Patients with CLN2 disease have shown a maintained treatment benefit, high rate of response, and lowering rates of seizure occurrence over 3 years in an ongoing extension trial.
Nicola Specchio, MD, PhD
After 3 or more years of treatment with cerliponase alfa (Brineura, BioMarin), patients with CLN2 disease have experienced a persistent treatment benefit, responder rates, and reduction in rates of seizures in an ongoing multicenter extension study, Study 190-202.
The recombinant human form of tripeptidyl peptidase 1 enzyme (rhTPP1) was the first approved treatment for forms of Batten disease, such as CLN2 disease. Among the 23 patients who continued from the original 48-week Study 190-201, the extension responder rates were at 83% (n=19) with a 12-fold reduction in the risk of a 2-point loss on the motor-language scale at 3 years.
Results of the study, led by Nicola Specchio MD, PhD, department of neuroscience, Bambino Gesu Children's Hospital, were presented in a poster at the 2019 International Epilepsy Congress, June 22-26, in Bangkok, Thailand.
Specchio and co-investigators wrote that additionally, there was an “attenuation in the loss of motor and language function compared with natural history patients” and that “adverse events, including hypersensitivity reactions and [intracerebroventricular] device-related infections, have been managed while maintaining subjects in the study.”
In the trial, the patients were administered cerliponase alfa in a 300-mg dose via an implanted Rickham or Ommaya device into the lateral cerebral ventricle every 14 days. At baseline, the mean motor language CLN2 scores was 3.5 (standard deviation [SD], 1.18; median, 3.0). In total, 71% (n=17) of the patients had ≥1 common mutation—common alleles are c.622C>T and c.509-1G>C—while 29.2% (n=7) had no common mutations.
“A response is defined as the absence of an unreversed 2-point decline or a score of 0 in the motor-language scale at 96 weeks,” Specchio and colleagues wrote, as it denotes a well-defined and significant decline in motor and language function.
At the extension baseline of 48 weeks, the responder rate was 87% (n=20; 95% CI, 66-97; P <.0002), and at 96 weeks, the responder rate remained the same. By 160 weeks, the rate had dipped slightly to the aforementioned 83% (95% CI, 61-95; P <.0013). The “durability of treatment effect is seen in the primary efficacy end point” the investigators noted.
There was also a delay in time to 2-point decline in motor-language scores with cerliponase alfa compared to the natural history of the disease (hazard ratio [HR] 0.08; 95% CI, 0.03-0.21; P ≤.0001). Ultimately, by Day 900, every patient in the natural history cohort had experienced a 2-point decline, whereas there cerliponase alfa group did not reach that point until past Day 1500.
After 96 weeks of therapy, the treatment difference was 3.3 points in motor-language score (0 to 6) change from baseline in favor of those treated with cerliponase alfa. After 160 weeks, the difference was 3.8 points in favor of the treated-group. As for change in motor-language (0 to 12) change from baseline, the respective treatment differences at 96 and 160 weeks were 5.1 and 6.8 points, both in favor of the treatment group.
A medical history of epilepsy or seizures was present in 92% (n=22) and 96% (n=23) experienced ≥1 seizure during the study period. From Week 0 to 24, the percent of patients experiencing a seizure was 88% (n=21), which decreased to 61% (n=14) by Week 72 to 96. By the last recorded date, in Week 168, the proportion of patients with seizures had been reduced to 59% (n=13). The proportion was lowest during Weeks 144 to 168, in which 48% (n=11) of patients experienced a seizure.
With respect to safety, every patient experienced at least 1 adverse event (AE). Notably, Specchio and colleagues wrote that “no deaths and no discontinuations/dose reductions due to AEs” occurred. The most common AEs were seizure (96%), pyrexia and upper respiratory tract infection (83%), and vomiting (75%). Serious AEs occurred in a number of patients, with hypersensitivity (29%) and device-related infections (21%) occurring most often.
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Specchio N, Schulz A, Gissen P, et al. Persistent treatment effect of cerliponase alfa in children with CLN2 disease: A 3 year update from an ongoing multicenter extension study. Presented at: 2019 International Epilepsy Congress. June 22-26, 2019; Bangkok, Thailand. Poster 333.