Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Alimentary tract and metabolism products - enzymes,, ATC code: A16AB22.


Mechanism of action
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.

Clinical efficacy and safety

Clinical studies in patients with LOPD
Study 1, EFC14028/COMET, was a multinational, multicentre, randomised, double-blinded study comparing the efficacy and safety of Nexviazyme 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 Nexviazyme or alglucosidase alfa once every other week for 12 months (49 weeks).

Study 1 included an open-label extension treatment period where all patients in the alglucosidase alfa arm were switched to Nexviazyme and continued treatment up to at least week 145. Overall, 95 patients entered the open-label period (51 from the Nexviazyme arm and 44 from the alglucosidase alfa arm). An additional paediatric patient was enrolled directly into the extension treatment period with Nexviazyme.

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 Nexviazyme 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 Nexviazyme 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.

For patients who switched from alglucosidase alfa to Nexviazyme treatment after week 49, the LS mean change in FVC % predicted from week 49 to week 145 was 0.81 (1.08) (95% CI: -1.32, 2.95). A stabilization in FVC % predicted was maintained after the switch to Nexviazyme in the alglucosidase alfa group with similar values to the Nexviazyme group at week 145. Patients who continued in the Nexviazyme arm maintained an improvement in FVC % predicted compared with baseline.



Table 4 – LS Mean change from baseline to week 49 in FVC % predicted in upright position Nexviazyme (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) LS mean (SE) change
Week 13                                                         3.05 (0.78)                   0.65 (0.81) from baseline
LS mean (SE) change
Week 25                                                         3.21 (0.80)                   0.57 (0.84) from baseline
LS mean (SE) change
Week 37                                                         2.21 (1.00)                   0.55 (1.05) from baseline
Week 49                         Mean (SD)                     65.49 (17.42)                 61.16 (13.49) Estimated change from baseline to week 49          LS mean (SE) change
2.89a (0.88)                  0.46a (0.93)
(MMRM)                          from baseline
Estimated difference
LS mean (95% CI)                              2.43a (-0.13,4.99) between groups in                            b p-value                                       0.0074 change from baseline to p-value c                                     0.0626 week 49 (MMRM)
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 Nexviazyme 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 Nexviazyme compared with alglucosidase alfa. The results for the 6MWT are detailed in Table 5.

For patients who switched from alglucosidase alfa to Nexviazyme treatment after week 49, the LS mean change in 6MWT (distance walked in meters) from week 49 to week 145 was -2.3 m (10.6), 95% CI: -23.2, 18.7. At Week 145, a stabilization in 6MWT was observed after the switch from the alglucosidase alfa group to Nexviazyme. The Nexviazyme arm participants sustained the improvement compared with baseline.

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, who started on Nexviazyme 20 mg/kg every other week, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline to week 49 was -53.90% (24.03), which was maintained at week 145 at -53.35% (72.73) in patients who continued treatment with Nexviazyme . In patients who started on alglucosidase alfa 20 mg/kg every other week , the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline to week 49 was -10.8% (32.33), further decreased to -48.04% (41.97) at week 145 after switching from alglucosidase alfa to Nexviazyme.



Table 5 – LS mean change from baseline to week 49 for additional secondary endpoints Endpoint                           Nexviazyme                Alglucosidase Alfa           LS mean difference LS mean change (SE)          LS mean change (SE)               (95% CI) 6-minute walk test
(6MWT) distance                      32.21 (9.93)                 2.19 (10.40)             30.01 (1.33, 58.69) (meters)a,b
Maximum Inspiratory
Pressure (MIP) (%                     8.71 (2.09)                  4.33 (2.19)             4.38 (-1.64, 10.39) predicted)c
Maximum Expiratory
10.97 (2.84)                  8.35 (2.97)             2.61 (-5.61, 10.83) Pressure (% predicted)c
Hand-held dynamometry
260.69 (46.07)               153.72 (48.54)           106.97 (-26.56, 240.5) (HHD) summary scores
Quick Motor function Test
3.98 (0.63)                  1.89 (0.69)              2.08 (0.22, 3.95) (QMFT) total score
Health-related survey on       PCSd score: 2.37 (0.99)             1.60 (1.07)              0.77 (-2.13, 3.67) quality of life (SF-12)        MCSe score: 2.88 (1.22)             0.76 (1.32)              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 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.

Clinical study in patients with IOPD
Study 2, ACT14132/mini-COMET, was a multi-stage, phase 2, open-label, multicentre, multinational, repeated ascending dose cohort of Nexviazyme 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 Nexviazyme 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 Nexviazyme. The secondary objective was to determine the efficacy of Nexviazyme. 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 Nexviazyme 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 Nexviazyme 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 Nexviazyme at 20 mg/kg every other week, mean (SD) percentage change was 0.34% (42.09).

The long-term effects of treatment with Nexviazyme 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.

Paediatric population

Nineteen paediatric patients aged from 1 to 12 years with IOPD previously treated with alglucosidase alfa have been treated with Nexviazyme (see section 4.2 and 4.8) and two paediatric patients aged 9 and 16 years with LOPD was treated with Nexviazyme .

The European Medicines Agency has deferred the obligation to submit the results of studies with Nexviazyme in one or more subsets of the paediatric population for the treatment of Pompe disease (see section 4.2 for information on paediatric use).

Pompe registry

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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Patients with late-onset Pompe disease (LOPD)
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.

Patients with infantile-onset Pompe disease (IOPD)

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.

Absorption

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.

Distribution

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.


Elimination
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.

Linearity/non-linearity

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.

Immunogenicity

In the study 1, EFC14028/COMET, 95.2% (59 of 62 patients) receiving Nexviazyme developed treatment-emergent ADA. Given the variability in ADA response, no clear trend of ADA peak titre and impact on PK was evident in patients at week 49.

Special populations

Population pharmacokinetic analyses in LOPD patients showed that body weight, age, and gender did not meaningfully influence the pharmacokinetics of avalglucosidase alfa.

Hepatic impairment
The pharmacokinetics of avalglucosidase alfa has not been studied in patients with hepatic impairment.

Renal 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.