Lamzede

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Lamzede

Composition:

Active substance: velmanase alfa;

1 vial contains 10 mg of velmanase alfa*;

after reconstitution, 1 ml of solution contains 2 mg of velmanase alfa (10 mg/5 ml);

Excipients: disodium phosphate dihydrate; sodium dihydrogen phosphate dihydrate; mannitol; glycine.

* Velmanase alfa is produced in Chinese hamster ovary cells using recombinant DNA technology.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white to almost white powder.

Pharmacotherapeutic group.

Agents affecting the digestive system and metabolism. Other agents affecting the digestive system and metabolism. Enzymes. Velmanase alfa.

ATC code A16AB15.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Velmanase alfa, the active substance of Lamzede, is a recombinant form of human alpha-mannosidase. The amino acid sequence in the monomeric form of the protein is identical to that of the naturally occurring human enzyme, alpha-mannosidase.

Velmanase alfa is administered to increase or replace endogenous alpha-mannosidase, an enzyme that catalyzes the sequential degradation of hybrid and complex high-mannose oligosaccharides in lysosomes, thereby reducing the accumulation of high-mannose oligosaccharides.

Clinical efficacy and safety

A total of 33 patients (20 male and 13 female, aged 6 to 35 years) were enrolled in exploratory and pivotal studies and received velmanase alfa across five clinical trials. Patients were diagnosed based on alpha-mannosidase activity in blood leukocytes being < 10% of normal levels. Patients with the most severe, rapidly progressive phenotype (with deterioration of general health within one year and central nervous system involvement) were excluded from these studies. Due to this criterion, patients included in the studies had mild to moderate disease severity, with varying abilities to perform endurance tests and considerable variability in clinical manifestations and age at onset.

Overall treatment effects were assessed based on pharmacodynamic markers (reduction in serum oligosaccharide levels) and functional outcomes (three-minute stair climbing test (3MSCT), six-minute walk test (6MWT), predicted forced vital capacity (FVC%) as a percentage of predicted value), and patient-reported outcomes including quality of life (Disability Index (DI) from the Childhood Health Assessment Questionnaire (CHAQ) and pain intensity assessed by the CHAQ VAS (visual analog scale)).

In the phase 3 pivotal, multicenter, double-blind, randomized, placebo-controlled, parallel-group study rhLAMAN-05, the efficacy and safety of velmanase alfa administered at a dose of 1 mg/kg body weight weekly as an intravenous infusion were evaluated over 52 weeks. A total of 25 patients were enrolled: 12 children (aged 6 to 17 years; mean age 10.9 years) and 13 adults (aged 18 to 35 years; mean age 24.6 years). All but one patient were treatment-naïve with respect to velmanase alfa. Of these, 15 patients (7 children and 8 adults) received active treatment, while 10 patients (5 children and 5 adults) received placebo. The study results (serum oligosaccharide concentration, 3MSCT, 6MWT, and FVC%) are presented in Table 1. A pharmacodynamic effect of the investigational treatment was demonstrated, with a statistically significant reduction in serum oligosaccharide levels compared to the placebo group. Results observed in patients under 18 years of age indicated improvement in their health status. In patients over 18 years of age, treatment resulted in stabilization of disease progression. Numerical improvements in most clinical endpoints (ranging from 2 to 8%) compared to the placebo group over the 1-year observation period suggest that velmanase alfa may slow disease progression.

Table 1: Results from the clinical placebo-controlled study rhLAMAN-05 (data source: rhLAMAN-05)

(1) For all patients: adjusted mean change and adjusted mean difference are presented, calculated using the ANCOVA statistical model.

(2) By age: unadjusted mean values and SD (standard deviation) are presented.

The long-term efficacy and safety of velmanase alfa were evaluated in an uncontrolled, open-label, phase 3 clinical study rhLAMAN-10 involving 33 patients (19 children and 14 adults aged 6 to 35 years at treatment initiation) who had previously participated in velmanase alfa studies. By combining the collected databases from all velmanase alfa studies, an integrated database was created. Statistically significant improvements in serum oligosaccharide levels, 3MSCT scores, lung function, serum IgG levels, and EQ-5D-5L scores (European Quality of Life 5-Dimension 5-Level questionnaire) were observed throughout the study up to the last assessment (Table 2). The effects of velmanase alfa were more pronounced in patients under 18 years of age.

Table 2: Changes in clinical outcome measures from baseline to last assessment in the rhLAMAN-10 study (data source: rhLAMAN-10)

Data indicate that the beneficial effects of treatment with velmanase alfa decrease with increasing disease severity and in the presence of respiratory infections associated with the disease.

A retrospective multivariate analysis of responders (patients who responded to therapy) confirms the advantage of longer-term treatment with velmanase alfa in 87.9% of responders at the time of last visit, based on at least two primary outcome measures (Table 3).

Table 3: Multivariate analysis of responders: MCID(1), proportion of responders by outcome measures and primary efficacy endpoints (data source: rhLAMAN-05; rhLAMAN-10)

(1) MCID (minimal clinically important difference) – minimal clinically important difference.

Children

Children under 6 years of age

The use of velmanase alfa in children under 6 years of age is supported by data from the clinical study rhLAMAN08.

Overall, there were no safety concerns regarding the use of velmanase alfa in pediatric patients under 6 years of age with alpha-mannosidosis. Antibodies to velmanase alfa developed in four out of five patients during the study, and neutralizing/inhibiting antibodies developed in three patients. Two patients (both with positive antibodies to velmanase alfa) experienced a total of 12 infusion-related reactions (IRRs), all of which were manageable and did not lead to discontinuation of the investigational treatment. Two concomitant IRRs were considered serious and resolved on the day they occurred. Premedication prior to infusion was used as needed as a measure to further reduce risks associated with IRRs. The efficacy analysis showed a reduction in serum oligosaccharide levels, an increase in IgG levels, and suggested improvement in endurance and hearing in the patient. The absence of accumulation of velmanase alfa at steady state, together with safety/efficacy results, supports the acceptability of the 1 mg/kg dose in younger children (under 6 years of age). The study indicates benefits of early treatment with velmanase alfa in children under 6 years of age.

Children aged 6 to 17 years

The appropriateness of using velmanase alfa in children aged 6 to 17 years is supported by data from clinical studies involving pediatric (19 out of 33 patients enrolled in pivotal and reference studies) and adult patients.

This medicinal product is authorized under "exceptional circumstances". This means that, due to the rarity of the disease, it has not been possible to obtain complete information about this medicinal product.

The European Medicines Agency will review any new information annually that may become available, and the manufacturer will update this product information for medical use as necessary.

Pharmacokinetics.

No differences in pharmacokinetics of the drug were observed based on gender in patients with alpha-mannosidosis.

Absorption

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

Distribution

As expected for proteins of this size, the volume of distribution at steady state was low (0.27 L/kg), indicating that the drug distributes only within plasma. The plasma clearance of velmanase alfa (mean rate 6.7 mL/h/kg) reflects the rapid uptake of velmanase alfa by cells via mannose receptors.

Biotransformation

The metabolic pathway of velmanase alfa is likely similar to that of other natural proteins, which are degraded into small peptides and subsequently into amino acids.

Elimination

After completion of the infusion, the plasma concentration of velmanase alfa decreased in two phases; the mean elimination half-life of the drug was approximately 30 hours.

Linearity/(non)linearity

Velmanase alfa demonstrated linear (i.e., first-order) pharmacokinetic behavior; Cmax (maximum plasma concentration) and AUC (area under the concentration-time curve) increased proportionally with the dose of the drug from 0.8 to 3.2 mg/kg (corresponding to 25–100 units/kg).

Special patient groups

Renal and hepatic impairment

Velmanase alfa is a protein, and therefore it is expected to be metabolized into amino acids. Proteins with a molecular weight exceeding 50,000 Da, such as velmanase alfa, are not eliminated by the kidneys. Therefore, hepatic and renal impairment are not expected to affect the pharmacokinetics of velmanase alfa.

Elderly patients (over 65 years of age)

As there are no patients with alpha-mannosidosis over 41 years of age in Europe, it is not expected that this product will be used in elderly patients.

Children

Pharmacokinetic data obtained from pediatric patients are consistent with those from the adult population. In particular, the absence of accumulation of velmanase alfa at steady state, along with safety/efficacy data, confirms that the 1 mg/kg dose is also acceptable for patients under 6 years of age.

Non-clinical safety data

Standard non-clinical studies on pharmacological safety, repeated-dose toxicity, juvenile toxicity, and toxic effects on reproductive function and fetal development revealed no special hazard to humans.

Clinical characteristics.

Indications.

The medicinal product Lamzede is indicated for use as enzyme replacement therapy for non-neurological manifestations of the disease in patients with mild to moderate alpha-mannosidosis.

Contraindications.

Severe allergic reaction to the active substance or to any of the excipients listed in the section "Composition".

Special precautions.

Lamzede must be reconstituted before administration and may only be administered by intravenous infusion.

Each vial is for single use only.

Instructions for solution preparation and administration of the medicinal product

Only healthcare professionals are authorized to reconstitute and administer Lamzede.

All aseptic techniques must be followed during solution preparation. Filter needles must not be used during solution preparation.

1. The number of vials required for solution preparation should be calculated based on the patient's body weight. The recommended dose of 1 mg/kg is determined using the following formula:
   • Patient's body weight (kg) × dose (mg/kg) = dose of the medicinal product for the individual patient (in mg).
   • Patient's dose (in mg) divided by 10 mg/vial (content of one vial) = number of vials required for solution reconstitution. If the calculated number of vials is not a whole number, it should be rounded up to the next whole number.
   • Approximately 30 minutes before reconstitution, the required number of vials should be removed from the refrigerator. Prior to reconstitution, vials should reach room temperature (between 15 and 25 °C).

The contents of each vial are reconstituted by slowly adding 5 mL of water for injections along the inner wall of each vial. One milliliter of reconstituted solution contains 2 mg of velmanase alfa. Only the volume of solution containing the recommended dose should be administered.

Example:

• Patient's body weight (44 kg) × dose (1 mg/kg) = dose of the medicinal product for the individual patient (44 mg).
• 44 mg divided by 10 mg/vial = 4.4 vials; therefore, the contents of 5 vials should be reconstituted.
• From the total volume of reconstituted solution, only 22 mL (corresponding to 44 mg of the medicinal product) should be administered to the patient.

1. The powder in the vial should be reconstituted by slowly adding water for injections into the vial, ensuring that drops do not fall directly onto the lyophilized powder. Rapid injection of water for injections from a syringe onto the powder should be avoided to minimize foaming. Reconstituted vials should stand on a flat surface for approximately 5–10 minutes. Afterwards, each vial should be gently tilted and rotated for 15–20 seconds to enhance dissolution of the powder. Vials must not be inverted, shaken, or agitated.
2. Immediately after preparation, the reconstituted solution should be visually inspected for particulate matter and discoloration. The solution should be clear. The solution must not be used if it contains opaque particles or if discoloration is observed. Due to the composition of the medicinal product, the reconstituted solution may occasionally contain certain protein particles in the form of thin white threads or translucent fibers, which will be removed by the infusion filter during administration (see point 5).
3. The reconstituted solution should be drawn slowly and carefully from each vial to avoid foaming in the syringe. If the calculated volume of solution exceeds the capacity of a single syringe, the necessary number of syringes should be prepared immediately to allow for rapid syringe replacement during infusion.
4. The reconstituted solution must be administered using an infusion system equipped with a pump and a low protein-binding filter with a pore size of 0.22 μm. The total infusion volume is determined by the patient's body weight and must be administered over at least 50 minutes. For patients with body weight less than 18 kg and for patients receiving less than 9 mL of reconstituted solution per infusion, the infusion rate should be adjusted so that the infusion duration is ≥ 50 minutes. The maximum infusion rate is 25 mL/h (see section "Administration and dosage"). The infusion duration can be calculated using the table below:

1. When the last syringe becomes empty, it should be replaced with a 20 ml syringe filled with sodium chloride solution 9 mg/ml (0.9%) for injection. To ensure that the patient receives the portion of Lamzede remaining in the infusion system, 10 ml of sodium chloride solution should be administered through this system.

Disposal

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction

Interaction studies with other medicinal products have not been conducted.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

General considerations regarding treatment

As the disease progressively damages target organs over time, delayed initiation of treatment makes it more difficult to restore damaged organs or improve the patient's condition. Like all other enzyme replacement therapies, velmanase alfa does not cross the blood-brain barrier. The physician should be aware that treatment with velmanase alfa does not affect irreversible complications of the disease (such as skeletal deformities, multiple dysostoses, neurological manifestations, and cognitive dysfunction).

Hypersensitivity

Hypersensitivity reactions have been reported in patients during clinical trials. Appropriate medical support should be readily available during administration of velmanase alfa. If a severe allergic or anaphylactic reaction occurs, administration of velmanase alfa should be immediately discontinued and current standards of emergency medical care should be followed.

Infusion-related reactions (IRRs)

Administration of velmanase alfa may lead to the development of IRRs, including anaphylactoid reactions (see section "Adverse reactions"). IRRs observed in clinical trials with velmanase alfa were characterized by rapid onset of symptoms and mild to moderate severity.

Management of IRRs should be based on the severity of the reaction and may include: reducing the infusion rate, administration of medications such as antihistamines, antipyretics, and/or corticosteroids, and/or discontinuation of velmanase alfa infusion followed by resumption of therapy with a prolonged infusion duration. Premedication with antihistamines and/or corticosteroids may prevent further reactions in patients who required symptomatic treatment. In clinical trials, most patients did not routinely receive any premedication prior to velmanase alfa infusions.

If symptoms of angioedema (swelling of the tongue or throat), upper airway obstruction, or hypotension occur during or immediately after infusion, anaphylactic or anaphylactoid reaction should be suspected. In such cases, appropriate treatment with antihistamines and corticosteroids should be administered. In the most severe cases, current standards of emergency medical care should be followed.

According to the physician's judgment, patients should be monitored for IRRs for one hour or longer after infusion.

Immunogenicity

Antibodies may contribute to the development of adverse reactions associated with the use of velmanase alfa. In the event of severe IRRs or a decrease or loss of treatment effect, patients should be tested for the presence of antibodies to velmanase alfa to further investigate the relationship between these events. If the patient's condition worsens during ERT, discontinuation of treatment should be considered.

This medicinal product has the potential to be immunogenic. In exploratory and pivotal clinical trials, IgG antibodies to velmanase alfa were detected in 8 out of 33 patients (24%).

In a pediatric clinical trial involving patients up to 6 years of age, IgG antibodies to velmanase alfa developed in 4 out of 5 patients (80%). In this study, immunogenicity testing was performed using a different, more sensitive method; therefore, the frequency of IgG antibody formation was higher but not comparable to data from previous studies.

No clear correlation was observed between antibody titers (levels of IgG antibodies to velmanase alfa) and reduced treatment efficacy or the development of anaphylaxis or other hypersensitivity reactions.

There is no evidence that antibody formation affects the clinical efficacy or safety of the medicinal product.

Sodium content

Lamzede contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of velmanase alfa in pregnant women. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonic/fetal development, parturition, or postnatal development (see section "Preclinical safety data"). Since velmanase alfa is used to normalize alpha-mannosidase levels in patients with alpha-mannosidosis, Lamzede is not recommended for use in pregnant women unless the woman's clinical condition requires treatment with velmanase alfa.

Breastfeeding

It is unknown whether velmanase alfa or its metabolites are excreted in human breast milk. However, it is considered that absorption of velmanase alfa from milk in breastfed infants is minimal, and therefore no adverse effects are expected. Lamzede may be used during breastfeeding.

Fertility

There are no clinical data on the effect of velmanase alfa on fertility. Animal studies with the medicinal product showed no evidence of impaired fertility.

Ability to affect reaction speed when driving vehicles or operating machinery

The effect of Lamzede on the ability to drive vehicles or operate machinery is absent or negligible.

Method of Administration and Dosage

Treatment should be carried out under the supervision of a physician experienced in managing patients with alpha-mannosidosis or in administering other enzyme replacement therapies (ERT) for lysosomal storage disorders. Lamzede must be administered by a healthcare professional trained in ERT administration and emergency management.

The efficacy of treatment with velmanase alfa should be periodically evaluated, and therapy should be discontinued if there is no clear clinical benefit.

Dosage

The recommended dose of the medicinal product is 1 mg/kg of the patient's body weight, administered once weekly via controlled-rate intravenous infusion. For information on infusion rate, see the section "Method of Administration" below.

Special Patient Groups

Renal or Hepatic Impairment

Dose adjustment is not required in patients with renal or hepatic impairment.

Elderly Patients

There is no data available on the use of the medicinal product in elderly patients.

Children

No dose adjustment is necessary when administering the medicinal product to children.

Method of Administration

For intravenous use only, administered as an infusion.

Instructions for Reconstituting the Medicinal Product Prior to Administration

The reconstituted solution should be clear and colorless. Do not use the solution if particulate matter is observed or if discoloration occurs (see section "Special Precautions").

The reconstituted solution of Lamzede should be administered using an infusion system equipped with a pump and a low protein-binding filter with a pore size of 0.22 µm. The infusion duration should be individually adjusted for each patient, considering that the maximum infusion rate allowing controlled protein delivery is 25 mL/hour. The infusion should last no less than 50 minutes. The physician may choose and prescribe a lower infusion rate if clinically justified, for example, at the beginning of treatment or if the patient has previously experienced infusion-related reactions (IRRs).

Methods for calculating infusion rate and duration based on patient body weight are described in the section "Special Precautions".

To ensure timely detection of IRRs, patients should be monitored for at least one hour after completion of the infusion—duration depending on the patient’s clinical condition and the physician’s judgment. Further instructions are provided in the section "Special Considerations".

Home Infusion

Home administration of Lamzede infusions may be considered for patients who tolerate the infusions well. The decision to transition a patient to home infusions should be made following evaluation and recommendation by the treating physician. Patients who experience infusion-related reactions during home administration, including hypersensitivity or anaphylactic reactions, must immediately reduce the infusion rate or discontinue the infusion, depending on the severity of the reaction, and contact a healthcare professional. The dose and infusion rate at home must remain the same as those used in the hospital setting; adjustments are permitted only under the supervision of a healthcare professional.

Prior to initiating home infusions, the physician and/or nurse must provide appropriate training and instructions to the patient and/or caregiver.

Children

The safety profile of velmanase alfa observed in clinical trials involving children and adolescents was similar to that observed in adult patients.

Overdose

There are no reports of overdose with velmanase alfa. The highest dose administered in clinical trials was a single infusion of 100 units/kg (approximately 3.2 mg/kg). During infusion of this higher dose, one patient experienced mild and transient (lasting 5 hours) fever. No treatment was required.

For information on the management of adverse reactions, see sections "Special Considerations" and "Adverse Reactions".

Adverse Reactions

Summary of Safety Profile

The most commonly observed adverse reactions during treatment with the medicinal product were: weight increased (15%), IRRs (13%), diarrhea (10%), headache (7%), arthralgia (7%), increased appetite (5%), and limb pain (5%).

Most of these adverse reactions were non-serious. IRRs included hypersensitivity reactions in 3 patients and an anaphylactoid reaction in 1 patient. These reactions were characterized by mild or moderate severity.

A total of 4 serious adverse reactions were reported (1 patient experienced loss of consciousness, 1 patient acute renal failure, and 1 patient chills and increased body temperature). In all cases, patients recovered without any complications.

List of Adverse Reactions in Tabular Form

Adverse reactions observed in 38 patients who received velmanase alfa in clinical studies are listed below in Table 4. Adverse reactions are classified by system organ classes and frequency of occurrence according to MedDRA (Medical Dictionary for Regulatory Activities) terminology. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Table 4: Adverse reactions observed in clinical studies in patients with alpha-mannosidosis receiving velmanase alfa

(1) The most accurate terms relating to the IRRs described below.

(2) Individual adverse reactions described below.

Description of individual adverse reactions

Infusion reactions

Infusion-related reactions (IRRs) were observed in 13% of patients (5 out of 38 patients) participating in clinical studies (including hypersensitivity, cyanosis, nausea, vomiting, fever, chills, feeling of warmth, malaise, urticaria, anaphylactoid reaction, and hyperhidrosis). All were of mild or moderate severity, and two serious adverse reactions were recorded (see section "Pharmacodynamics"). All patients who experienced IRRs recovered completely.

Acute renal failure

In clinical studies, one patient developed acute renal failure considered potentially treatment-related. This was a case of moderate acute renal failure, which led to temporary discontinuation of investigational treatment and was fully resolved within 3 months. Concomitant long-term treatment with high-dose ibuprofen was noted as a potential risk factor for this adverse reaction.

Loss of consciousness

One patient experienced loss of consciousness considered related to the investigational treatment. This occurred 8 days after the last infusion and after 14 months of treatment. A relationship with the investigational drug could not be excluded despite the long interval between the last infusion and the event. The patient regained consciousness within seconds, was taken to hospital, received 9 mg/ml (0.9%) sodium chloride solution for infusion, and was discharged after 6 hours of observation. The patient continued participation in the study without dose adjustment.

No other cases of loss of consciousness related to the drug have been reported either in clinical or commercial settings.

Pediatric population

Children under 6 years of age

A total of 5 patients with alpha-mannosidosis under 6 years of age received velmanase alfa in a clinical study. The safety profile was similar to that observed in previous studies, with comparable frequency, type, and severity of adverse effects.

Children aged 6 to 17 years

The safety profile of velmanase alfa in clinical studies including children and adolescents was similar to that in adult patients. Of all patients with alpha-mannosidosis who received velmanase alfa in clinical studies, 58% (19 out of 33) were aged 6 to 17 years at study entry.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Reconstituted infusion solution

Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8 °C.

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, storage conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at a temperature of 2–8 °C.

Storage conditions.

Store and transport at 2–8 °C.

Keep in the original packaging to protect from light, in a place inaccessible to children.

Packaging.

10 mg in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Chiesi Farmaceutici S.p.A.

Manufacturer's location and address of place of business.

Via San Leonardo 96, 43122, Parma, Italy.

Marketing authorization holder.

Chiesi Pharmaceuticals GmbH.

Address of marketing authorization holder.

Gonzagagasse 16/16, 1010 Vienna, Austria.