BRINEURA 150MG Solution for infusion

Pharmacotherapeutic group: alimentary tract and metabolism, other drugs, enzymes, ATC code: A16AB17. Mechanism of action Cerliponase alfa is a recombinant form of human tripeptidyl peptidase-1 (rhTPP1).​​​‍​​‍​​​​‍​​‍‍ Cerliponase alfa is a proteolytically inactive proenzyme (zymogen) that is activated in the lysosome. Cerliponase alfa is taken up by target cells and transported to lysosomes via the cation-independent mannose-6-phosphate receptor (CI-MPR, also known as the M6P/IGF2 receptor). The glycosylation profile of cerliponase alfa results in consistent cellular uptake and lysosomal targeting for activation. The activated proteolytic enzyme (rhTPP1) cleaves tripeptides from the N-terminus of target proteins without known substrate specificity. Deficient levels of TPP1 cause CLN2 disease, leading to neurodegeneration, loss of neurological function, and death in childhood. Immunogenicity Anti-drug antibodies (ADA) were frequently detected in both serum and cerebrospinal fluid. No evidence of ADA impact on pharmacokinetics, efficacy, or safety was observed. However, data are limited. Clinical efficacy and safety The safety and efficacy of Brineura were evaluated in three open-label clinical studies in a total of 38 patients with CLN2 disease aged 1 to 9 years at baseline, compared with untreated CLN2 patients from a natural history database (natural history control group). These studies used the motor and language domains of a disease-specific clinical rating scale (see Table 3) to assess disease progression (referred to as the CLN2 clinical rating scale ML score). Each domain includes a score from 3 (apparently normal) to 0 (severely impaired) with a total possible score of 6, where unit decrements represent key events in the loss of previously acquired walking and speech abilities. Table 3: Motor-Language Score – CLN2 Clinical Rating Scale Domain Score Assessment Motor 3 Apparently normal gait. No conspicuous ataxia, no pathological falls. 2 Independent walking defined as the ability to take 10 unsupported steps. Will have obvious instability and may have occasional falls. 1 Requires external assistance for walking or can only crawl/creep. 0 Can no longer walk or crawl/creep. Language 3 Apparently normal language. Intelligible and generally age-appropriate. No decline has been noted yet. 2 Language has become recognizably abnormal: some intelligible words, can form short sentences to communicate ideas, requests, or needs. This score signifies decline from a previous level of ability (from the individual maximum the child achieved). 1 Hardly intelligible. Few recognizable words. 0 No intelligible words or vocalizations. In the pivotal study 190-201, a total of 24 patients aged 3 to 9 years at baseline were treated with Brineura 300 mg every other week. Of these, 23 patients were treated for 48 weeks (1 patient discontinued early after Week 1 due to inability to continue with study procedures). Mean baseline ML score was 3.5 (standard deviation (SD) 1.20) with a range of 1 to 6; no patients with advanced disease progression were enrolled (inclusion criteria: mild to moderate CLN2 disease progression). A total of 20 of 23 (87%) patients receiving Brineura for 48 weeks did not have an irreversible 2-point decline, compared with the expected 2-point decline over 48 weeks in the untreated patient population (p = 0.0002, binomial test assuming p 0 = 0.50). A total of 15 of 23 patients (65%) had no overall decline in ML score, regardless of baseline score, and 2 of these 15 patients had a one-point score increase during the treatment period. Five patients had a one-point decrease and 3 patients had a 2-point decrease. All 23 patients completed study 190-201 and continued into extension study 190-202, in which they were treated with Brineura 300 mg every other week for a total duration of 288 weeks. Efficacy results from studies 190-201 and 190-202 were pooled and compared with a natural history control group that included patients who met the inclusion criteria for studies 190-201 and 190-202. Median time to irreversible 2-point decline or reaching an ML score of 0 in Brineura-treated patients (n = 23) was 272 weeks compared with 49 weeks in the natural history control group (n = 42) (hazard ratio 0.14, 95% CI 0.06 to 0.33; p < 0.0001). Median time to reaching an ML score of 0, indicating loss of all ability to move and communicate, was not reached in Brineura-treated patients compared with 109 weeks in the natural history control group (hazard ratio 0.01; 95% CI 0.00 to 0.08; p < 0.0001). An exploratory survival analysis showed that the estimated median age of death in the natural history control group was 10.4 years; 95% CI, 9.5 to 12.5 years. No deaths occurred in Brineura-treated patients during the study, with a median (min, max) age at last assessment of 10.3 (7.8; 13.1) years (n = 23). In patients treated with Brineura 300 mg every other week, the mean rate of decline was 0.38 points per 48 weeks. When compared with the estimated natural history rate of decline of 2.13 points per 48 weeks, the study results are statistically significant (p < 0.0001) (see Table 4). The observed treatment effect was considered clinically meaningful relative to the natural history of untreated CLN2 disease. Table 4: Motor-Language CLN2 Clinical Rating Scale 0 to 6 Points: Rate of Decline per 48 Weeks (Intent-to-Treat (ITT) Population) Rate of decline (points / 48 weeks) a Study 190-201/202 participantsTotal (n = 23) Natural history controlgroup (n = 42) p-value b Mean (SD) 0.38 (0.499) c 2.13 (0.952) c <0.0001 Median 0.30 2.08 Min, max 0.00; 2.18 0.45; 4.27 95% CI limits 0.16; 0.59 1.84; 2.43 a Rate of decline per patient per 48 weeks: (baseline CLN2 score – last CLN2 score) / (elapsed time in units of 48 weeks) b p-value based on a one-sample T-test comparing rate of decline to a value of 2 c Positive estimates indicate clinical deterioration; negative estimates indicate clinical improvement Estimated mean change from baseline in Brineura-treated patients compared with the natural history control group (n = 42 patients) demonstrated attenuation of disease progression and durability of treatment effect up to the last assessment (Week 321) (see Figure 2). Figure 2: Mean Change from Baseline in Motor-Language Score on a 0–6 Point Scale (Natural History Control Group vs. Brineura-Treated Patients Week Natural History N: CLN2 Change from Baseline 300 mg every other week) Vertical bars represent the standard error of the mean Solid line: clinical studies 190-201 and 190-202 Dashed line: natural history control group 190-901 Volumetric MRI measurements show a reduced rate of loss. In study 190-203, a total of 14 patients with CLN2 disease aged 1 to 6 years at baseline (8 of 14 patients were younger than 3 years) were treated with Brineura for up to 142.6 weeks (1 patient withdrew from treatment to receive commercial treatment) and safety follow-up for 24 weeks. The mean (SD) baseline ML score was 4.6 (1.69) with a range of 1 to 6. Brineura-treated patients were compared with natural history comparators matched by age, CLN2 motor-language score, and combined genotype. The mean (±SD) rate of decline on the ML scale was 0.15 (0.243) points per 48 weeks for matched Brineura-treated patients (n = 12) and 1.30 (0.857) points per 48 weeks for matched natural history comparators (n = 29). The mean difference in rate of decline between groups was 1.15 points (SE 0.174), 95% CI 0.80, 1.50 points; p < 0.0001). Median time to irreversible 2-point decline or a score of 0 in Brineura-treated patients was not reached by the last assessment (Week 169) compared with 103 weeks among natural history comparators (hazard ratio 0.091: 95% CI, 0.021; 0.393; p < 0.0001). Median time to reaching an ML score of 0 was not reached in Brineura-treated patients compared with 163 weeks among matched natural history comparators (hazard ratio 0.00; 95% CI, 0.00; 0.00; p = 0.0032). A total of 10 of 12 (83%) treated patients had less than a 2-point decline on the ML scale from initial to last assessment. Eight patients (67%) had no clinical progression on the ML scale, two patients (17%) lost one point, and two patients (17%) lost 2 points. None of the treated patients reached a zero score on the ML scale compared with 10 of 29 (34%) matched natural history comparator patients. In patients younger than 3 years, the mean (SD) rate of decline on the ML scale was 0.04 (0.101) points per 48 weeks for matched treated patients (n = 8) compared with 1.09 (0.562) points per 48 weeks for matched natural history comparators (n = 20) (difference 1.05 points; p < 0.0001). Seven of the treated patients younger than 3 years with a baseline ML score of 6 remained at an ML score of 6 at the last measured time point, representing apparently normal gait and speech. Three of these seven patients remained free of any additional CLN2 disease symptoms at Week 145, as assessed by the CLN2 rating scale, brain imaging, and adverse events, while all matched comparators had developed symptoms. In this Brineura-treated patient population, a delay in disease onset was demonstrated. Exceptional circumstances This medicinal product has been authorised under "exceptional circumstances". This means that due to the rarity of the disease for which it is indicated, it has not been possible to obtain complete information on the benefits and risks of this medicinal product. The European Medicines Agency will review any new information that may become available on an annual basis and this summary of product characteristics will be updated as necessary.