Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122, Parma, Italy
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes
ATC code: A16AB15
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.
A total of 33 patients (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 velmanase alfa for 12 months (n=15) | Treatment with placebo for 12 months (n=10) | Velmanase alfa vs. placebo | |||
|---|---|---|---|---|---|
| Patients | Baseline actual value Mean (SD) | Absolute change from baseline Mean | Baseline actual value Mean (SD) | Absolute change from baseline Mean | Adjusted mean difference |
| Serum oligosaccharide concentration (μmol/l) | |||||
| Overall1 | 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 years2 | 7.3 (1.1) | -5.2 (1.5) | 6.0 (2.4) | -0.8 (1.7) | - |
| ≥18 years2 | 6.3 (1.1) | -5.1 (1.0) | 7.2 (1.0) | -2.4 (1.4) | |
| 3MSCT (steps/min) | |||||
| Overall1 | 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 years2 | 56.2 (12.5) | 3.5 (10.0) | 57.8 (12.6) | -2.3 (5.4) | - |
| ≥18 years2 | 50.0 (9.8) | -1.9 (6.7) | 53.2 (20.1) | -2.5 (6.2) | |
| 6MWT (metres) | |||||
| Overall1 | 459.6 (72.26) | 3.74 | 465.7 (140.5) | -3.61 | 7.35 |
| [95% CI] | [-20.32; 27.80] | [-33.10; 25.87] | [-30.76; 45.46] | ||
| p-value | p=0.692 | ||||
| <18 years2 | 452.4 (63.9) | 12.3 (43.2) | 468.8 (79.5) | 3.6 (43.0) | - |
| ≥18 years2 | 465.9 (82.7) | -2.5 (50.4) | 462.6 (195.1) | -12.8 (41.6) | |
| FVC (% of predicted) | |||||
| Overall1 | 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 years2 | 69.7 (16.8) | 14.2 (8.7) | 88.0 (10.9) | 8.0 (4.2) | - |
| ≥18 years2 | 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 n=33 | Baseline actual value Mean (SD) | Last observation % change from baseline (SD) | p-value [95% CI] |
|---|---|---|---|---|
| Serum oligosaccharide concentration (μmol/l) | Overall | 6,90 (2,30) | -62,8 (33,61) | <0,001 [-74,7; -50,8] |
| 3MSCT (steps/min) | Overall | 53.60 (12.53) | 13.77 (25.83) | 0.004 [4.609; 22.92] |
| 6MWT (metres) | Overall | 466.6 (90.1) | 7.1 (22.0) | 0.071 [-0.7; 14.9] |
| FVC (% of predicted) | Overall | 84.9 (18.6) | 10.5 (20.9) | 0.011 [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: MCID1 Responders Rates by Endpoints and Domains (source data: rhLAMAN-05; rhLAMAN-10):
| Domain | Criterion | Responders Rates | ||
|---|---|---|---|---|
| rhLAMAN-05 study n=25 | rhLAMAN-10 study n=33 | |||
| Placebo 12 months | Lamzede 12 months | Lamzede Last Observation | ||
| Pharmacodynamic | Oligosaccharides | 20.0% | 100% | 91.0% |
| Pharmacodynamic Domain Response | Oligosaccharides | 20.0% | 100% | 91.0% |
| 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
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 concomitant 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 young paediatric patients (aged below 6 years). The study suggests benefits of early treatment with velmanase alfa in children aged below 6 years.
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.
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease, it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
There were no apparent pharmacokinetic gender differences in patients with alpha-mannosidosis disease.
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.
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.
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.
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.
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).
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. As no patients older than 41 years have been identified across Europe, no relevant use in elderly patients is expected.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, juvenile toxicity and toxicity to reproduction and development.
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