Vpriv

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VPRIV (VPRIV)

Composition:

Active substance: velaglucerase alfa;

1 vial contains 400 IU of velaglucerase alfa;

Excipients: sucrose; sodium citrate, dihydrate; citric acid, monohydrate; polysorbate 20.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white or off-white powder.

After reconstitution – clear or slightly opalescent, colorless solution.

Pharmacotherapeutic group. Medicinal products for the treatment of gastrointestinal disorders and metabolic diseases. Enzymes.

ATC Code: A16AB10.

Pharmacological Properties

Pharmacodynamics

Gaucher disease is an autosomal recessive disorder caused by mutations in the glucocerebrosidase gene, resulting in deficiency of the lysosomal enzyme beta-glucocerebrosidase. In patients with Gaucher disease, glucocerebroside accumulates progressively in macrophages, leading to cellular infiltration and the formation of foamy cells or Gaucher cells.

The disease belongs to the group of lysosomal storage disorders. Its clinical manifestations are due to the distribution of Gaucher cells in organs and tissues, and include the development of organomegaly, skeletal deformities and abnormalities, bone crises, and sometimes severe anemia and thrombocytopenia.

Velaglucerase alfa is an enzyme produced using a human cell line via gene activation technology. The monomer molecular weight is approximately 63 kDa. Velaglucerase alfa is a glycoprotein consisting of 497 amino acids and contains 5 N-linked glycosylation sites, 4 of which are occupied by glycans rich in mannose. The mannose residues allow the enzyme to specifically bind to mannose receptors on the cell surface, promoting targeted cellular internalization of the enzyme into intracellular lysosomes, followed by catabolism of accumulated glucocerebroside.

Velaglucerase alfa replaces the deficient beta-glucocerebrosidase enzyme, which catalyzes the breakdown of glucocerebroside into glucose and ceramide within lysosomes. This reduces the accumulation of glucocerebroside and improves the pathophysiological manifestations of type I Gaucher disease: hemoglobin concentration and platelet count increase, and liver and spleen volumes decrease.

Clinical Efficacy and Safety

Studies in treatment-naïve patients

Study 025 – an open-label, 9-month study involving 12 adult (≥ 18 years) patients who had not previously received enzyme replacement therapy (i.e., had not received it for at least 12 months prior to study initiation). Velaglucerase alfa was initially administered to 3 patients at escalating doses (15, 30, 60 U/kg), while treatment in the other 9 patients started at 60 U/kg.

Clinically meaningful increases in hemoglobin concentration and platelet count were observed as early as 3 months after initiation of treatment. Reductions in liver and spleen volumes occurred by 6 and 9 months, respectively.

Ten patients who completed study 025 participated in an open-label extension study (025EXT), 8 of whom completed it. After at least 12 months of continued treatment with velaglucerase alfa, all patients had their dose reduced from 60 to 30 U/kg upon achieving at least 2 of the 4 "Year 1" therapeutic goals for enzyme replacement therapy in type I Gaucher disease.

Patients received doses ranging from 30 to 60 U/kg (mean dose 35 U/kg) once every two weeks for 84 months (7 years). Sustained clinical efficacy was demonstrated throughout treatment, with improvements in hemoglobin concentration, platelet count, and reductions in liver and spleen volumes.

By month 57, 8 out of 8 patients achieved at least a 2-point reduction in bone marrow burden score in the lumbar spine assessed by MRI. Improvement in mean Z-score of the lumbar spine and femoral neck bone mineral density was observed by month 24 (0.4; 95% confidence interval [CI] 0.1, 0.7) and month 33 (0.4; 95% CI 0.2, 0.6), respectively. After 7 years of treatment, the mean improvement in Z-scores from baseline was 0.7 (95% CI 0.4, 1.0) for the lumbar spine and 0.5 (95% CI 0.2, 0.7) for the femoral neck. No patient was reclassified to a more severe WHO category based on bone density compared to baseline.

Study 032 – a 12-month, randomized, double-blind, parallel-group study evaluating efficacy in 25 patients aged ≥2 years who had not previously received enzyme replacement therapy (i.e., had not received it for at least 30 months prior to study initiation). Patients were also required to have Gaucher disease-related anemia and thrombocytopenia or organomegaly. Patients were randomized to receive velaglucerase alfa at 45 U/kg (N = 13) or 60 U/kg (N = 12) once every two weeks.

Administration of velaglucerase alfa at 60 U/kg intravenously once every two weeks demonstrated clinically significant increases in mean hemoglobin concentration (+2.4 g/dL) and platelet count (+50.9 × 10⁹/L) compared to baseline, with liver volume decreasing from 1.46 to 1.22 times normal (mean reduction 17%) and spleen volume decreasing from 14.0 to 5.75 times normal (mean reduction 50%). At the 45 U/kg dose, significant increases were observed in hemoglobin concentration (+2.4 g/dL) and platelet count (+40.9 × 10⁹/L) compared to baseline, with liver volume decreasing from 1.40 to 1.24 times normal (mean reduction 6%) and spleen volume decreasing from 14.5 to 9.50 times normal (mean reduction 40%).

Study 039 – a 9-month, randomized, double-blind, parallel-group, non-inferiority study comparing velaglucerase alfa with the active comparator imiglucerase in 34 patients aged ≥2 years who had not previously received enzyme replacement therapy (i.e., had not received it for at least 12 months prior to study initiation). Patients were required to have Gaucher disease-related anemia and thrombocytopenia or organomegaly. Patients received either 60 U/kg (N = 17) of velaglucerase alfa or 60 U/kg (N = 17) of imiglucerase once every two weeks.

The mean absolute increase from baseline in hemoglobin concentration was 1.624 g/dL (± 0.223) over 9 months of treatment with velaglucerase alfa. This increase in hemoglobin concentration was demonstrated to be clinically and statistically non-inferior to that of imiglucerase (mean change difference from baseline [velaglucerase alfa – imiglucerase]: 0.135 g/dL). There were no statistically significant differences between velaglucerase alfa and imiglucerase in changes in platelet count, liver and spleen volumes over 9 months of treatment, or in time to first hemoglobin response (defined as an increase of 1 g/dL from baseline).

Studies in patients switching from imiglucerase to velaglucerase alfa

Study 034 – a 12-month, open-label safety study involving 40 patients aged ≥2 years who had received imiglucerase at doses of 15–60 U/kg for at least 30 consecutive months. The dose had to be stable for at least the last 6 months prior to study initiation. Velaglucerase alfa was administered at the same dose and regimen as imiglucerase. Changes in hemoglobin concentration and platelet count were calculated relative to baseline values defined at the end of imiglucerase treatment. Patients previously receiving less than 15 U/kg of imiglucerase were assigned to 15 U/kg of velaglucerase alfa.

In patients switching from imiglucerase to velaglucerase alfa, hemoglobin concentration and platelet count remained at therapeutic levels throughout the 12-month treatment period.

Study 058 – an open-label clinical safety study involving 211 patients, including 205 patients previously treated with imiglucerase and 6 treatment-naïve patients. The age of 57 patients was over 65 years (56 of whom had previously received imiglucerase). Patients previously treated with imiglucerase received velaglucerase alfa infusions once every two weeks at the same dose as imiglucerase, ranging from 15 to 60 U/kg.

Patients previously treated with imiglucerase received a mean of 8 infusions of velaglucerase alfa over a mean duration of 15.1 weeks. The safety profile in these patients was similar to that observed in previous clinical trials. Only 1 out of 163 patients developed antibodies to velaglucerase alfa during the study.

Mean hemoglobin concentration and platelet count remained stable throughout the study in patients previously treated with imiglucerase and remained within baseline ranges.

Extension Study 044

All 95 patients (73 adults and 22 children) who participated in studies 032, 034, and 039 continued into an open-label extension study. Fifty-seven patients were treatment-naïve. All patients had received enzyme replacement therapy for at least 2 years and were followed for a mean of 4.5 years (range: 2.3 to 5.8 years).

In this study, hemoglobin concentration, platelet count, liver volume, and spleen volume were assessed after 24 months of treatment. Results are presented in Table 1.

In this study, bone mineral density was determined by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck. In 31 patients who had not previously received VPRIV, the mean baseline Z-score for lumbar spine bone mineral density was –1.820 (95% CI: –2.21, –1.43) and increased to 0.62 (95% CI: 0.39, 0.84) over 24 months of treatment. Similar results were observed in patients who had received imiglucerase for 9 months and then switched to VPRIV for 15 months. In patients who switched from long-term imiglucerase therapy to VPRIV, lumbar spine bone mineral density values were maintained over 24 months. No significant changes in femoral neck bone mineral density were observed.

In 9 children, an increase in the mean Z-score was observed over 60 months of treatment among patients who had not previously received therapy, indicating a linear increase in treatment benefit. Similar treatment effects were observed over 48 months in children who had received imiglucerase for 9 months followed by switching to VPRIV. Children who switched from long-term imiglucerase therapy to VPRIV in study 034 had a higher baseline Z-score, which remained stable throughout the study period.

These treatment effects on hemoglobin levels, platelet counts, organ volumes, bone mineral density, and height were maintained through the end of the study.

Study 402

Study 402 was an open-label, uncontrolled Phase IV study evaluating the effect of VPRIV on bone pathology in 21 adult patients with type 1 Gaucher disease who had not previously received treatment. The primary efficacy analysis was conducted in 16 subjects who completed 24 months of treatment with VPRIV. At baseline, the mean age of patients was 46 years, and the mean Z-score for bone mineral density was –1.93 (0.876).

In this study, the primary efficacy endpoint was the change from baseline to 24 months in the Z-score of lumbar spine bone mineral density, measured by dual-energy X-ray absorptiometry (DXA). A positive trend was observed for the primary efficacy endpoint [mean change (SD) in lumbar spine bone mineral density Z-score from baseline to 24 months was 0.17 (0.394), 95% CI: –0.04, 0.38]; however, the effect was not statistically significant (p-value 0.1077). After 1 year of treatment, no significant effect of VPRIV on lumbar spine bone mineral density Z-score was observed.

Secondary endpoints [ITT population (all randomized patients who received at least one dose of study drug): observed cases (OC)] were consistent with previous studies.

Table 2: Secondary endpoints in study SHP-GCB-402 – mean value at baseline (SD), mean change from baseline to month 24, 95% CI

The safety profile was consistent with data from previous studies; no new safety signals were identified.

Children

Use in children aged 4 to 17 years was supported by results from controlled studies involving both adults and children [20 out of 94 (21%)]. Safety and efficacy profiles were similar in children and adults. Study results allow the use of the medicinal product in children from 2 years of age. The efficacy and safety profile is expected to be similar to that observed in children aged 2 years and older, although data on use in children under 4 years of age are lacking. Effects on growth were observed specifically during study 044.

Phase I/II study HGT-GCB-068 was conducted to evaluate the efficacy and safety of intravenous velaglucerase alfa for ERT in children and adolescents with type 3 Gaucher disease who had not previously received treatment. This was a multicenter, open-label study in which velaglucerase alfa was administered to 6 patients (aged 2 to 17 years at enrollment) with a confirmed diagnosis of type 3 Gaucher disease at a dose of 60 units/kg as intravenous infusions every two weeks for 12 months.

In this small exploratory study, neurological efficacy outcomes and the safety profile of intravenous velaglucerase alfa in patients with type 3 Gaucher disease were consistent with those observed in patients with type 1 Gaucher disease. No significant improvement in neurological manifestations of type 3 Gaucher disease was observed in this study, except in one patient.

The safety and efficacy of velaglucerase alfa in children under 4 years of age have not yet been established. Data are lacking.

The European Medicines Agency has waived the obligation to submit results of studies with the medicinal product Vpriv in all subgroups of the pediatric population with Gaucher disease type 2 (for use in pediatrics, see "Method of administration and dosage").

Pharmacokinetics.

No differences in pharmacokinetic parameters were observed between male and female patients with Gaucher disease. No cases of antibody development against velaglucerase were observed. Therefore, the impact of antibodies on the pharmacological profile of velaglucerase alfa could not be assessed.

Absorption

Following a 60-minute intravenous infusion, plasma concentrations of velaglucerase alfa increase during the first 20 minutes, with peak plasma concentration (Cmax) reached within 40–60 minutes. After completion of the infusion of velaglucerase alfa at doses of 15, 30, 45, and 60 units/kg, enzyme concentration declines rapidly according to a mono- or biphasic elimination curve, with elimination half-life (t1/2) ranging between 5 and 12 minutes.

Distribution

Pharmacokinetic parameters of velaglucerase alfa exhibit a linear or near-linear profile, with Cmax and area under the concentration–time curve (AUC) increasing proportionally with dose escalation from 15 to 60 units/kg. The steady-state volume of distribution is approximately 10% of body weight. The high clearance of velaglucerase alfa (6.7–7.6 mL/min/kg) is maintained and is associated with rapid uptake of the enzyme by macrophages mediated by mannose receptors.

Excretion

The clearance of velaglucerase alfa in children (N = 7, aged 4 to 17 years) does not differ from that observed in adults (N = 15, aged 19 to 62 years).

Clinical characteristics.

Indications.

The drug Vpriv is indicated for long-term enzyme replacement therapy in patients with Gaucher disease type I.

Contraindications.

Severe allergic reactions to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies of Vpriv with other medicinal products have not been conducted.

Special precautions for use.

Traceability

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

Hypersensitivity.

Hypersensitivity reactions, including symptoms of anaphylaxis, have been observed in patients participating in clinical trials and in the post-marketing period. Most hypersensitivity reactions occurred within 12 hours after infusion. The most common symptoms of hypersensitivity include nausea, rash, dyspnea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, and headache.

Infusion reactions.

An infusion reaction is any adverse drug reaction occurring within 24 hours of the start of velaglucerase alfa infusion. Infusion reactions (IRs) were the most common adverse reactions in patients participating in clinical trials. Often, IRs occurred as hypersensitivity reactions. The most common symptoms of hypersensitivity include nausea, rash, dyspnea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, and headache. Symptoms indicating anaphylaxis have been observed in patients during clinical trials and in the post-marketing period. In addition to symptoms related to hypersensitivity reactions, IRs may present as fatigue, dizziness, fever, increased blood pressure, pruritus, blurred vision, or vomiting. In treatment-naïve patients, most infusion reactions occurred within the first 6 months of therapy.

Prevention and management of infusion reactions, including hypersensitivity reactions

Management of infusion reactions should be based on the severity of the reaction, and appropriate measures may include slowing the infusion rate, administration of medications such as antihistamines, antipyretics, and/or corticosteroids, or discontinuation of treatment followed by re-initiation with prolonged infusion duration.

Due to the risk of hypersensitivity reactions, including anaphylaxis, appropriate medical support, including trained personnel for intensive care management, should be readily available during administration of velaglucerase alfa. If an anaphylactic or other acute reaction occurs in or outside a clinical setting, the infusion should be stopped immediately and appropriate medical treatment initiated. If an anaphylactic reaction occurs outside a clinical setting, consideration should be given to continuing treatment under clinical supervision.

Treatment should be administered with caution to patients who develop symptoms of hypersensitivity to velaglucerase alfa or other enzyme replacement therapies.

Pre-medication with antihistamines and/or corticosteroids may prevent subsequent reactions when symptomatic treatment has been required.

Immunogenicity.

The formation of antibodies to velaglucerase alfa may be associated with infusion reactions, including allergic-type hypersensitivity reactions. During clinical trials, one out of 94 (1%) patients developed IgG antibodies to velaglucerase alfa; in vitro analysis showed them to be neutralizing. IgE antibodies to velaglucerase alfa were not detected.

Post-marketing phase

During an additional post-marketing study, one patient developed IgG antibodies to the medicinal product Vpriv. Additionally, several cases of positive neutralizing antibodies and lack of effect have been reported during post-marketing surveillance.

If a physician suspects lack of response or loss of efficacy potentially related to antibody formation, the patient may be tested for antibodies at the physician’s discretion.

Sodium.

This medicinal product contains 12.15 mg of sodium per vial, equivalent to 0.6% of the WHO recommended maximum daily intake of sodium for adults (2 g). Caution should be exercised when administering this product to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Women of reproductive potential with Gaucher disease may experience disease exacerbation during pregnancy and the postpartum period. For women with Gaucher disease considering pregnancy, a benefit-risk assessment is required.

Pregnancy

Data on the use of velaglucerase alfa in pregnant women are lacking or limited. Animal studies have not shown any direct or indirect adverse effects of velaglucerase alfa on pregnancy, embryonal/fetal development, parturition, or postnatal development. Careful monitoring of pregnancy progression and clinical manifestations of Gaucher disease is necessary to determine appropriate therapy. Caution should be exercised when prescribing this medicinal product to pregnant women.

Breastfeeding

It is unknown whether velaglucerase alfa or its metabolites are excreted in human milk. Velaglucerase alfa is a synthetic form of beta-glucocerebrosidase, which is a normal component of human milk. Studies with other forms of the enzyme have shown very low levels of the enzyme in breast milk. A decision on whether to discontinue breastfeeding or to discontinue/abstain from treatment with Vpriv should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Effect on fertility

Animal studies have not shown impairment of fertility.

Ability to affect reaction speed when driving or operating machinery.

Vpriv has no or negligible influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Each vial of the medicinal product VPRIV is intended for single use only and contains 400 IU of velaglucerase alfa. VPRIV is intended for intravenous infusion therapy.

Dosage

The recommended dose is 60 IU/kg administered once every two weeks.

Individual dose adjustment may be considered based on achieving and maintaining therapeutic goals. Clinical trials have evaluated doses ranging from 15 to 60 IU/kg administered once every two weeks. Patients currently receiving imiglucerase as enzyme replacement therapy for type 1 Gaucher disease may initiate VPRIV treatment using the same dose and frequency. Doses exceeding 60 IU/kg have not been studied.

Patients switching from imiglucerase to VPRIV should receive an equivalent dose and frequency of velaglucerase alfa.

Route of Administration

The infusion duration is 60 minutes. VPRIV requires reconstitution and dilution prior to administration. The product must be administered only through a 0.22 µm filter.

The procedure must be performed under aseptic conditions.

Reconstitution procedure:

1. Determine the number of vials required based on the patient's body weight and the recommended dose.
2. Remove the required number of vials from the refrigerator. Transfer 4.3 mL of sterile water for injection into each vial.
3. After reconstitution, gently swirl the contents of each vial without shaking. The extracted volume from each vial will be 4 mL (100 IU/mL).
4. Perform a visual inspection of the solution in the vials for further dilution.

The solution should be clear or slightly opalescent and colorless. Do not use if discoloration or presence of foreign particles is observed.

1. Withdraw the calculated volume of the drug from the appropriate number of vials and dilute in a total volume of 100 mL of 9 mg/mL (0.9%) sodium chloride infusion solution. Gently mix without shaking. The infusion should be administered within 24 hours after reconstitution.

Treatment with VPRIV should be administered under the supervision of a physician experienced in managing patients with Gaucher disease. Home administration under the supervision of a healthcare professional may be acceptable only for patients who have received at least three infusions without complications. Appropriate medical support, including trained personnel for emergency management, must be available during administration of velaglucerase alfa. If anaphylactic or other acute reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment (see section "Special Warnings and Precautions for Use").

Special Patient Populations

Elderly patients (≥ 65 years of age)

Elderly patients may receive the same dose (15 to 60 IU/kg) as other adult patients.

Renal or hepatic impairment

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

Pediatric patients.

The medicinal product is used in pediatric practice.

Twenty out of 94 patients (21%) who received velaglucerase alfa in clinical trials were in the pediatric and adolescent age range (4 to 17 years of age). The safety and efficacy profiles in children and adolescents were similar to those observed in adult patients.

The safety and efficacy of velaglucerase alfa in children under 4 years of age have not been established. Data are lacking.

Overdose.

Information regarding cases of velaglucerase alfa overdose is limited. In most cases, no additional adverse events were reported. However, in the event of accidental or intentional overdose, patients should be closely monitored, and treatment should be symptomatic and supportive. There is no specific antidote. In clinical trials, the maximum dose of velaglucerase alfa was 60 IU/kg (see section "Special Warnings and Precautions for Use***"***).

Adverse Reactions

The most serious adverse reactions in patients participating in clinical studies were hypersensitivity reactions (2.1%).

The most common adverse reactions were infusion reactions (39.4%). The most frequently reported symptoms of infusion reactions included headache, dizziness, arterial hypotension, arterial hypertension, nausea, fatigue/asthenia, and fever/pyrexia (see also section "Special Warnings and Precautions for Use"). Infusion reaction was the only adverse event leading to discontinuation of therapy.

Adverse reactions observed in patients with Type 1 Gaucher disease are listed in Table 3 by system organ class and frequency according to MedDRA classification. Reactions are classified by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Table 3: Adverse reactions observed during treatment with VPRIV in patients with Type 1 Gaucher disease

*Adverse reactions, information on which was obtained from post-marketing reports

Description of selected adverse reactions

Vomiting. In some cases, vomiting may be severe and serious. Vomiting most commonly occurs during infusion and within 24 hours after infusion.

Other special populations

Elderly patients (aged 65 years and older)

The safety profile of VPRIV in clinical studies involving patients aged 65 years and older was similar to that observed in other adult patients.

Children

The safety profile of VPRIV in clinical studies involving children and adolescents aged 4 to 17 years was similar to that observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It 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 cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life. 3 years.

Chemical and physical stability during use has been demonstrated in stability studies for 24 hours at a temperature of 2 to 8 °C, protected from light.

Storage conditions.

Store in the original packaging in a refrigerator (at 2–8 °C) to protect from light.

Keep out of reach of children.

Do not freeze.

From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, the duration and conditions of storage of the prepared product prior to administration are the responsibility of the user and must not exceed 24 hours at a temperature of 2 to 8 °C.

Packaging.

20 ml vial (Type I glass) with a stopper (butyl rubber with fluorinated coating), aluminum seal, and removable cap. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Takeda Pharmaceuticals International AG Ireland Branch.

Manufacturer's address and location of its operations.

Block 2 Mezzanine Plaza, 50-58 Baggot Street Lower, Dublin 2, D02 HW68, Ireland.

INSTRUCTIONS

for medical use of the medicinal product

VPRIV

(VPRIV)

Composition:

Active substance: velaglucerase alfa;

1 vial contains 400 IU of velaglucerase alfa;

Excipients: sucrose; sodium citrate, dihydrate; citric acid, monohydrate; polysorbate 20.

Pharmaceutical form. Powder for solution for infusion.

Main physico-chemical characteristics: white or off-white powder.

After reconstitution – clear or slightly opalescent, colorless solution.

Pharmacotherapeutic group. Medicinal products for the treatment of gastrointestinal disorders and metabolic diseases. Enzymes.

ATC code A16AB10.

Pharmacological properties.

Pharmacodynamics.

Gaucher disease is an autosomal recessive disorder caused by mutations in the glucocerebrosidase gene, resulting in deficiency of the lysosomal enzyme beta-glucocerebrosidase. In patients with Gaucher disease, glucocerebroside progressively accumulates in macrophages, leading to cellular infiltration, formation of foam cells, or Gaucher cells.

The disease belongs to the group of lysosomal storage disorders, and its clinical manifestations are determined by the distribution of Gaucher cells in organs and tissues, including development of organomegaly, skeletal deformities and abnormalities, bone crises, and sometimes severe anemia and thrombocytopenia.

Velaglucerase alfa is an enzyme produced using human cell line technology via gene activation. The molecular mass of the monomer is approximately 63 kDa. Velaglucerase alfa is a glycoprotein consisting of 497 amino acids and containing 5 N-linked glycosylation sites, 4 of which are occupied by high-mannose glycans. The mannose residues enable the enzyme to specifically bind to mannose receptors on the cell surface, resulting in cellular internalization of the enzyme targeted to intracellular lysosomes, and subsequent catabolism of accumulated glucocerebroside.

Administration of velaglucerase alfa replaces the deficient beta-glucocerebrosidase enzyme, which catalyzes the breakdown of glucocerebroside into glucose and ceramide within lysosomes, thereby reducing the accumulation of glucocerebroside and improving the pathophysiological manifestations of type I Gaucher disease: hemoglobin concentration and platelet count increase, and liver and spleen volumes decrease.

Clinical efficacy and safety

Studies in treatment-naïve patients

Study 025 – an open-label, 9-month study involving 12 adult (≥18 years) patients who had not previously received enzyme replacement therapy (i.e., had not been on therapy for at least 12 months prior to study initiation). Velaglucerase alfa was initially administered to 3 patients in escalating doses (15, 30, 60 U/kg), while the remaining 9 patients started treatment at 60 U/kg.

Clinically significant increases in hemoglobin concentration and platelet count were observed from the start of treatment, evident after 3 months. Reductions in liver and spleen volumes occurred after 6 and 9 months, respectively.

Ten patients who completed Study 025 participated in an open-label extension study (025EXT), 8 of whom completed it. After at least 12 months of continued treatment with Velaglucerase alfa, all patients had their dose reduced from 60 to 30 U/kg following achievement of at least 2 of the 4 therapeutic goals of "Year 1" of enzyme replacement therapy for type I Gaucher disease.

Patients received doses ranging from 30 to 60 U/kg (mean dose 35 U/kg) once every two weeks for 84 months (7 years). Sustained clinical activity was demonstrated throughout treatment, as evidenced by improvements in hemoglobin concentration, platelet count, and reductions in liver and spleen volumes.

By month 57, all 8 patients achieved at least a 2-point reduction on the lumbar spine bone marrow burden score assessed by MRI. Improvement in mean Z-scores of the lumbar spine and femoral neck bone mineral density was observed by month 24 (0.4; 95% confidence interval [CI] 0.1, 0.7) and month 33 (0.4; 95% CI 0.2, 0.6), respectively. After 7 years of treatment, the mean improvement in Z-scores from baseline was 0.7 (95% CI 0.4, 1.0) for the lumbar spine and 0.5 (95% CI 0.2, 0.7) for the femoral neck. No patient was reclassified to a worse WHO category based on bone density compared to baseline.

Study 032 – a 12-month, randomized, double-blind, parallel-group study evaluating efficacy in 25 patients aged ≥2 years who had not previously received enzyme replacement therapy (i.e., had not received it for at least 30 months prior to study initiation). Patients were also required to have Gaucher disease-related anemia and thrombocytopenia or organomegaly. Patients were randomized to receive Velaglucerase alfa at 45 U/kg (N = 13) or 60 U/kg (N = 12) once every two weeks.

Administration of velaglucerase alfa at 60 U/kg intravenously once every two weeks demonstrated clinically significant increases in mean hemoglobin concentration (+2.4 g/dL) and platelet count (+50.9 × 10⁹/L) compared to baseline, with liver volume decreasing from 1.46 to 1.22 times normal (mean reduction 17%) and spleen volume decreasing from 14.0 to 5.75 times normal (mean reduction 50%). At 45 U/kg, significant increases in hemoglobin concentration (+2.4 g/dL) and platelet count (+40.9 × 10⁹/L) were observed compared to baseline, with liver volume decreasing from 1.40 to 1.24 times normal (mean reduction 6%) and spleen volume decreasing from 14.5 to 9.50 times normal (mean reduction 40%).

Study 039 – a 9-month, randomized, double-blind, active-comparator study designed to demonstrate non-inferiority to imiglucerase in a parallel-group efficacy study involving 34 patients aged ≥2 years who had not previously received enzyme replacement therapy (i.e., had not received it for at least 12 months prior to study initiation). Patients were required to have Gaucher disease-related anemia and thrombocytopenia or organomegaly. Patients received either 60 U/kg (N = 17) of Velaglucerase alfa or 60 U/kg (N = 17) of imiglucerase once every two weeks.

The mean absolute increase in hemoglobin concentration from baseline was 1.624 g/dL (±0.223) over 9 months of treatment with Velaglucerase alfa. This increase in hemoglobin concentration was demonstrated to be clinically and statistically non-inferior to that achieved with imiglucerase (mean change from baseline over 9 months [Velaglucerase alfa – imiglucerase]: 0.135 g/dL). There were no statistically significant differences between Velaglucerase alfa and imiglucerase in changes in platelet count, liver volume, spleen volume over 9 months of treatment, or time to first hemoglobin response (defined as an increase of 1 g/dL from baseline).

Studies in patients switching from imiglucerase to Velaglucerase alfa

Study 034 – a 12-month, open-label safety study involving 40 patients aged ≥2 years who had received imiglucerase at doses of 15 to 60 U/kg for at least 30 months without interruption. The dose had to be stable for at least the last 6 months prior to study initiation. Velaglucerase alfa was administered at the same dose and regimen as imiglucerase. Changes in hemoglobin concentration and platelet count were calculated as changes from baseline values defined at the end of imiglucerase treatment. Patients who had received less than 15 U/kg of imiglucerase were assigned to 15 U/kg of Velaglucerase alfa.

In patients switching from imiglucerase to Velaglucerase alfa, hemoglobin concentration and platelet count remained at therapeutic levels throughout the 12 months of treatment.

Study 058 – an open-label clinical safety study involving 211 patients, including 205 patients previously treated with imiglucerase and 6 treatment-naïve patients. The age of 57 patients was over 65 years (56 of whom had previously received imiglucerase). Patients previously treated with imiglucerase received biweekly infusions of Velaglucerase alfa at the same dose as imiglucerase, ranging from 15 to 60 U/kg.

Patients previously treated with imiglucerase received a mean of 8 infusions of Velaglucerase alfa over a mean duration of 15.1 weeks. The safety profile in these patients was similar to that observed in previous clinical trials. Only 1 of 163 patients developed antibodies to velaglucerase alfa during the study.

Mean hemoglobin concentration and platelet count in patients previously treated with imiglucerase remained stable throughout the study and within baseline ranges.

Extension Study 044

All 95 patients (73 adults and 22 children) who participated in Studies 032, 034, and 039 continued into an open-label extension study. Fifty-seven patients were treatment-naïve. All patients had received enzyme replacement therapy for at least 2 years and were followed for a mean of 4.5 years (range: minimum 2.3 years, maximum 5.8 years).

In this study, hemoglobin concentration, platelet count, liver volume, and spleen volume were assessed after 24 months of treatment. Results are presented in Table 1.

In this study, bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck. In 31 patients who had not previously received VPRIV, the mean baseline Z-score for lumbar spine bone mineral density was –1.820 (95% CI: –2.21, –1.43) and increased to 0.62 (95% CI: 0.39, 0.84) over 24 months of treatment. Similar results were observed in patients who had received imiglucerase for 9 months followed by VPRIV for 15 months. In patients who switched from long-term imiglucerase therapy to VPRIV, lumbar spine bone mineral density values were maintained over 24 months. No significant changes in femoral neck bone mineral density were observed.

In 9 children, an increase in the mean Z-score was observed over 60 months of treatment among patients who had not previously received therapy, indicating a linear benefit over time. Similar treatment effects were observed over 48 months in children who had received imiglucerase for 9 months followed by switching to VPRIV. Children who switched from long-term imiglucerase therapy to VPRIV in Study 034 had a higher baseline Z-score, which remained stable throughout the study period.

These treatment effects on hemoglobin levels, platelet counts, organ volumes, bone mineral density, and height were maintained throughout the study duration.

Study 402

Study 402 was an open-label, uncontrolled Phase IV study evaluating the effect of VPRIV on bone pathology in 21 adult patients with type 1 Gaucher disease who had not previously received treatment. The primary efficacy analysis was conducted in 16 subjects who completed 24 months of treatment with VPRIV. At study baseline, the mean age of patients was 46 years, and the mean Z-score for bone mineral density was –1.93 (0.876).

The primary efficacy endpoint in this study was the change from baseline to 24 months in the Z-score for lumbar spine bone mineral density, measured by dual-energy X-ray absorptiometry (DXA). A positive trend was observed for the primary efficacy endpoint [mean change (SD) in lumbar spine bone mineral density Z-score from baseline to 24 months was 0.17 (0.394), 95% CI: –0.04, 0.38]; however, the effect was not statistically significant (p-value 0.1077). After 1 year of treatment, no significant effect of VPRIV on lumbar spine bone mineral density Z-score was detected.

Secondary endpoints [ITT population (all randomized patients who received at least one dose of study drug): OC (observed cases)] were consistent with previous studies.

Table 2: Secondary endpoints in Study SHP-GCB-402 – mean baseline value (SD), mean change from baseline to Month 24, 95% CI

The safety profile was consistent with previous findings; no new safety signals were identified.

Children

Use in children aged 4 to 17 years was supported by results from controlled studies involving both adults and children [20 out of 94 (21%)]. Safety and efficacy profiles were similar in children and adults. Study results support the use of the medicinal product in children aged 2 years and older. The efficacy and safety profile is expected to be similar to that observed in children aged 2 years and above, although data on use in children under 4 years of age are lacking. Effects on growth were observed specifically during study 044.

Phase I/II study HGT-GCB-068 was conducted to evaluate the efficacy and safety of intravenous velaglucerase alfa for long-term enzyme replacement therapy (ERT) in children and adolescents with type 3 Gaucher disease who had not previously received treatment. This was a multicenter, open-label study in which velaglucerase alfa was administered at a dose of 60 units/kg as intravenous infusions every two weeks for 12 months in 6 patients (aged 2 to 17 years at enrollment) with confirmed type 3 Gaucher disease.

In this small exploratory study, neurological efficacy outcomes and the safety profile of intravenous velaglucerase alfa in patients with type 3 Gaucher disease were consistent with those observed in patients with type 1 Gaucher disease. No significant improvement in neurological manifestations of type 3 Gaucher disease was observed in this study, except in one patient.

The safety and efficacy of velaglucerase alfa in children under 4 years of age have not yet been established. Data are lacking.

The European Medicines Agency has waived the requirement to submit results of studies with Vpriv in all pediatric subpopulations with Gaucher disease type 2 (for use in pediatrics, see "Posology and method of administration").

Pharmacokinetics

No differences in pharmacokinetic parameters were observed between male and female patients with Gaucher disease. No cases of antibody development against velaglucerase were observed. Therefore, the impact of antibodies on the pharmacological profile of velaglucerase alfa could not be assessed.

Absorption

Following a 60-minute intravenous infusion, plasma concentrations of velaglucerase alfa increase during the first 20 minutes, with peak plasma concentration (Cmax) reached between 40 and 60 minutes. After completion of infusion at doses of 15, 30, 45, and 60 units/kg, enzyme concentration declines rapidly according to a mono- or biphasic elimination curve, with elimination half-life (t1/2) ranging between 5 and 12 minutes.

Distribution

Pharmacokinetic parameters of velaglucerase alfa exhibit a linear or near-linear profile, with Cmax and area under the concentration-time curve (AUC) increasing proportionally with dose escalation from 15 to 60 units/kg. The steady-state volume of distribution is approximately 10% of body weight. The high clearance of velaglucerase alfa (6.7–7.6 mL/min/kg) is maintained and is associated with rapid uptake of the enzyme by macrophages via mannose receptors.

Excretion

The clearance of velaglucerase alfa in children (N = 7, aged 4 to 17 years) does not differ from that observed in adults (N = 15, aged 19 to 62 years).

Clinical characteristics.

Indications.

Vpriv is indicated for long-term enzyme replacement therapy in patients with type I Gaucher disease.

Contraindications.

Severe allergic reactions to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interaction studies between Vpriv and other medicinal products have not been conducted.

Special precautions for use.

Traceability

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

Hypersensitivity.

Hypersensitivity reactions, including symptoms of anaphylaxis, have been observed in patients participating in clinical trials and during the post-marketing period. Most hypersensitivity reactions occurred within 12 hours after infusion. The most common symptoms of hypersensitivity include nausea, rash, dyspnea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, and headache.

Infusion reactions.

An infusion reaction is any adverse drug reaction occurring within 24 hours of the start of velaglucerase alfa infusion. Infusion reactions (IRs) were the most commonly reported adverse reactions in patients participating in clinical studies. Often, IRs occurred as hypersensitivity reactions. The most common symptoms of hypersensitivity include nausea, rash, dyspnea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, and headache. Symptoms indicative of anaphylaxis have been observed in patients during clinical trials and in the post-marketing period. In addition to symptoms associated with hypersensitivity reactions, IRs may present as fatigue, dizziness, fever, increased blood pressure, pruritus, blurred vision, or vomiting. In treatment-naïve patients, most infusion reactions occurred within the first 6 months of therapy.

Prevention and management of infusion reactions, including hypersensitivity reactions

Management of infusion reactions should be based on the severity of the reaction, and appropriate measures may include slowing the infusion rate, administration of medications such as antihistamines, antipyretics, and/or corticosteroids, or discontinuation of treatment followed by resumption with an extended infusion duration.

Due to the risk of hypersensitivity reactions, including anaphylaxis, appropriate medical support, including qualified personnel for intensive care management, should be available when administering velaglucerase alfa. If an anaphylactic or other acute reaction occurs in or outside a clinical setting, the infusion should be stopped immediately and appropriate medical treatment provided. If an anaphylactic reaction occurs outside a clinical setting, continuation of treatment under clinical supervision should be considered.

Treatment should be administered with caution in patients who experience symptoms of hypersensitivity to velaglucerase alfa or other enzyme replacement therapies.

Pre-medication with antihistamines and/or corticosteroids may prevent subsequent reactions when symptomatic treatment is required.

Immunogenicity.

The formation of antibodies to velaglucerase alfa may be associated with infusion reactions, including allergic-type hypersensitivity reactions. During clinical trials, one out of 94 patients (1%) developed IgG antibodies to velaglucerase alfa; in vitro analysis showed these antibodies to be neutralizing. IgE antibodies to velaglucerase alfa were not detected.

Post-marketing phase

During an additional post-marketing study, one patient developed IgG antibodies to Vpriv. Additionally, several cases of positive neutralizing antibodies and lack of effect have been reported during post-marketing surveillance.

If a physician suspects lack of response or loss of efficacy potentially related to antibody formation, the patient may be tested for antibodies at the physician’s discretion.

Sodium.

This medicinal product contains 12.15 mg of sodium per vial, equivalent to 0.6% of the WHO recommended maximum daily intake of sodium for adults (2 g). Caution should be exercised when administering this product to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Females of reproductive potential

In females of reproductive potential with Gaucher disease, disease exacerbation may occur during pregnancy and the postpartum period. For women with Gaucher disease considering pregnancy, a benefit-risk assessment is required.

Pregnancy

Data on the use of velaglucerase alfa in pregnant women are lacking or limited. Animal studies have not shown any direct or indirect adverse effects of velaglucerase alfa on pregnancy, embryonic/fetal development, parturition, or postnatal development. Careful monitoring of pregnancy progression and clinical manifestations of Gaucher disease is required to determine appropriate therapy. Caution should be exercised when prescribing this medicinal product to pregnant women.

Breastfeeding

It is unknown whether velaglucerase alfa or its metabolites are excreted in human milk. Velaglucerase alfa is a synthetic form of beta-glucocerebrosidase, which is a normal component of human milk. Studies with other forms of the enzyme have shown very low levels of the enzyme in breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with Vpriv, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Effects on fertility

Animal studies have not shown any impairment of fertility.

Ability to influence the speed of reactions when driving or operating machinery.

Vpriv has no or negligible effect on the ability to drive or operate machinery.

Administration and Dosage

Each vial of the medicinal product Uplyso is intended for single use only and contains 400 IU of velaglucerase alfa. Uplyso is intended for intravenous infusion therapy.

Dosage

The recommended dose is 60 IU/kg administered once every two weeks.

Individual dose adjustment may be considered based on achieving and maintaining therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 IU/kg administered once every two weeks. Patients currently receiving imiglucerase as enzyme replacement therapy for type 1 Gaucher disease may initiate treatment with Uplyso using the same dose and frequency. Doses higher than 60 IU/kg have not been studied.

Patients switching from imiglucerase to Uplyso should receive an equivalent dose and frequency of velaglucerase alfa.

Administration Method

The infusion duration is 60 minutes. Uplyso requires reconstitution and dilution prior to administration. The product must be administered only through a 0.22 µm pore size filter.

The procedure must be performed under aseptic conditions.

Reconstitution procedure:

1. Determine the number of vials required based on the patient's body weight and the recommended dosage.
2. Remove the required number of vials from the refrigerator. Transfer 4.3 mL of sterile water for injection into each vial.
3. After reconstitution, gently mix the contents of each vial without shaking. The extracted volume from each vial will be 4 mL (100 IU/mL).
4. Perform a visual inspection of the solution in the vials for further dilution.

The solution should be clear or slightly opalescent and colorless. Do not use if there is a change in color or presence of foreign particles.

1. Withdraw the calculated volume of the drug from the appropriate number of vials and dilute it in a total volume of 100 mL of 9 mg/mL (0.9%) sodium chloride infusion solution. Mix gently without shaking. The infusion should be administered within 24 hours after reconstitution.

Treatment with Uplyso should be administered under the supervision of a physician experienced in managing patients with Gaucher disease. Home administration under the supervision of a healthcare professional may be acceptable only for patients who have received at least three infusions without complications. Appropriate medical support, including properly trained personnel for emergency interventions, must be available during administration of velaglucerase alfa. If anaphylactic or other acute reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment (see section "Special Warnings and Precautions for Use").

Special Patient Populations

Elderly patients (≥ 65 years)

Elderly patients may receive the same dose (15 to 60 IU/kg) as other adult patients.

Renal or hepatic impairment

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

Pediatric population

The medicinal product is used in pediatric practice.

Twenty out of 94 patients (21%) who received velaglucerase alfa in clinical studies were in the pediatric and adolescent age range (4 to 17 years). The safety and efficacy profiles in children and adolescents were similar to those observed in adult patients.

The safety and efficacy of velaglucerase alfa in children under 4 years of age have not been established. Data are lacking.

Overdose

Information regarding cases of velaglucerase alfa overdose is limited. In most cases, no additional adverse events were reported. However, in the event of accidental or intentional overdose, patients should be closely monitored, and treatment should be symptomatic and supportive. There is no specific antidote. In clinical studies, the maximum dose of velaglucerase alfa was 60 IU/kg (see section "Special Warnings and Precautions for Use***"***).

Adverse Reactions

The most serious adverse reactions in patients participating in clinical studies were hypersensitivity reactions (2.1%).

The most common adverse reactions were infusion-related reactions (39.4%). The most frequently reported symptoms of infusion-related reactions included headache, dizziness, arterial hypotension, arterial hypertension, nausea, fatigue/asthenia, and fever/increased body temperature (see also section "Special Warnings and Precautions for Use"). Infusion-related reaction was the only adverse reaction leading to discontinuation of therapy.

Adverse reactions observed in patients with type 1 Gaucher disease are listed in Table 3 by system organ class and frequency according to MedDRA classification. Reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 3: Adverse reactions observed during treatment with VPRIV in patients with type 1 Gaucher disease

*Adverse reactions, information on which was obtained from post-marketing reports

Description of selected adverse reactions

Vomiting. In some cases, vomiting may be severe and serious. Vomiting most commonly occurs during infusion and within 24 hours after infusion.

Other special populations

Geriatric patients (aged 65 years and older)

The safety profile of Vpriv in clinical studies involving patients aged 65 years and older was similar to that observed in other adult patients.

Children

The safety profile of Vpriv in clinical studies involving children and adolescents aged 4 to 17 years was similar to that observed in adult patients.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy 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 the following link: https://aisf.dec.gov.ua.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life. 3 years.

Chemical and physical stability during use has been demonstrated in stability studies for up to 24 hours at a temperature of 2 to 8 °C, protected from light.

Storage conditions.

Store in the original packaging in a refrigerator (at 2–8 °C) to protect from light.

Keep out of reach of children.

Do not freeze.

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

Packaging.

20 ml vial (Type I glass) with a stopper (butyl rubber with fluorinated coating), aluminum seal, and removable cap. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Shire Pharmaceuticals Ireland Limited.

Manufacturer's address and location of operations.

Block 2/3 Mizzen Plaza, 50-58 Baggot Street Lower, Dublin 2, D02 Y754, Ireland