group were significantly less likely than NHCs to have an unreversed two-point decline in the combined motor-language score (hazard ratio [HR] 0.08, 95% confidence interval [CI], 0.02–0.23; P<0.001), as well as in the motor score alone (HR, 0.04; 95% CI, 0.00–0.29; P=0.002) and the language score alone (HR, 0.15; 95% CI, 0.04–0.52; P=0.003). Nine percent of treated individuals had a decline of two points at 345 days (49.2 weeks). In the 17 matched pairs after 96 weeks, the mean decrease in motor-language score was 0.50±0.71 points among the treated cohort versus 2.80±1.10 points in the NHCs. The most common adverse events among the safety population were convulsions (96%), fever (71%), vomiting (63%), hypersensitivity reactions (63%), upper respiratory tract infection (54%), and common cold (42%). Fifty-five serious adverse events were reported in 20 individuals (83%) determined to be related to either the drug or intraventricular device. Despite high adverse events, the direct intraventricular delivery of cerliponase alfa appear to sustain worsening motor and language function in pediatric individuals with CLN2. Decline was defined as having an unreversed two-point decline or an unreversed score of 0 in the motor domain of the CLN2 Clinical Rating Scale. The results showed that when compared to the natural cohort group at 96 weeks, 21 of 21 (100%) of the matched cerliponase alfa (Brineura)-treated individuals had an absence of two-point decline in motor language (ML) score compared with nine of 21 (43%) of the untreated individuals. Also, the majority (95%) of the cerliponase alfa (Brineura)-treated individuals demonstrated sustained ambulation, as evidenced by less than a two-point decline in the CLN2 motor domain score.
al, cerliponase alfa (Brineura) was given to pediatric individuals between 1 and 6 years of age (n=14) with symptomatic and presymptomatic CLN2 primarily evaluating motor function over 169 weeks (3.25 years). This study was conducted to determine safety, efficacy, and dosing and frequency among those less than 3 years of age. Thirteen of the 14 treated were matched with up to three NHCs on the basis of age, CLN2 motor score, and genotype (i.e., 0, one, or two key mutations). By week 169, none of the individuals treated with cerliponase alfa (Brineura) had a two-point decline, or score of zero, on the CLN2 scale. Among the matched NHCs (n=31), 65% of individuals had unreversed two-point decline, or score of zero, by last assessment. The median time to decline for the matched NHCs was 133 weeks. Of the NHCs under 3 years of age (n=18), 61% had a two-point decline or score of zero in the CLN2 score by last visit. The phase II study appears to demonstrate some efficacy among all pediatric individuals in the treatment group compared to the matched pairs, including those under age 3 years who were previously never evaluated prior to this clinical trial. The FDA label did not provide safety results specific to this study.
Several limitations exist among the evaluated studies. The phase II trial (NCT02678689) has not undergone the peer-review process, thereby omitting pertinent details regarding the eight individuals under 3 years of age such as participant characteristics, statistical analyses, and safety results. Further, due to the aggregation of motor and language scales, it is unclear which domain may have declined over another. Although the FDA indicates cerliponase alfa (Brineura) to slow the loss of ambulation alone, capturing language decline may be as essential as motor for a comprehensive understanding of disease progression when treated with cerliponase alfa (Brineura). Interestingly, a minimal clinically important difference on the CLN2 Clinical Rating Scale Motor-Language Domain (CLN2 scale) is typically defined as one point; however, the studies used a two-point decline to demarcate clinical importance, which may limit an understanding of the individual's true decline in motor-language function. Regardless, intraventricular administration of cerliponase alfa (Brineura) appears to demonstrate a slower or even halted rate of decline in motor and language function compared to that of historical controls in all pediatric ages. Further expansion on the current evidence will require awaiting the publication of peer-reviewed data from the phase II trial.
