Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes.
ATC code: A16AB15.
Mechanism of action

Velmanase alfa, the active substance of Lamzede, is a recombinant form of human alpha-mannosidase.
The amino acid sequence of the monomeric protein is identical to the naturally occurring human enzyme, alpha-mannosidase.
Velmanase alfa is intended to supplement or replace natural alpha-mannosidase, an enzyme that catalyses the sequential degradation of hybrid and complex high-mannose oligosaccharides in the lysosome, reducing the amount of accumulated mannose-rich oligosaccharides.

Clinical efficacy and safety

A total of 33 patients enrolled in the exploratory and pivotal studies (20 males and 13 females, ranging in age from 6 to 35 years) were exposed to velmanase alfa in five clinical studies. Patients were diagnosed based on alpha-mannosidase activity <10% of normal activity in blood leukocytes. Patients with the most severe rapidly progressing phenotype (with a deterioration within one year and central nervous system involvement) were excluded. Based on this criteria mild to moderate patients, presenting heterogeneous severity with ability to perform endurance tests, large variability of clinical manifestations and age of onset were enrolled.

Overall effects of treatment were evaluated in the domains of pharmacodynamics (reduction of serum oligosaccharides), functional (three-minute stair climbing test (3MSCT), six-minute walking test (6MWT), and forced vital capacity (FVC) % predicted) and quality of life (childhood health assessment questionnaire (CHAQ) disability index (DI) and CHAQ VAS pain (visual analogue scale)).

In the phase 3 pivotal multi-centre, double-blind, randomised, placebo-controlled, parallel group study rhLAMAN-05, the efficacy and safety of repeated administrations of velmanase alfa over 52 weeks at a dose of 1 mg/kg given weekly as intravenous infusion were investigated. A total of 25 patients were enrolled, including 12 paediatric subjects (age range: 6 to 17 years; mean: 10.9 years) and 13 adult subjects (age range: 18 to 35 years; mean: 24.6). All but one patient were naïve to the treatment with velmanase alfa. In total 15 patients (7 paediatrics and 8 adults) received active treatment and 10 patients received placebo (5 paediatrics and 5 adults). The results (serum oligosaccharide concentration, 3MSCT, 6MWT and FVC%) are presented in table 2. A pharmacodynamic effect with statistically significant decrease of serum oligosaccharides in comparison to placebo was demonstrated. The results observed in patients below 18 years of age showed an improvement. In patients over 18 years old a stabilisation has been demonstrated. The numerical improvement of most clinical endpoints over placebo (2 to 8%) observed in the year of observation could be suggestive of the ability of velmanase alfa to slow down the existing disease progression.


Table 2: Results from placebo-controlled clinical study rhLAMAN-05 (source data: rhLAMAN-05)

Treatment with                        Treatment with             Velmanase velmanase alfa for 12 months             placebo for 12 months             alfa (n=15)                                (n=10)                 vs. placebo Patients     Baseline         Absolute             Baseline       Absolute         Adjusted actual value     change from          actual value   change from          mean Mean (SD)         baseline            Mean (SD)       baseline         difference Mean                                Mean
Serum oligosaccharide concentration (μmol/l)
Overall(1)      6.8 (1.2)        -5.11                 6.6 (1.9)        -1.61            -3.50 
[95% CI]                        [-5.66; -4.56]                      [-2.28; -0.94]   [-4.37; -2.62] p-value                                                                                 p<0.001 <18 years(2)     7.3 (1.1)        -5.2 (1.5)           6.0 (2.4)      -0.8 (1.7)           - ≥18 years(2)     6.3 (1.1)        -5.1 (1.0)           7.2 (1.0)      -2.4 (1.4) 3MSCT (steps/min)
Overall(1)    52.9 (11.2)            0.46            55.5 (16.0)        -2.16             2.62 
[95% CI]                         [-3.58; 4.50]                       [-7.12; 2.80]    [-3.81; 9.05] p-value                                                                                 p=0.406 <18 years(2)    56.2 (12.5)       3.5 (10.0)         57.8 (12.6)      -2.3 (5.4)            - 
≥18 years(2)     50.0 (9.8)       -1.9 (6.7)         53.2 (20.1)      -2.5 (6.2) 
6MWT (metres)
Overall(1)  459.6 (72.26)            3.74        465.7 (140.5)          -3.61             7.35 
[95% CI]                           [-20.32;                         [-33.10;         [-30.76; 45.46] p-value                             27.80]                          25.87]              p=0.692 
<18 years(2)   452.4 (63.9)      12.3 (43.2)         468.8 (79.5)     3.6 (43.0)            - 
≥18 years(2)   465.9 (82.7)       -2.5 (50.4)    462.6 (195.1)       -12.8 (41.6) 
FVC (% of predicted)
Overall(1)   81.67 (20.66)           8.20        90.44 (10.39)           2.30             5.91 
[95% CI]                        [1.79; 14.63]                       [-6.19; 10.79]   [-4.78; 16.60] p-value                                                                                 p=0.278 <18 years(2)    69.7 (16.8)       14.2 (8.7)         88.0 (10.9)       8.0 (4.2)            - 
≥18 years(2)    93.7 (17.7)        2.2 (7.2)         92.4 (10.8)      -2.8 (15.5) (1)
For overall: adjusted mean change and adjusted mean difference estimated by ANCOVA model are presented
(2)
By age: unadjusted mean and SD are presented.

The long-term efficacy and safety of velmanase alfa was investigated in the uncontrolled, open label, phase 3 clinical study rhLAMAN-10 in 33 subjects (19 paediatrics and 14 adults, from 6 to 35 years at treatment initiation) who previously participated in velmanase alfa studies. An integrated database was created by pooling cumulative databases from all studies with velmanase alfa. Statistically significant improvements were detected in serum oligosaccharide levels, 3MSCT, pulmonary function, serum IgG and EQ-5D-5L (euro quality of life-5 dimensions) over time, up to the last observation (table 3). The effects of velmanase alfa were more evident in patients younger than 18 years.

Table 3: Change of clinical endpoints from baseline to the last observation in rhLAMAN-10 study (source data: rhLAMAN-10)

Parameter                   Patients              Baseline          Last           p-value n=33               actual value    observation       [95% CI]
Mean          % change
(SD)       from baseline
(SD)
Serum oligosaccharide       Overall                        6.90           -62.8             <0.001 concentration (µmol/L)                                    (2.30)         (33.61)        [-74.7; -50.8] 3MSCT (steps/min)           Overall                       53.60           13.77              0.004 (12.53)         (25.83)       [4.609; 22.92]
6MWT (metres)               Overall                       466.6             7.1              0.071 (90.1)          (22.0)         [-0.7; 14.9]
FVC (% of predicted)        Overall                        84.9            10.5              0.011 (18.6)          (20.9)          [2.6; 18.5]

Data suggest that the beneficial effects of the treatment with velmanase alfa diminish with the increase of disease burden and disease-related respiratory infections.

A post-hoc multiparametric responders analysis supports the benefit of longer treatment with velmanase alfa in 87.9% of responders in at least 2 domains at last observation (table 4).

Table 4: Multiparametric responder analysis: MCID(1) Responders Rates by Endpoints and Domains (source data: rhLAMAN-05; rhLAMAN-10)

Responders Rates rhLAMAN-05 study       rhLAMAN-10 study
Domain                   Criterion                n=25                  n=33 Placebo     Lamzede         Lamzede
12 months 12 months      Last Observation
Pharmacodynamic                 Oligosaccharides      20.0%       100%            91.0% Pharmacodynamic Domain
Oligosaccharides        20.0%          100%             91.0%
Response
Functional                     3MSCT                    10.0%          20.0%            48.5% 6MWT                     10.0%          20.0%            48.5%
FVC (%)                  20.0%          33.3%            39.4%
Functional Domain Response Combined                     30.0%          60.0%            72.7% Quality of Life                CHAQ-DI                  20.0%          20.0%            42.2% CHAQ-VAS                 33.3%          40.0%            45.5%
QoL Domain                     Combined                 40.0%          40.0%            66.7% Overall response               Three domains              0            13.3%            45.5% Two domains              30.0%          73.3%            42.4%
One domain               30.0%          13.3%             9.1%
No domains               40.0%            0               3.0%
(1)
MCID: minimal clinically important difference

Paediatric population

Children below 6 years old
Use of velmanase alfa in the children below 6 years is supported by the evidence of the clinical study rhLAMAN08.

Overall, there were no safety issues from use of velmanase alfa in paediatric patients below 6 years of age with alpha-mannosidosis. Four of 5 patients developed anti-velmanase alfa antibodies during the study, and 3 patients developed neutralising/inhibitory antibodies. Two Patients (both anti-velmanase alfa antibodies positive) experienced a total of 12 IRRs, all manageable, with no event leading to discontinuation of study treatment. Two IRRs were assessed as serious and resolved on the same day of occurrence. Premedication before infusion was used, when necessary, as a measure to further reduce risks related to IRRs. Efficacy analysis demonstrated reduction in concentrations of serum oligosaccharides, increase in IgG levels, and suggested improved endurance and hearing. Lack of accumulation of velmanase alfa at steady state and the safety/efficacy results confirm that the dose of 1 mg/kg is appropriate in paediatric patients (aged below 6 years). The study suggests benefits of early treatment with velmanase alfa in children aged below 6 years.

Children age group 6 to 17 years old
Use of velmanase alfa in the age group 6 to 17 years is supported by evidence from clinical studies in paediatric (19 out of 33 patients enrolled in the exploratory and pivotal studies) and adult patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

There were no apparent pharmacokinetic gender differences in patients with alpha-mannosidosis disease.

Absorption

Lamzede is administered through intravenous infusion. At steady-state after weekly infusion administration of 1 mg/kg of velmanase alfa, the mean maximum plasma concentration was about 8 µg/mL and was reached at 1.8 hours after the start of administration corresponding to the mean infusion duration time.

Distribution

As expected for a protein of this size, the steady-state volume of distribution was low (0.27 L/kg), indicating distribution confined to plasma. The clearance of velmanase alfa from plasma (mean 6.7 mL/h/kg) is consistent with a rapid cellular uptake of velmanase alfa via mannose receptors.

Biotransformation

The metabolic pathway of velmanase alfa is predicted to be similar to other natural occurring proteins that degrade into small peptides and finally into amino acids.

Elimination

After the end of the infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with a mean terminal elimination half-life of about 30 hours.

Linearity/(Non)linearity

Velmanase alfa exhibited a linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUC increased proportionally to the dose with doses ranging from 0.8 to 3.2 mg/kg (corresponding to 25 and 100 units/kg).

Special populations

Renal or hepatic impairment
Velmanase alfa is a protein and is predicted to be metabolically degraded into amino acids. Proteins larger than 50 000 Da, such as velmanase alfa, are not eliminated renally. Consequently, hepatic and renal impairment are not expected to affect the pharmacokinetic of velmanase alfa.
Elderly (≥65 years old)

As no patients older than 41 years have been identified across Europe, no relevant use in elderly patients is expected.

Paediatric population

Pharmacokinetic data from paediatric patients recapitulate the data from the adult population. In particular, lack of accumulation of velmanase alfa at steady state, as well as the safety/efficacy data, confirm that the dose of 1 mg/kg is appropriate also in patients younger than 6 years.