Mepsevii 2 mg/mL concentrate for solution for infusion.

Each mL of concentrate contains 2 mg vestronidase alfa*. Each vial of 5 mL concentrate contains 10 mg vestronidase alfa.

*Vestronidase alfa is a recombinant form of human beta-glucuronidase (rhGUS) and is produced in Chinese Hamster Ovary cell culture by recombinant DNA technology.

Excipient(s) with known effect

Each vial contains 17.8 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless to slightly yellow solution.

Mepsevii is indicated for the treatment of non-neurological manifestations of Mucopolysaccharidosis VII (MPS VII; Sly syndrome).

Treatment should be supervised by a healthcare professional experienced in the management of patients with MPS VII or other inherited metabolic disorders. Administration of vestronidase alfa should be carried out by an appropriately trained healthcare professional with the ability to manage medical emergencies.

Posology

The recommended dose of vestronidase alfa is 4 mg/kg of body weight administered by intravenous infusion every two weeks.

To minimise the risk of hypersensitivity reactions, a non-sedating antihistamine with or without an antipyretic medicinal product should be administered 30-60 minutes prior to the start of the infusion (see section 4.4). Infusion should be avoided if the patient has an acute febrile or respiratory illness at the time.

Special populations

Elderly

The safety and efficacy of vestronidase alfa in patients older than 65 years have not been established. No alternative dose regimen is recommended in these patients (see section 5.1).

Renal and hepatic impairment

The safety and efficacy of vestronidase alfa in patients with renal or hepatic impairment have not been evaluated. No alternative dose regimen is recommended in these patients.

Paediatric population

The posology in the paediatric population is the same as in adults. Currently available data are described in section 4.8 and section 5.1.

Method of administration

For intravenous use only.

For instructions on dilution of the medicinal product before administration, see section 6.6.

The total diluted volume of the solution for infusion should be administered with a rate titration regimen over approximately 4 hours.

The rate of infusion should be as follows: in the first hour, 2.5% of the total volume will be infused, with the balance infused over the subsequent three hours. Any dead space in the lines should be accounted for to ensure 2.5% of the total infusion volume is delivered into the patient's bloodstream during the first hour of infusion. The lowest rate administered to a patient in the clinical development program was 0.5 mL/hour during the first 30 minutes of infusion, followed by 1 mL/hour over the next 30 minutes, equalling 0.75 mL as the lowest total volume infused during the first hour.

Do not flush the line containing vestronidase alfa to avoid a rapid bolus of infused enzyme. Due to the low infusion rate, additional sodium chloride 9 mg/mL (0.9%) solution for infusion may be added through a separate line (piggyback or Y tube) to maintain sufficient intravenous flow. After the first hour, the rate can be increased to infuse the remainder of the solution for infusion over 3 hours as tolerated according to the recommended rate guidelines in Table 2.

The infusion rate may be slowed, temporarily interrupted or discontinued in the event of hypersensitivity reactions (see section 4.4).

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Traceability

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

General

The effects of treatment with vestronidase alfa should be periodically evaluated and discontinuation of treatment should be considered in cases where clear benefits (including stabilisation of disease manifestations) are not observed. Discontinuation of treatment may cause significant worsening of the patient's clinical status.

As end organ damage progresses over time, it is more difficult for the treatment to reverse the damage or to show improvements. It should be considered by the treating physician that the administration of vestronidase alfa does not affect the irreversible complications (e.g. skeletal deformities).

Vestronidase alfa, at the exposure observed in humans, is not expected to cross the blood-brain-barrier and therefore it is not likely to impact the neurological manifestations of the disease.

Hypersensitivity reactions including anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have been reported with vestronidase alfa; therefore, appropriate medical support should be readily available when vestronidase alfa is administered (see section 4.8).

Infusion should be avoided if the patient has an acute febrile or respiratory illness at the time.

It is recommended that premedication with non-sedating antihistamines with or without antipyretics be administered 30-60 minutes prior to the start of the infusion (see section 4.2).

It is important to administer vestronidase alfa according to the recommended infusion rate schedule (see Table 2 in section 6.6).

If severe hypersensitivity reactions occur, the infusion of vestronidase alfa should be stopped immediately and appropriate treatment should be initiated. Management of hypersensitivity reactions should be based on the severity of the reaction and include temporary interruption or discontinuation of the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroids for mild to moderate reactions. Consider rapid sodium chloride 9 mg/mL (0.9%) solution for infusion for decreased blood pressure and oxygen for hypoxia. Patients should be observed for a minimum of 60 minutes after completing the infusion of vestronidase alfa.

Patients should be informed of the signs and symptoms of hypersensitivity reactions and instructed to seek immediate medical care should such signs and symptoms occur. The risks and benefits of re-administering vestronidase alfa should be considered following a severe hypersensitivity reaction.

Spinal/cervical cord compression

Spinal or cervical cord compression is a known and serious complication of MPS VII. During enzyme replacement therapy, spinal cord injury can occur due to improved neck and spine mobility. Patients with MPS VII receiving vestronidase alfa should be monitored for signs and symptoms of spinal cord compression or neck instability including neck or back pain, weakness of limbs, changes in reflexes or urinary and faecal incontinence. Appropriate clinical treatment should be immediately sought.

Sodium restricted diet

This medicinal product contains 17.8 mg sodium per vial and is administered in sodium chloride 9 mg/mL (0.9%) solution for infusion (see section 6.6). For each vial dosed, including the corresponding diluent volume, the sodium intake is 35.5 mg sodium. This amount is equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g for sodium for an adult. Mepsevii is considered high in sodium. This should be taken into consideration during dilution of the medicinal product for patients on a controlled sodium diet or for those patients with congestive heart failure needing to restrict sodium and total water intake.

No interaction studies have been performed. Because it is a recombinant human protein and its enzyme action is within the lysosome, vestronidase alfa is not expected to interact with other medicinal products.

Pregnancy

There are no data on the use of vetronidase alfa in pregnant women. Animal studies with vestronidase alfa do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, or pre- and postnatal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Mepsevii during pregnancy, unless the potential benefit to the mother outweighs the potential theoretical risks to the foetus.

Breast-feeding

There are no data from studies in breast-feeding women. It is not known whether vestronidase alfa is excreted in human milk, but systemic exposure via breast-milk is not expected. Due to lack of human data, vestronidase alfa should only be administered to a breast-feeding woman if the potential benefit of vestronidase alfa to the mother and the benefit of breast-feeding to the infant outweighs the potential theoretical risks to the infant.

Fertility

No human data are available on the effect of vestronidase alfa on fertility. Animal studies with vestronidase alfa do not indicate any impact on male or female fertility (see section 5.3).

Mepsevii has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions from 4 clinical trials in 23 patients treated with vestronidase alfa were rash (17.4%), urticaria (17.4%), infusion site extravasation (17.4%), anaphylactoid reaction (13%), infusion site swelling (8.7%), pruritus (8.7%) and diarrhoea (8.7%). Most adverse reactions were mild to moderate in severity.

Tabulated list of adverse reactions

The assessment of adverse reactions was based on the exposure of 23 patients from 4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every two weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.

Table 1 lists the adverse reactions reported from 4 clinical trials in 23 patients treated with Mepsevii. Adverse reactions are presented by System Organ Class and frequency. Frequencies are defined as 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), and very rare (< 1/10 000).

Table 1 Adverse reactions reported in patients treated with Mepsevii

*Refer to description of selected adverse reactions for details on the febrile convulsion reported in 1 of 23 trial patients.

** Rash includes grouped PTs of rash, rash papular, rash pruritic, rash maculo-papular, papule, and macule

*** Infusion site extravasation includes one PT of extravasation

**** One adverse reaction of Peripheral swelling is included within the frequency of Infusion site swelling as the event is classified as intravenous catheter issue.

Description of selected adverse reactions

Febrile convulsion

One patient receiving a vestronidase alfa dose of 4 mg/kg experienced a febrile convulsion during treatment at the week 66, within 3 days of diphtheria, tetanus, pertussis vaccination. The infusion was stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the febrile convulsion resolved. The patient subsequently was re-challenged without recurrence and continued on vestronidase alfa treatment. This event was assessed as possibly related to vestronidase alfa due to the temporal association with the infusion.

Immunogenicity

Eighteen out of 23 patients (78%) from 4 clinical trials developed anti-recombinant human beta-glucuronidase (rhGUS) antibodies (ADA), ten of whom further developed neutralizing antibodies (NAb) on at least one occasion, but not consistently over time. There is no definitive correlation between the antibody titre and neutralizing antibody development. In most patients, a pattern of attenuated immunogenicity with chronic exposure was suggested by declining antibody titres over time on continuous treatment. The presence of ADA (non-NAb and NAb) does not appear to affect reduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs) and development of hypersensitivity reactions including infusion associated reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no experience with overdoses of vestronidase alfa. For the management of adverse reactions, see sections 4.4 and 4.8.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB18

Mechanism of action

Mucopolysaccharidosis VII is a lysosomal storage disorder characterised by the deficiency of beta-glucuronidase (GUS) that results in glycosaminoglycans (GAGs) accumulation in cells throughout the body leading to multisystem tissue and organ damage.

Vestronidase alfa is a recombinant form of human GUS and is intended to provide exogenous GUS enzyme for uptake into cellular lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.

Clinical efficacy and safety

The clinical program for vestronidase alfa included 23 treatment naïve patients with MPS VII from 4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every two weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age.

Studies 301 and 202

In a multi-centre, randomised, placebo-controlled, blind-start, single-crossover phase 3 trial (study UX003-CL301, referred to as study 301), 12 patients with MPS VII received vestronidase alfa 4 mg/kg every two weeks for 24 to 48 weeks. The patients were randomised in a blinded manner into 4 groups: 3 patients received vestronidase alfa immediately for 48 weeks (Group A), 3 patients received placebo for 8 weeks then vestronidase alfa for 40 weeks (Group B), 3 patients received placebo for 16 weeks then vestronidase alfa for 32 weeks (Group C), and 3 patients received placebo for 24 weeks then vestronidase alfa for 24 weeks (Group D). Patients who were enrolled in study 301 were eligible to roll over to study UX003-CL202 (referred to as study 202), an open-label extension trial in which patients received additional doses of vestronidase alfa at 4 mg/kg intravenously every other week for up to 144 weeks. Ten patients rolled over directly from the end of study 301 to week 0 of study 202 while 2 patients (17%) had gaps in treatment before enrolling in study 202.

Of the 12 patients enrolled in study CL301, 4 were male and 8 were female and ranged in ages from 8 to 25 years (median 14 years). Nine patients were younger than 18 years of age. MPS VII diagnosis was confirmed by GUS enzyme activity assay for 5 patients, by genotyping for 3 patients, and via both enzyme assay and genotyping for 4 patients. Patients with MPS VII who received Hematopoietic Stem Cell Transplant therapy were excluded in this study. The extremely small population of patients with MPS VII globally necessitated the enrolment of all patients able to participate in this clinical trial, resulting in a highly variable group. Clinical endpoints were not assessable in some patients due to their extent of disease, age or level of cognition (23 out of 72 assessments [~32%] in 6 domains for 12 patients were non-assessable at baseline).

The primary endpoint was the percent reduction in urinary GAG excretion (Dermatan Sulfate, DS) before and after 24 weeks of treatment with vestronidase alfa. The key secondary endpoint was the multi-domain clinical responder index (MDRI) score consisting of six domains [six-minute walk test (6MWT), forced vital capacity (FVC), shoulder flexion, visual acuity, Bruininks-Oseretsky test of motor proficiency (BOT-2) fine motor and gross motor function] after 24 weeks of treatment and fatigue total score as measured by the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL).

Minimal important differences (MIDs) were pre-specified for the six MDRI domains plus fatigue, which are: 6MWT (≥23 meters and ≥10% change from baseline), FVC (5% absolute change or 10% relative change from baseline in FVC%pred), shoulder flexion (20 degree change of both shoulder range of motion), visual acuity (3 lines (corrected, both eyes)), BOT-2 fine motor (fine motor precision: change of 0.72, and manual dexterity: change of 1.47), BOT-2 gross motor (balance: 0.57, and running speed and agility: 0.59), and fatigue (10 points of total score).

Primary endpoint: uGAG reduction

After 24 weeks of treatment with vestronidase alfa, a rapid and sustained, highly significant reduction in uGAG (DS) excretion was achieved with a LS mean (±SE) percentage change of -64.82% (±2.468%) (p<0.0001). All 12 patients were responders, pre-specified as ≥ 50% reduction in uGAG on at least one visit during the first 24 weeks of treatment. In addition, uGAG response (% change from study week 0) shows a similar magnitude of reduction in uGAG in all groups after crossover to active treatment. The reductions in uGAG DS that were observed in study 301 were sustained when patients (n=12) rolled over into the extension study 202 and received vestronidase alfa for up to 3.6 years total between the 2 studies. Reduction in uGAG DS excretion was achieved with LS mean (SE) percentage changes of 62% (4.9%) at study 202 week 0 and 58% (7.2%) at week 48 (n=10). In patients who continued beyond study 202 week 48, the mean percentage reduction in uGAG DS was greater than 70% at all subsequent assessment visits through study 202 week 144 (n=4).

Key secondary endpoints: multi-domain clinical responder index (MDRI) and 6-minute walk test (6MWT)

For the clinical (secondary) endpoints, beneficial responses were observed although not in all patients. After 24 weeks of vestronidase alfa treatment in study 301, the overall MDRI results, both pre-specified and post hoc (6 MDRI domains plus fatigue domain) analyses, were positive with an increase of +0.5 domains (p=0.0527) and +0.8 domains (p=0.0433) including fatigue, respectively (t-test). For patients who continued into study 202, a mean (SD) improvement in MDRI was observed at week 24 (+0.7 [1.01] domains) and at week 48 (+0.9 [1.30] domains).

For 6MWT, the distance increased from baseline to treatment week 24 in study 301 by a LS mean (±SE) of 20.8 m (±16.75 m) in 9 patients who were able to perform the assessment at baseline and at least one post-baseline visit. Six patients had 6MWT results at treatment week 24. Three of these (50%) met the pre-defined MID at treatment week 24 and had sustained walking improvements of 65 meters, 80 meters and 83 meters. For patients who continued into study 202, 8 patients were able to perform the 6MWT at week 48. Sustained 6MWT results were observed with a mean distance of 308.4 m (range: 80-556), for a mean (SE) increase from study 301 baseline of 19.0 m (16.4 m).

Other investigations

Study UX003-CL201 (referred to as study 201) was a single arm, open-label, dose exploration trial that enrolled three MPS VII patients, ranging in age from 5 years to 25 years. After 120 weeks of exposure to vestronidase alfa, one patient demonstrated a 21% improvement over baseline in forced vital capacity (FVC% predicted) on pulmonary function testing in addition to a 105 meter improvement in the 6MWT. Two other patients with baseline hepatosplenomegaly had reduction in liver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of treatment.

Study UX003-CL203 (referred to as study 203) was an open-label, uncontrolled single arm study that enrolled eight patients less than 5 years of age who received vestronidase alfa at a dose of 4 mg/kg every two weeks for 48 weeks of treatment period and additional up to 240 weeks during optional continuation period. The study evaluated reduction of urinary GAG excretion, growth velocity and hepatosplenomegaly.

uGAG reduction

Treatment with vestronidase alfa resulted in a rapid and sustained, significant (p<0.0001) reduction in uGAG DS excretion with an LS mean (SE) percent change of 60% (6.6) at week 4 which was sustained at 61% (6.4) at week 48. Patients who entered the continuation period up to week 132 experienced further reduction in uGAG DS.

Growth

At baseline, all 8 patients had impaired growth. The mean (SD) standing height z-score improved from baseline by +0.196 (0.30) at week 48. A non-significant trend toward increased growth velocity was observed after vestronidase alfa treatment, from a mean (SD) z-score of 2.59 (1.49) at baseline to-0.392 (2.10) post-baseline (p=0.27).

Hepatomegaly

All patients with hepatomegaly assessed by ultrasound examination at baseline (n=3/8) had decreased liver size to within normal range for age and sex prior to study termination.

Exceptional Circumstances

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.

The pharmacokinetics of vestronidase alfa were evaluated in a total of 23 MPS VII patients including 19 paediatric patients and 4 adults from 3 clinical trials. After repeated dosing of 4 mg/kg every other week, the maximal serum concentration (C_max) was 17.3 ± 9.6 mcg/mL (mean ± s.d.; range: 4.7 to 35.7 mcg/mL) and the area under the concentration-time curve from time zero to the last measurable concentration (AUC_0-t) was 50.9 ± 32.2 mcg*h/mL (mean ± s.d.; range: 17.4 to 153 mcg*h/mL). The pharmacokinetics of vestronidase alfa are time independent with repeat dosing. The limited pharmacokinetic data at steady state suggest dose proportional increase in exposure of vestronidase alfa over the dose range of 1 - 4 mg/kg every other week.

Distribution

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation the total volume of distribution (V_ss) was 0.26 ± 0.13 L/kg (range: 0.10 to 0.60 L/kg).

Biotransformation

Vestronidase alfa is a recombinant human enzyme and is therefore eliminated by proteolytic degradation into small peptides and amino acids.

Elimination

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 0.079 ± 0.045 L/h/kg (range: 0.038 to 0.20 L/h/kg); the mean ± standard deviation of the elimination half-life (t_1/2) was 2.6 ± 0.6 hours (range: 0.9 to 3.6 hours).

Excretion

No excretion studies have been conducted in humans. Vestronidase alfa is not expected to be eliminated through renal or faecal excretion.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity in rats, repeated dose toxicity in MPS VII mice and juvenile monkeys, fertility and embryo-foetal development in rats or rabbits, and pre- and postnatal development in rats.

Genotoxicity studies and carcinogenicity studies have not been performed with vestronidase alfa. Based on mechanism of action, rhGUS is not expected to be tumorigenic.

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Histidine

Polysorbate 20

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years

After dilution

Chemical and physical in-use stability of the diluted medicinal product has been demonstrated for up to 36 hours under refrigeration at 2 °C – 8 °C followed by up to 6 hours at room temperature up to a maximum of 25 °C.

From a microbiological safety point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user, but should normally not be longer than 36 hours at 2 °C – 8 °C followed by up to 6 hours at room temperature up to a maximum of 25 °C.

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Colourless glass vial (Type I) with a rubber stopper with fluoro-resin coating, and an aluminium over seal with a plastic flip-off cap.

Pack size: 1 vial containing 5 mL of concentrate for solution for infusion.

Each vial of Mepsevii is intended for single use only. Mepsevii must be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection using aseptic technique according to the steps described below. The diluted solution for infusion should be administered to patients using a low-protein binding infusion bag and set (a non di (2-ethylhexyl) phthalate [DEHP] bag could be used) and the application of an infusion set equipped with an in-line, low-protein binding 0.2 μm filter is recommended.

1. Determine the number of vials to be diluted based on the patient's actual weight and the recommended dose of 4 mg/kg, using the following calculations (a-b):

a. Total dose (mg) = Patient's weight (kg) x 4 mg/kg (recommended dose)

b. Total number of vials = Total dose (mg) divided by 10 mg/vial

2. Round to the next whole vial and remove the required number of vials (refer to Table 2) from the refrigerator to allow them to reach room temperature up to a maximum of 25 °C. Do not heat, microwave or shake vials.

a. Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mL concentration

3. Dilute the calculated dose 1:1 using equal volume of sodium chloride 9 mg/mL (0.9%) solution for injection for intravenous infusion. The total infusion volume is based on the total Mepsevii dose and volume (refer to Table 2). The above calculated dose diluted 1:1 in sodium chloride 9 mg/mL (0.9%) solution for injection should be added to a new empty infusion bag. Dilution preparation should be done at room temperature.

4. Prior to withdrawing Mepsevii from the vial, visually inspect for particulate matter and discolouration. The Mepsevii concentrate solution for infusion should be colourless to slightly yellow. Do not use if the solution is discoloured or if there is particulate matter in the solution.

5. Slowly withdraw Mepsevii from the appropriate number of vials using caution to avoid excessive agitation and any air or frothing. A sufficiently large needle (18 gauge) should be used to minimise bubbles in the solution.

6. Slowly add Mepsevii to the infusion bag using care to avoid agitation, ensuring liquid to liquid contact without generating bubbles or turbulence.

7. Gently rock the infusion bag to ensure proper distribution of Mepsevii. Do not shake the solution.

Table 2. Recommended infusion rate schedule by patient weight for administration of Mepsevii at recommended dose of 4 mg/kg

Disposal

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

Ultragenyx Germany GmbH

Rahel-Hirsch-Str. 10

10557 Berlin

Germany

PLGB 47793/0002

28/07/2023

28/07/2023

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.