Nexviazyme

Avalglucosidase alfa.

White to pale yellow lyophilised powder.
Each vial contains 100 mg of avalglucosidase alfa.
After reconstitution, each vial contains a total extractable volume of 10.0 ml at a concentration of 10 mg of avalglucosidase alfa* per ml.
*Avalglucosidase alfa is a human acid α-glucosidase produced in Chinese hamster ovary cells (CHO) by recombinant DNA technology, which is subsequently conjugated with approximately 7 hexamannose structures (each containing two terminal mannose-6-phosphate (M6P) moieties) to oxidised sialic acid residues on the molecule, thereby increasing bis-M6P levels.
Excipients/Inactive Ingredients: Histidine, Histidine hydrochloride monohydrate, Glycine, Mannitol, Polysorbate 80.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB22.
Pharmacology: Pharmacodynamics: Mechanism of action: Avalglucosidase alfa is a recombinant human acid α-glucosidase (rhGAA) that provides an exogenous source of GAA. Avalglucosidase alfa is a modification of alglucosidase alfa in which approximately 7 hexamannose structures each containing 2 terminal mannose-6-phosphate (bis-M6P) moieties are conjugated to oxidized sialic acid residues on alglucosidase alfa. Avalglucosidase alfa has a 15-fold increase in mannose-6-phosphate (M6P) moieties compared with alglucosidase alfa. Binding to M6P receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalised and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity to degrade glycogen.
Clinical efficacy and safety: Clinical studies in patients with LOPD: Study 1, EFC14028/COMET, was a multinational, multicentre, randomised, double-blinded study comparing the efficacy and safety of Nexviazyme and alglucosidase alfa in 100 treatment-naïve LOPD patients aged 16 to 78 years of age at the initiation of treatment. Patients were randomised in a 1:1 ratio based on baseline forced vital capacity (FVC), gender, age, and country to receive 20 mg/kg of Nexviazyme or alglucosidase alfa once every other week for 12 months (49 weeks). The study included an open-label, long-term, follow-up phase of up to 5 years for all patients, in which patients in the alglucosidase alfa arm were switched to treatment with Nexviazyme.
The primary endpoint of study 1 was the change in FVC % predicted in the upright position from baseline to 12 months (week 49). At week 49, the LS mean change (SE) in FVC % predicted for patients treated with Nexviazyme and alglucosidase alfa was 2.89% (0.88) and 0.46% (0.93), respectively. The clinically significant LS mean difference of 2.43% (95% CI: -0.13, 4.99) between Nexviazyme and alglucosidase alfa in FVC % predicted exceeded the pre-defined non-inferiority margin of -1.1 and achieved statistical non-inferiority (p=0.0074). The study did not demonstrate statistical significance for superiority (p=0.0626) and the testing of the secondary endpoints was performed without multiplicity adjustment.
The results for the primary endpoint are detailed in Table 1. (See Table 1.)

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The key secondary endpoint of study 1 was change in total distance walked in 6 minutes (6-Minute Walk Test, 6MWT) from baseline to 12 months (week 49). At week 49, the LS mean change from baseline (SE) in 6MWT for patients treated with Nexviazyme and alglucosidase alfa was 32.21 m (9.93) and 2.19 m (10.40) respectively. The LS mean difference of 30.01 m (95% CI: 1.33,58.69) showed numerical improvement with Nexviazyme compared with alglucosidase alfa. The results for the 6MWT are detailed in Table 2. Additional secondary endpoints of the study were maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), Hand-held dynamometry (HHD) summary score, quick motor function test (QMFT) total score, and SF-12 (health-related survey on quality of life, both physical and mental component scores). The results for these endpoints are detailed in Table 2. In treatment-naïve LOPD patients aged 16 to 78, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline for patients treated with Nexviazyme 20 mg/kg every other week and alglucosidase alfa 20 mg/kg every other week was -53.90% (24.03) and -10.8% (32.33), respectively, in week 49. (See Table 2.)

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In the EFC14028/COMET study, efficacy data were available in 24 patients at week 97, 17 patients at week 121, and 11 patients at week 145. Additionally, 9 patients randomised to alglucosidase alfa who switched the treatment to avalglucosidase alfa after week 49 continued the treatment for up to 2 years. FVC % predicted values remained elevated over baseline throughout dosing with avalglucosidase alfa for as long as 97 weeks in 24 patients who had reached this timepoint. Efficacy data in EFC14028/COMET study at week 97 for patients who switched from alglucosidase alfa to avalglucosidase alfa at week 49 showed numerical improvement for FVC % predicted and 6MWT. In the same study, the observed mean 6MWT distance remained elevated over baseline throughout dosing with avalglucosidase alfa for as long as 145 weeks in 10 patients who had reached this timepoint.
In an open-label, uncontrolled study in LOPD patients, the FVC % predicted and 6MWT showed maintenance of effect during the long-term treatment with avalglucosidase alfa 20 mg/kg every other week for up to 6 years.
Clinical study in patients with IOPD: Study 2, ACT14132/mini-COMET, was a multi-stage, phase 2, open-label, multicentre, multinational, repeated ascending dose cohort of Nexviazyme in paediatric IOPD patients (1-12 years of age) who demonstrated either clinical decline or sub-optimal clinical response while on treatment with alglucosidase alfa. The study enrolled a total of 22 patients; cohort 1 had 6 patients who demonstrated clinical decline and received 20 mg/kg every other week for 25 weeks, cohort 2 had 5 patients who demonstrated clinical decline and received 40 mg/kg every other week for 25 weeks, and cohort 3 had 11 patients who demonstrated sub-optimal response and received either Nexviazyme at 40 mg/kg every other week for 25 weeks (5 patients) or alglucosidase alfa at their stable pre-study dose (ranging between 20 mg/kg every other week and 40 mg/kg weekly) for 25 weeks (6 patients).
The primary objective of study 2 was to evaluate the safety and tolerability of administering Nexviazyme. The secondary objective was to determine the efficacy of Nexviazyme. Data showed stabilization or improvement in efficacy outcomes of gross motor function classification measure-88 (GMFM-88), quick motor function test (QMFT), Pompe paediatric evaluation of disability inventory (Pompe-PEDI), left ventricular mass (LVM) Z score, eyelid position measurements in patients previously declining or insufficiently controlled with alglucosidase alfa. Treatment effect was more pronounced with 40 mg/kg every other week compared to the 20 mg/kg every other week. Two out of six patients treated with Nexviazyme at 20 mg/kg every other week (cohort 1) demonstrated further clinical decline and received dose increase from 20 to 40 mg/kg every other week at week 55 and 61 respectively. All patients who received 40 mg/kg every other week maintained this dose for the duration of the study without further clinical decline.
In paediatric IOPD patients (<18 years of age) treated with Nexviazyme at 40 mg/kg every other week who demonstrated either clinical decline (cohort 2) or sub-optimal clinical response (cohort 3) while on treatment with alglucosidase alfa, the mean percentage (SD) change in urinary hexose tetrasaccharides from baseline was -40.97% (16.72) and -37.48% (17.16), respectively, after 6 months. In patients previously declining treated with Nexviazyme at 20 mg/kg every other week, mean (SD) percentage change was 0.34% (42.09).
The long-term effects of treatment with Nexviazyme were evaluated in 10 patients at week 49, 8 patients at week 73, and 3 patients at week 97. In patients with IOPD previously declining with alglucosidase alfa, the efficacy on specific parameters of decline, including motor function, cardiac left ventricular mass, and eyelid position measurements, was sustained up to 2 years.
Paediatric population: Nineteen paediatric patients aged from 1 to 12 years with IOPD previously treated with alglucosidase alfa have been treated with Nexviazyme (see Dosage & Administration and Adverse Reactions) and two paediatric patients aged 9 and 16 years with LOPD was treated with Nexviazyme.
The European Medicines Agency has deferred the obligation to submit the results of studies with Nexviazyme in one or more subsets of the paediatric population for the treatment of Pompe disease (see Dosage & Administration for information on paediatric use).
Pompe registry: Medical or healthcare professionals are encouraged to register patients who are diagnosed with Pompe disease at www.registrynxt.com. Patient data will be anonymously collected in this registry. The objectives of the "Pompe registry" are to enhance the understanding of Pompe disease and to monitor patients and their response to enzyme replacement therapy over time, with the ultimate goal of improving clinical outcomes for these patients.
Pharmacokinetics: Patients with late-onset Pompe disease (LOPD): The pharmacokinetics of avalglucosidase alfa was evaluated in a population analysis of 75 LOPD patients aged 16 to 78 years who received 5 to 20 mg/kg of avalglucosidase alfa every other week.
Patients with infantile-onset Pompe disease (IOPD): The pharmacokinetics of avalglucosidase alfa was characterized in 16 patients aged 1 to 12 years who were treated with avalglucosidase alfa, which included 6 patients treated with 20 mg/kg and 10 patients treated with 40 mg/kg doses every other week. All patients were treatment-experienced.
Absorption: In LOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week, the mean Cmax and mean AUC2W were 273 μg/mL (24%) and 1220 μg∙h/ml (29%), respectively.
In IOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week and 7-hour IV infusion for 40 mg/kg every other week, the mean Cmax ranged from 175 to 189 μg/ml for the 20 mg/kg dose and 205 to 403 μg/ml for 40 mg/kg dose. The mean AUC2W ranged from 805 to 923 μg∙hr/ml for the 20 mg/kg dose and 1720 to 2630 μg∙hr/ml for 40 mg/kg dose.
Distribution: In LOPD patients, the typical population PK model predicted central compartment volume of distribution of avalglucosidase alfa was 3.4 L.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, the mean volume of distribution at steady state ranged between 3.5 to 5.4 L.
Elimination: In LOPD patients, the typical population PK model predicted linear clearance was 0.87 L/h. Following 20 mg/kg every other week, the mean plasma elimination half-life was 1.55 hours.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, mean plasma clearance ranged from 0.53 to 0.70 L/h, and mean plasma elimination half-life from 0.60 to 1.19 hours.
Linearity/non-linearity: The exposure to avalglucosidase alfa increased in a dose-proportional manner between 5 to 20 mg/kg in LOPD patients and between 20 and 40 mg/kg in IOPD patients. No accumulation was observed following every other week dosing.
Immunogenicity: In the study 1, EFC14028/COMET, 96.1% (49 of 51 patients) receiving Nexviazyme developed treatment-emergent ADA. No clear trend of ADA impact on PK was observed.
In clinical study ACT14132/mini-COMET, 16 IOPD patients received either 20 mg/kg or 40 mg/kg q2w avalglucosidase alfa and 6 IOPD patients received alglucosidase alfa. All patients were previously treated with alglucosidase alfa. Treatment-emergent ADA developed in 6 of the 16 avalglucosidase alfa treated patients (Table 5) and none developed neutralizing antibodies. The peak titer range was 100 to 6400. None of the patients developed a high ADA response ≥12800. No effect of ADA on PK could be evidenced during this study.
Special populations: Population pharmacokinetic analyses in LOPD patients showed that body weight, age, and gender did not meaningfully influence the pharmacokinetics of avalglucosidase alfa.
Hepatic impairment: The pharmacokinetics of avalglucosidase alfa has not been studied in patients with hepatic impairment.
Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics of avalglucosidase alfa was conducted. On the basis of a population pharmacokinetic analysis of data from 75 LOPD patients receiving 20 mg/kg, including 6 patients with mild renal impairment (glomerular filtration rate: 60 to 89 ml/min; at baseline), no relevant effect of renal impairment on avalglucosidase alfa exposure was observed.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity that included safety pharmacology endpoints.
Avalglucosidase alfa caused no adverse effects in a combined male and female fertility study in mice up to 50 mg/kg IV every other day (9.4 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD) (see Use in Pregnancy & Lactation).
In an embryo-foetal toxicity study in mice, administration of avalglucosidase at the highest dose of 50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD) produced increased post-implantation loss and mean number of late resorptions. No effects were seen at 20 mg/kg/day (4.8 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD). Avalglucosidase alfa does not cross the placenta in mice, suggesting that the embryo-foetal effects at 50 mg/kg/day were related to maternal toxicity from the immunologic response. No malformations or developmental variations were observed.
No adverse effects were observed in an embryo-foetal toxicity study in rabbits administered avalglucosidase alfa up to 100 mg/kg/day IV (91 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD).
There were no adverse effects in a pre- and post-natal developmental toxicity study in mice following administration of avalglucosidase alfa once every other day. The NOAEL for reproduction in the dams and for viability and growth in the offspring was 50 mg/kg every other day IV.
In juvenile mice, avalglucosidase alfa was generally well tolerated following administration for 9 weeks at doses up to 100 mg/kg every other week IV (~2 to 5 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for patients with IOPD). However, the highest dose tested in juvenile animals is not enough to discard a potential risk for IOPD patients at 40 mg/kg based on exposure margin.

Nexviazyme (avalglucosidase alfa) is indicated for long-term enzyme replacement therapy for the treatment of patients with Pompe disease (acid α-glucosidase deficiency).

Nexviazyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.
Posology: Patients may be pre-treated with antihistamines, antipyretics, and/or corticosteroids to prevent or reduce allergic reactions.
The recommended dose of avalglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks.
Dose modification for IOPD patients: For IOPD patients who experience lack of improvement or insufficient response in cardiac, respiratory, and/or motor function while receiving 20 mg/kg, a dose increase to 40 mg/kg every other week should be considered in the absence of safety concerns (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload).
In patients who do not tolerate avalglucosidase alfa at 40 mg/kg every other week (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload), consider decreasing the dose to 20 mg/kg every other week (see Precautions).
Special populations: Elderly patients: No dose adjustment is required in patients >65 years.
Hepatic impairment: The safety and efficacy of avalglucosidase alfa in patients with hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.
Renal impairment: No dose adjustment is required in patients with mild renal impairment. The safety and efficacy of avalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated and no specific dose regimen can be recommended for these patients (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population (patients 6 months of age and younger): The safety and efficacy of avalglucosidase alfa in children 6 months of age and younger have not yet been established. There are no data available in patients 6 months of age and younger.
Method of administration: Nexviazyme vials are for single use only and the medicinal product should be administered as an intravenous infusion.
The infusion should be administered incrementally as determined by patient response and comfort.
It is recommended that the infusion begins at an initial rate of 1 mg/kg/hour and is gradually increased every 30 minutes if there are no signs of infusion-associated reactions (IARs), in accordance with Table 3. Vital signs should be obtained at each step, before increasing the infusion rate. (See Table 3.)

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In the event of anaphylaxis or severe hypersensitivity reaction or severe IARs, administration of Nexviazyme should be immediately discontinued and appropriate medical treatment should be initiated. In the event of mild to moderate hypersensitivity reactions or IARs, the infusion rate may be slowed or temporarily stopped and/or appropriate medical treatment initiated (see Precautions).
Symptoms may persist despite temporarily stopping the infusion; therefore, the treating physician should wait at least 30 minutes for symptoms of the reactions to resolve before deciding to stop the infusion for the remainder of the day. If symptoms subside, infusion rate should be resumed for 30 minutes at half the rate, or less, of the rate at which the reactions occurred, followed by an increase in infusion rate by 50% for 15 to 30 minutes. If symptoms do not recur, the infusion rate should be increased to the rate at which the reactions occurred and consider continuing to increase the rate in a stepwise manner until the maximum rate is achieved.
Home infusion: Infusion of Nexviazyme at home may be considered for patients who are tolerating their infusions well and have no history of moderate or severe IARs for a few months. The decision to have a patient move to home infusion should be made after evaluation and upon recommendation by the treating physician. A patient's underlying co-morbidities and ability to adhere to the home infusion requirements need to be taken into account when evaluating the patient for eligibility to receive home infusion. The following criteria should be considered: The patient must have no ongoing concurrent condition that, in the opinion of the physician, may affect patient's ability to tolerate the infusion.
The patient is considered medically stable. A comprehensive evaluation must be completed before the initiation of home infusion.
The patient must have received Nexviazyme infusions supervised by a physician with expertise in management of Pompe patients for a few months that could be in a hospital or in another appropriate setting of outpatient care. Documentation of a pattern of well-tolerated infusions with no IARs, or mild IARs that have been controlled with premedication, is a prerequisite for the initiation of home infusion.
The patient must be willing and able to comply with home infusion procedures.
Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. The healthcare professional should be available at all times during the home infusion and a specified time after infusion, depending on patient's tolerance prior to starting home infusion.
If the patient experiences adverse reactions during the home infusion, the infusion process should be stopped immediately, and appropriate medical treatment should be initiated (see Precautions). Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present. Dose and infusion rate must not be changed without consulting the responsible physician.
For instructions on reconstitution and dilution of medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.

Excessive infusion rate of Nexviazyme may result in hot flush. In a clinical study, paediatric patients received doses up to 40 mg/kg of body weight once every 2 weeks and no specific signs and symptoms were identified following the higher doses. For management of adverse reactions, see Precautions and Adverse Reactions.

Nexviazyme is contraindicated in individuals with a history life threatening hypersensitivity to the active substance or to any of the excipients listed in Description (see Precautions and Adverse Reactions).

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.
Hypersensitivity reactions (including anaphylaxis): Hypersensitivity reactions, including anaphylaxis, have been reported in Nexviazyme-treated patients (see Adverse Reactions).
Appropriate medical support measures, including cardiopulmonary resuscitation equipment especially for patients with cardiac hypertrophy and patients with significantly compromised respiratory function, should be readily available when Nexviazyme is administered.
If severe hypersensitivity or anaphylaxis occur, Nexviazyme should be discontinued immediately, and appropriate medical treatment should be initiated. The risks and benefits of re-administering Nexviazyme following anaphylaxis or severe hypersensitivity reaction should be considered. Some patients have been re-challenged using slower infusion rates at a dose lower than the recommended dose.
In patients with severe hypersensitivity, desensitization procedure to Nexviazyme may be considered. If the decision is made to re-administer the medicinal product, extreme caution should be exercised, with appropriate resuscitation measures available. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose.
If mild or moderate hypersensitivity reactions occur, the infusion rate may be slowed or temporarily stopped.
Infusion-associated reactions (IARs): In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the infusion of Nexviazyme and were more likely with higher infusion rates (see Adverse Reactions).
Patients with an acute underlying illness at the time of Nexviazyme infusion appear to be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs. Antihistamines, antipyretics, and/or corticosteroids can be given to prevent or reduce IARs. However, IARs may still occur in patients after receiving pre-treatment.
If severe IARs occur, immediate discontinuation of the administration of Nexviazyme should be considered and appropriate medical treatment should be initiated. The benefits and risks of re-administering Nexviazyme following severe IARs should be considered. Some patients have been re-challenged using slower infusion rates at a dose lower than the recommended dose. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose. If mild or moderate IARs occur regardless of pre-treatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms (see Adverse Reactions).
Immunogenicity: Treatment emergent anti-drug antibodies (ADA) were reported in both treatment naïve (95%) and treatment-experienced patients (49%) (see Adverse Reactions).
IARs and hypersensitivity reactions may occur independent of the development of ADA. The majority of IARs and hypersensitivity reactions were mild or moderate and were managed with standard clinical practices. In clinical studies, the development of ADA did not impact clinical efficacy (see Adverse Reactions).
ADA testing may be considered if patients do not respond to therapy. Adverse-event-driven immunologic testing, including IgG and IgE ADA, may be considered for patients who have risk for allergic reaction or previous anaphylactic reaction to alglucosidase alfa.
Risk of acute cardiorespiratory failure: Caution should be exercised when administering Nexviazyme to patients susceptible to fluid volume overload or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusion. Appropriate medical support and monitoring measures should be readily available during Nexviazyme infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.
Cardiac arrhythmia and sudden death during general anaesthesia for central venous catheter placement: Caution should be used when administering general anaesthesia for the placement of a central venous catheter or for other surgical procedures in patients with IOPD with cardiac hypertrophy.
Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia, and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation, have been associated with the use of general anaesthesia in IOPD patients with cardiac hypertrophy.
Effects on ability to drive and use machines: Nexviazyme may have a minor influence on the ability to drive and use machines. Because dizziness, hypotension and somnolence have been reported as IARs, this may affect the ability to drive and use machines on the day of the infusion (see Adverse Reactions).

Pregnancy: There are no available data on the use of Nexviazyme in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. Indirect foetal effects in mice were considered related to an anaphylactic response to avalglucosidase alfa (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. No conclusions can be drawn regarding whether or not Nexviazyme is safe for use during pregnancy. Nexviazyme should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the foetus.
Breast-feeding: There are no available data on the presence of Nexviazyme in human milk or the effects of Nexviazyme on milk production or the breast-fed infant. No conclusions can be drawn regarding whether or not Nexviazyme is safe for use during breast-feeding. Nexviazyme should be used during breast-feeding only if the potential benefits to the mother outweigh the potential risks, including those to the breast-fed child (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Fertility: There are no clinical data on the effects of Nexviazyme on human fertility. Animal studies in mice showed no impairment of male or female fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: Serious adverse reactions reported in patients treated with Nexviazyme were chills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, respiratory distress, nausea, skin discoloration, chest discomfort, pyrexia, blood pressure increased, body temperature increased, heart rate increased, and oxygen saturation decreased. Hypersensitivity reactions were reported in 43.5% of patients, anaphylaxis in 1.4%, and IARs in 26.1% in patients. A total of 2.9% patients receiving Nexviazyme in clinical studies permanently discontinued treatment; 0.7% patients each discontinued the treatment because of the following events considered to be related to Nexviazyme: respiratory distress, chest discomfort, dizziness, cough, nausea, flushing, ocular hyperaemia, and erythema.
The most frequently reported adverse drug reactions (ADRs) (>5%) were pruritus (9.4%), rash (8%), headache (7.2%), urticaria (6.5%), fatigue (6.5%), nausea (5.8%), and chills (5.1%).
The pooled safety analysis from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET, TDR12857/NEO, and LTS13769/NEO-EXT) included a total of 138 patients (118 adult and 20 paediatric patients) treated with Nexviazyme. ADRs reported in patients treated with Nexviazyme in the pooled analysis of clinical studies are listed in Table 4.
Tabulated list of adverse reactions: Adverse reactions (reported in at least 3 patients) per System Organ Class, presented by frequency categories: 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).
Due to the small patient population, an adverse reaction reported in 2 patients is classified as common. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 4.)

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In a comparative study, EFC14028/COMET, 100 LOPD patients aged 16 to 78 naïve to enzyme replacement therapy were treated either with 20 mg/kg of Nexviazyme (n=51) or 20 mg/kg of alglucosidase alfa (n=49). Serious adverse reactions were reported in 2% of patients treated with Nexviazyme and 6.1% of those treated with alglucosidase alfa. A total of 8.2% patients receiving alglucosidase alfa in the study permanently discontinued treatment due to adverse reactions; none of the patients from the Nexviazyme group permanently discontinued the treatment. The most frequently reported ADRs (>5%) were headache, nausea, pruritus, urticaria, and fatigue.
Description of selected adverse reactions: Hypersensitivity (including anaphylaxis): In a pooled safety analysis, 60/138 (43.5%) patients experienced hypersensitivity reactions including 6/138 (4.3%) patients who reported severe hypersensitivity reactions and 2/138 (1.4%) patients who experienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis symptoms included respiratory distress, chest pressure, generalised flushing, cough, dizziness, nausea, redness on palms, swollen lower lip, decreased breath sounds, redness on feet, swollen tongue, itchy palms and feet, and oxygen desaturation. Symptoms of severe hypersensitivity reactions included respiratory failure, respiratory distress, and rash.
Infusion-associated reactions (IARs): In a pooled safety analysis, IARs were reported in approximately 42/138 (30.4%) of patients treated with avalglucosidase alfa in clinical studies. Severe IARs were reported in 3/138 (2.2%) of patients including symptoms of chest discomfort, nausea, and increased blood pressure. IARs reported in more than 1 patient included chills, cough, diarrhoea, erythema, fatigue, headache, influenza-like illness, nausea, ocular hyperaemia, pain in extremity, pruritus, rash, rash erythematous, tachycardia, urticaria, vomiting, chest discomfort, dizziness, hyperhidrosis, lip swelling, oxygen saturation decreased, pain, palmar erythema, swollen tongue and tremor. The majority of IARs were assessed as mild to moderate.
In the comparative study EFC14028/COMET study, fewer LOPD patients in the avalglucosidase alfa group reported at least 1 IAR (13/51 [25.5%]) in comparison to the alglucosidase alfa group (16/49 [32.7%]). Severe IARs were not reported in patients in the avalglucosidase alfa group and reported in 2 patients in the alglucosidase alfa group (dizziness, visual impairment, hypotension, dyspnoea, cold sweat, and chills). The most frequently reported TEAEs (>2 patients) in the avalglucosidase alfa group were pruritus (7.8%) and urticaria (5.9%) and in the alglucosidase alfa group were nausea (8.2%), pruritus (8.2%), and flushing (6.1%). The majority of IARs reported in 7 (13.7%) patients were of mild severity in the avalglucosidase alfa group and 10 [20.4%] patients in the alglucosidase alfa group).
Immunogenicity: The incidence of ADA response to avalglucosidase alfa in Nexviazyme-treated patients with Pompe disease is shown in Table 5. The median time to seroconversion was 8.3 weeks.
In treatment-naïve adult patients, the occurrence of IAR was observed in both ADA-positive and ADA-negative patients. Increase in the incidence of IAR and hypersensitivity were observed with higher IgG ADA titres. In treatment-naïve patients, a trend for increases in the incidence of IARs was observed with increasing ADA titres, with the highest incidence of IARs (61.5%) reported in the high ADA peak titre range ≥12,800, compared with an incidence of 17.2% in patients with intermediate ADA titre 1,600-6,400, an incidence of 7.1% in those with low ADA titre 100-800 and an incidence of 33.3% in those who were ADA negative. In enzyme replacement therapy (ERT) experienced adult patients, the occurrences of IARs and hypersensitivity were higher in patients who developed treatment emergent ADA compared to patients who were ADA negative. One (1) treatment naïve patient and 1 treatment-experienced patient developed anaphylaxis. The occurrences of IARs were similar between paediatric patients with ADA positive and negative status. There were no paediatric patients who developed anaphylactic reactions (see Precautions).
In clinical study EFC14028/COMET, 2 patients reported High Sustained Antibody Titres (HSAT) to Nexviazyme but this was not associated with a loss of efficacy. ADA cross-reactivity studies showed that the majority of patients generate antibodies that are cross-reactive to alglucosidase alfa. At week 49, antibodies specific to Nexviazyme were detected in 3 (5.9%) patients. ADA did not impact measures of efficacy while limited impacts on PK and PD were observed primarily with high titre patients (see Pharmacology: Pharmacokinetics under Actions). (See Table 5.)

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Paediatric population: Adverse drug reactions reported from clinical studies in the paediatric population (19 paediatric patients with IOPD between 1-12 years of age (mean age of 6.8) and one 16-year-old paediatric patient with LOPD) were similar to those reported in adults.

No interaction studies have been performed. Because it is a recombinant human protein, avalglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: Vials are for single use only.
Reconstitution: Aseptic technique should be used during reconstitution.
1. The number of vials have to be determined to be reconstituted based on individual patient's weight and the recommended dose of 20 mg/kg or 40 mg/kg.
Patient weight (kg) x dose (mg/kg) = patient dose (in mg). Patient dose (in mg) divided by 100 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, it should be rounded up to the next whole number.
Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg). 320 mg divided by 100 mg/vial = 3.2 vials; therefore, 4 vials should be reconstituted.
Example: Patient weight (16 kg) x dose (40 mg/kg) = patient dose (640 mg).
640 mg divided by 100 mg/vial = 6.4 vials; therefore, 7 vials should be reconstituted.
2. The required number of vials needed for the infusion should be removed from the refrigerator and set aside for approximately 30 minutes to allow them to reach room temperature.
3. Each vial should be reconstituted by slowly injecting 10.0 ml of water for injections (WFI) to each vial. Each vial will yield 100 mg/10 ml (10 mg/ml). Forceful impact of the WFI on the powder and foaming should be avoided. This is performed by slow drop-wise addition of the WFI down the inside of the vial and not directly onto the lyophilised powder. Each vial should be tilted and rolled gently to dissolve the lyophilised powder. It should not be inverted, swirled, or shaken.
4. Immediate visual inspection should be performed on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection particles are observed or if the solution is discoloured, the reconstituted medicinal product should not be used. The solution should be allowed to become dissolved.
Dilution: 5. The reconstituted solution should be diluted in 5% glucose in water to a final concentration of 0.5 mg/ml to 4 mg/ml. See Table 6 for the recommended total infusion volume based on the patient weight.
6. The volume of reconstituted solution from each vial should be slowly withdrawn (calculated according to patient's weight).
7. The reconstituted solution should be added slowly and directly into the 5% glucose solution. Foaming or agitation of the infusion bag should be avoided. Air introduction into the infusion bag should be avoided.
8. To mix the infusion bag solution, gently invert or massage the infusion bag to mix. It should not be shaken.
9. To avoid administration of inadvertently introduced particles during dose IV preparation, it is recommended to use an in-line, low protein binding, 0.2 μm filter to administer Nexviazyme. After the infusion is complete, the intravenous line should be flushed with glucose 5% in water.
10. Nexviazyme should not be infused in the same intravenous line with other medicinal products. (See Table 6.)

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Store in a refrigerator (2°C - 8°C).
For storage conditions after reconstitution and dilution of the medicinal product, see Shelf life.
Shelf life: Unopened vials: 4 years.
Reconstituted medicinal product: After reconstitution, chemical, physical, and microbiological in-use stability has been demonstrated for 24 hours at 2°C - 8°C.
From a microbiological point of view, the reconstituted product should be used immediately.
If not used for dilution immediately, in-use storage times and conditions prior to dilution are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.
Diluted medicinal product: After dilution, chemical, physical and microbiological in-use stability has been demonstrated between 0.5 mg/ml and 4 mg/ml for 24 hours at 2°C - 8°C, followed by 9 hours at room temperature (up to 25°C) to allow for infusion.
Use Aseptic Techniques: From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, followed by 9 hours at room temperature (up to 25°C) to allow for infusion.

Other Agents Affecting Metabolism

A16AB22 - avalglucosidase alfa ; Belongs to the class of enzymes. Used in the treatment of alimentary tract and metabolism problems.

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