Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
Pharmacotherapeutic group: <not yet assigned>
ATC code: <not yet assigned>
Avalglucosidase alfa is a recombinant human acid α-glucosidase (rhGAA) that provides an exogenous source of GAA. Avalglucosidase alfa is a modification of alglucosidase alfa in which approximately 7 hexamannose structures each containing 2 terminal mannose-6-phosphate (bis-M6P) moieties are conjugated to oxidized sialic acid residues on alglucosidase alfa. Avalglucosidase alfa has a 15-fold increase in mannose-6-phosphate (M6P) moieties compared with alglucosidase alfa. Binding to M6P receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalised and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity to degrade glycogen.
Study 1, EFC14028/COMET, was a multinational, multicentre, randomised, double-blinded study comparing the efficacy and safety of Nexviadyme and alglucosidase alfa in 100 treatment-naïve LOPD patients aged 16 to 78 years of age at the initiation of treatment. Patients were randomised in a 1:1 ratio based on baseline forced vital capacity (FVC), gender, age, and country to receive 20 mg/kg of Nexviadyme or alglucosidase alfa once every other week for 12 months (49 weeks). The study included an open-label, long-term, follow-up phase of up to 5 years for all patients, in which patients in the alglucosidase alfa arm were switched to treatment with Nexviadyme.
The primary endpoint of study 1 was the change in FVC % predicted in the upright position from baseline to 12 months (week 49). At week 49, the LS mean change (SE) in FVC % predicted for patients treated with Nexviadyme and alglucosidase alfa was 2.89% (0.88) and 0.46% (0.93), respectively. The clinically significant LS mean difference of 2.43% (95% CI: -0.13, 4.99) between Nexviadyme and alglucosidase alfa in FVC % predicted exceeded the pre-defined non-inferiority margin of -1.1 and achieved statistical non-inferiority (p=0.0074). The study did not demonstrate statistical significance for superiority (p=0.0626) and the testing of the secondary endpoints was performed without multiplicity adjustment.
The results for the primary endpoint are detailed in Table 4.
Table 4. LS Mean change from baseline to week 49 in FVC % predicted in upright position:
| Nexviadyme (n=51) | Alglucosidase Alfa (n=49) | ||
|---|---|---|---|
| Forced Vital Capacity % predicted in upright position | |||
| Pre-treatment baseline | Mean (SD) | 62.55 (14.39) | 61.56 (12.40) |
| Week 13 | LS mean (SE) change from baseline | 3.05 (0.78) | 0.65 (0.81) |
| Week 25 | LS mean (SE) change from baseline | 3.21 (0.80) | 0.57 (0.84) |
| Week 37 | LS mean (SE) change from baseline | 2.21 (1.00) | 0.55 (1.05) |
| Week 49 Estimated change from baseline to week 49 (MMRM) | Mean (SD) | 65.49 (17.42) | 61.16 (13.49) |
| LS mean (SE) change from baseline | 2.89a (0.88) | 0.46a (0.93) | |
| Estimated difference between groups in change from baseline to week 49 (MMRM) | LS mean (95% CI) p-valueb p-valuec | 2.43a (-0.13,4.99) 0.0074 0.0626 | |
MMRM: mixed model repeated measure.
a On the basis of MMRM model, the model includes baseline FVC % predicted (as continuous), sex, age (in years at baseline), treatment group, visit, interaction term between treatment group and visit as fixed effects.
b Non-inferiority margin of -1.1% c Superiority not achieved
The key secondary endpoint of study 1 was change in total distance walked in 6 minutes (6-Minute Walk Test, 6MWT) from baseline to 12 months (week 49). At week 49, the LS mean change from baseline (SE) in 6MWT for patients treated with Nexviadyme and alglucosidase alfa was 32.21 m (9.93) and 2.19 m (10.40) respectively. The LS mean difference of 30.01 m (95% CI: 1.33,58.69) showed numerical improvement with Nexviadyme compared with alglucosidase alfa. The results for the 6MWT are detailed in Table 5. Additional secondary endpoints of the study were maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), Hand-held dynamometry (HHD) summary score, quick motor function test (QMFT) total score, and SF-12 (health-related survey on quality of life, both physical and mental component scores). The results for these endpoints are detailed in Table 5.
In treatment-naïve LOPD patients aged 16 to 78, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline for patients treated with Nexviadyme 20 mg/kg every other week and alglucosidase alfa 20 mg/kg every other week was -53.90% (24.03) and -10.8% (32.33), respectively, in week 49.
Table 5. LS mean change from baseline to week 49 for additional secondary endpoints:
| Endpoint | Nexviadyme LS mean change (SE) | Alglucosidase Alfa LS mean change (SE) | LS mean difference (95% CI) |
|---|---|---|---|
| 6-minute walk test (6MWT) distance (meters)a,b | 32.21 (9.93) | 2.19 (10.40) | 30.01 (1.33, 58.69) |
| Maximum Inspiratory Pressure (MIP) (% predicted)c | 8.70 (2.09) | 4.29 (2.19) | 4.40 (-1.63, 10.44) |
| Maximum Expiratory Pressure (% predicted)c | 10.89 (2.84) | 8.38 (2.96) | 2.51 (-5.70, 10.73) |
| Hand-held dynamometry (HHD) summary scores | 260.69 (46.07) | 153.72 (48.54) | 106.97 (-26.56, 240.5) |
| Quick Motor function Test (QMFT) total score | 3.98 (0.63) | 1.89 (0.69) | 2.08 (0.22, 3.95) |
| Health-related survey on quality of life (SF-12) | PCSd score: 2.37 (0.99) MCSe score: 2.88 (1.22) | 1.60 (1.07) 0.76 (1.32) | 0.77 (-2.13, 3.67) 2.12 (-1.46, 5.69) |
a The MMRM model for 6MWT distance adjusts for baseline FVC % predicted and baseline 6MWT (distance walked in meters), age (in years, at baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
b LS mean (SE) change from baseline at Weeks 13, 25, and 37 was 18.02 (8.79), 27.26 (9.98), and 28.43 (9.06), respectively, in the avalglucosidase alfa group and 15.11 (9.16), 9.58 (10.41), and 15.49 (9.48), respectively, in the alglucosidase alfa group.
c Post-hoc sensitivity analysis excluding 4 patients (2 in each treatment arm) with supraphysiologic baseline MIP and MEP values.
d Physical Component Summary.
e Mental Component Summary.
In the EFC14028/COMET study, efficacy data were available in 24 patients at week 97, 17 patients at week 121, and 11 patients at week 145. Additionally, 9 patients randomised to alglucosidase alfa who switched the treatment to avalglucosidase alfa after week 49 continued the treatment for up to 2 years. FVC % predicted values remained elevated over baseline throughout dosing with avalglucosidase alfa for as long as 97 weeks in 24 patients who had reached this timepoint. Efficacy data in EFC14028/COMET study at week 97 for patients who switched from alglucosidase alfa to avalglucosidase alfa at week 49 showed numerical improvement for FVC % predicted and 6MWT. In the same study, the observed mean 6MWT distance remained elevated over baseline throughout dosing with avalglucosidase alfa for as long as 145 weeks in 10 patients who had reached this timepoint.
In an open-label, uncontrolled study in LOPD patients, the FVC % predicted and 6MWT showed maintenance of effect during the long-term treatment with avalglucosidase alfa 20 mg/kg every other week for up to 6 years.
Study 2, ACT14132/mini-COMET, was a multi-stage, phase 2, open-label, multicentre, multinational, repeated ascending dose cohort of Nexviadyme in paediatric IOPD patients (1-12 years of age) who demonstrated either clinical decline or sub-optimal clinical response while on treatment with alglucosidase alfa. The study enrolled a total of 22 patients; cohort 1 had 6 patients who demonstrated clinical decline and received 20 mg/kg every other week for 25 weeks, cohort 2 had 5 patients who demonstrated clinical decline and received 40 mg/kg every other week for 25 weeks, and cohort 3 had 11 patients who demonstrated sub-optimal response and received either Nexviadyme at 40 mg/kg every other week for 25 weeks (5 patients) or alglucosidase alfa at their stable pre-study dose (ranging between 20 mg/kg every other week and 40 mg/kg weekly) for 25 weeks (6 patients).
The primary objective of study 2 was to evaluate the safety and tolerability of administering Nexviadyme. The secondary objective was to determine the efficacy of Nexviadyme. Data showed stabilization or improvement in efficacy outcomes of gross motor function classification measure-88 (GMFM-88), quick motor function test (QMFT), Pompe paediatric evaluation of disability inventory (Pompe-PEDI), left ventricular mass (LVM) Z score, eyelid position measurements in patients previously declining or insufficiently controlled with alglucosidase alfa. Treatment effect was more pronounced with 40 mg/kg every other week compared to the 20 mg/kg every other week. Two out of six patients treated with Nexviadyme at 20 mg/kg every other week (cohort 1) demonstrated further clinical decline and received dose increase from 20 to 40 mg/kg every other week at week 55 and 61 respectively. All patients who received 40 mg/kg every other week maintained this dose for the duration of the study without further clinical decline.
In paediatric IOPD patients (<18 years of age) treated with Nexviadyme at 40 mg/kg every other week who demonstrated either clinical decline (cohort 2) or sub-optimal clinical response (cohort 3) while on treatment with alglucosidase alfa, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline was -40.97% (16.72) and -37.48% (17.16), respectively, after 6 months. In patients previously declining treated with Nexviadyme at 20 mg/kg every other week, mean (SD) percentage change was 0.34% (42.09).
The long-term effects of treatment with Nexviadyme were evaluated in 10 patients at week 49, 8 patients at week 73, and 3 patients at week 97. In patients with IOPD previously declining with alglucosidase alfa, the efficacy on specific parameters of decline, including motor function, cardiac left ventricular mass, and eyelid position measurements, was sustained up to 2 years.
Nineteen paediatric patients aged from 1 to 12 years with IOPD previously treated with alglucosidase alfa have been treated with Nexviadyme (see section 4.2 and 4.8) and two paediatric patients aged 9 and 16 years with LOPD was treated with Nexviadyme.
The European Medicines Agency has deferred the obligation to submit the results of studies with Nexviadyme in one or more subsets of the paediatric population for the treatment of Pompe disease (see section 4.2 for information on paediatric use).
Medical or healthcare professionals are encouraged to register patients who are diagnosed with Pompe disease at www.registrynxt.com. Patient data will be anonymously collected in this registry. The objectives of the “Pompe registry” are to enhance the understanding of Pompe disease and to monitor patients and their response to enzyme replacement therapy over time, with the ultimate goal of improving clinical outcomes for these patients.
The pharmacokinetics of avalglucosidase alfa was evaluated in a population analysis of 75 LOPD patients aged 16 to 78 years who received 5 to 20 mg/kg of avalglucosidase alfa every other week.
The pharmacokinetics of avalglucosidase alfa was characterized in 16 patients aged 1 to 12 years who were treated with avalglucosidase alfa, which included 6 patients treated with 20 mg/kg and 10 patients treated with 40 mg/kg doses every other week. All patients were treatment-experienced.
In LOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week, the mean Cmax and mean AUC2W were 273 µg/mL (24%) and 1220 µg∙h/ml (29%), respectively.
In IOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week and 7-hour IV infusion for 40 mg/kg every other week, the mean Cmax ranged from 175 to 189 μg/ml for the 20 mg/kg dose and 205 to 403 µg/ml for 40 mg/kg dose. The mean AUC2W ranged from 805 to 923 μg∙hr/ml for the 20 mg/kg dose and 1720 to 2630 μg∙hr/ml for 40 mg/kg dose.
In LOPD patients, the typical population PK model predicted central compartment volume of distribution of avalglucosidase alfa was 3.4 L.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, the mean volume of distribution at steady state ranged between 3.5 to 5.4 L.
In LOPD patients, the typical population PK model predicted linear clearance was 0.87 L/h. Following 20 mg/kg every other week, the mean plasma elimination half-life was 1.55 hours.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, mean plasma clearance ranged from 0.53 to 0.70 L/h, and mean plasma elimination half-life from 0.60 to 1.19 hours.
The exposure to avalglucosidase alfa increased in a dose-proportional manner between 5 to 20 mg/kg in LOPD patients and between 20 and 40 mg/kg in IOPD patients. No accumulation was observed following every other week dosing.
In the study 1, EFC14028/COMET, 96.1% (49 of 51 patients) receiving Nexviadyme developed treatment-emergent ADA. No clear trend of ADA impact on PK was observed.
Population pharmacokinetic analyses in LOPD patients showed that body weight, age, and gender did not meaningfully influence the pharmacokinetics of avalglucosidase alfa.
The pharmacokinetics of avalglucosidase alfa has not been studied in patients with hepatic impairment.
No formal study of the effect of renal impairment on the pharmacokinetics of avalglucosidase alfa was conducted. On the basis of a population pharmacokinetic analysis of data from 75 LOPD patients receiving 20 mg/kg, including 6 patients with mild renal impairment (glomerular filtration rate: 60 to 89 ml/min; at baseline), no relevant effect of renal impairment on avalglucosidase alfa exposure was observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity that included safety pharmacology endpoints.
Avalglucosidase alfa caused no adverse effects in a combined male and female fertility study in mice up to 50 mg/kg IV every other day (9.4 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD) (see section 4.6).
In an embryo-foetal toxicity study in mice, administration of avalglucosidase at the highest dose of 50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD) produced increased post-implantation loss and mean number of late resorptions. No effects were seen at 20 mg/kg/day (4.8 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD). Avalglucosidase alfa does not cross the placenta in mice, suggesting that the embryo-foetal effects at 50 mg/kg/day were related to maternal toxicity from the immunologic response. No malformations or developmental variations were observed.
No adverse effects were observed in an embryo-foetal toxicity study in rabbits administered avalglucosidase alfa up to 100 mg/kg/day IV (91 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD).
There were no adverse effects in a pre- and post-natal developmental toxicity study in mice following administration of avalglucosidase alfa once every other day. The NOAEL for reproduction in the dams and for viability and growth in the offspring was 50 mg/kg every other day IV.
In juvenile mice, avalglucosidase alfa was generally well tolerated following administration for 9 weeks at doses up to 100 mg/kg every other week IV (~2 to 5 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for patients with IOPD). However, the highest dose tested in juvenile animals is not enough to discard a potential risk for IOPD patients at 40 mg/kg based on exposure margin.
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