2.1 Recommended Dosage and Administration

• Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1)].
• NEXVIAZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.3)].
• NEXVIAZYME is administered as intravenous infusion. For patients weighing:
  • ≥30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.4)]
  • <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.4)]
• The initial recommended infusion rate is 1 mg/kg/hour. Gradually increase the infusion rate every 30 minutes if there are no signs of infusion-associated reactions (IARs) [see Dosage and Administration (2.4)].

2.2 Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions

• In the event of a severe hypersensitivity reaction (including anaphylaxis) or a severe infusion-associated reaction (IAR), immediately discontinue NEXVIAZYME administration and initiate appropriate medical treatment [see Warnings and Precautions (5.1)].
• In the event of a mild to moderate hypersensitivity reaction or a moderate IAR, consider temporarily holding or slowing the infusion rate and initiating appropriate medical treatment [see Warnings and Precautions (5.1, 5.2)]. If symptoms:
  • Persist despite temporarily holding the infusion, wait at least 30 minutes for symptoms to resolve before deciding to stop the infusion for the day.
  • Subside, resume the infusion for 30 minutes at half the rate at which the reaction occurred, and subsequently increase the infusion rate by 50% for 15 minutes to 30 minutes. If symptoms do not recur, increase the infusion rate to the rate at which the reaction occurred and consider continuing to increase the rate in a stepwise manner.

2.3 Reconstitution and Dilution Instructions

Reconstitute and dilute NEXVIAZYME in the following manner. Use aseptic technique during preparation.

2.4 Administration Instructions

1. It is recommended to use an in-line, low protein binding, 0.2 micrometer filter to administer NEXVIAZYME.
2. Administer the infusion incrementally, as determined by the patient's response and comfort.
   When the recommended dose is 20 mg/kg
   • Initial and Subsequent Infusions: The recommended starting infusion rate is 1 mg/kg/hour. If there are no signs of infusion-associated reactions (IARs), gradually increase the infusion rate every 30 minutes in each of the following three steps: 3 mg/kg/hour, 5 mg/kg/hour, and then 7 mg/kg/hour; then, maintain the infusion rate at 7 mg/kg/hour until the infusion is complete. The approximate total infusion duration is 4 hours to 5 hours.
   
   When the recommended dose is 40 mg/kg
   • Initial Infusion: The recommended starting infusion rate is 1 mg/kg/hour. If there are no signs of IARs, gradually increase the infusion rate every 30 minutes in each of the following three steps: 3 mg/kg/hour, 5 mg/kg/hour, and then 7 mg/kg/hour; then, maintain the infusion rate at 7 mg/kg/hour until the infusion is complete (4-step process). The approximate total infusion duration is 7 hours.
   • Subsequent Infusions: The recommended starting infusion rate is 1 mg/kg/hour, with gradual increase in infusion rate every 30 minutes if there are no signs of IARs. The process may use either the above 4-step process or the following 5-step process: 3 mg/kg/hour, 6 mg/kg/hour, 8 mg/kg/hour, and then 10 mg/kg/hour; then, maintain the infusion rate at 10 mg/kg/hour until the infusion is complete. The approximate total 5-step infusion duration is 5 hours.
3. After the infusion is complete, flush the intravenous line with 5% Dextrose Injection.
4. Discard any unused diluted product after 9 hours.
5. Do not infuse NEXVIAZYME in the same intravenous line with other products.

5.1 Hypersensitivity Reactions Including Anaphylaxis

Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration.

• If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, NEXVIAZYME should be discontinued immediately and appropriate medical treatment should be initiated. The risks and benefits of readministering NEXVIAZYME following severe hypersensitivity reaction (including anaphylaxis) should be considered. Some patients have been rechallenged using slower infusion rates at a dosage lower than the recommended dosage. In patients with severe hypersensitivity reaction, a desensitization procedure to NEXVIAZYME may be considered. If the decision is made to readminister NEXVIAZYME, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the approved recommended dosage.
• If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily stopped.

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in NEXVIAZYME-treated patients. In clinical studies, 67 (48%) NEXVIAZYME-treated patients experienced hypersensitivity reactions, including 6 (4%) patients who reported severe hypersensitivity reactions and 3 (2%) additional patients who experienced anaphylaxis; 1 (1%) patient experiencing anaphylaxis discontinued from the study. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis signs and symptoms included respiratory distress, chest discomfort, flushing, cough, erythema, lip swelling, pruritus, swollen tongue, dysphagia, and rash. Symptoms of severe hypersensitivity reactions included respiratory distress, erythema, urticaria, tongue edema, and rash. Increased incidence of hypersensitivity reactions was observed in patients with higher antidrug antibody (ADA) titers [see Adverse Reactions (6.2)].

5.2 Infusion-Associated Reactions

Antihistamines, antipyretics, and/or corticosteroids can be given prior to NEXVIAZYME administration to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pretreatment.

If severe IARs occur, consider immediate discontinuation of NEXVIAZYME, initiation of appropriate medical treatment, and the benefits and risks of readministering NEXVIAZYME following severe IARs. Some patients have been rechallenged 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 recommended approved dose.

If mild or moderate IARs occur regardless of pretreatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms.

In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the NEXVIAZYME infusion and were more likely to occur with higher infusion rates. IARs were reported in 48 (34%) NEXVIAZYME-treated patients in clinical studies. In these studies, 5 (4%) NEXVIAZYME-treated patients reported 10 severe IARs including symptoms of chest discomfort, nausea, dysphagia, erythema, respiratory distress, tongue edema, urticaria, and increased blood pressure. The majority of IARs were assessed as mild to moderate. IARs that led to treatment discontinuation were chest discomfort, cough, dizziness, erythema, flushing, nausea, ocular hyperemia, and respiratory distress. Increased incidence of IARs was observed in patients with higher ADA titers [see Adverse Reactions (6.2)].

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.

5.3 Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during the NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion in these patients. Some patients may require prolonged observation times.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other avalglucosidase alfa products may be misleading.

The incidence of anti-avalglucosidase alfa-ngpt antibodies (antidrug antibodies, ADA) in NEXVIAZYME-treated patients with Pompe disease is shown in Table 3. In NEXVIAZYME-treated patients (mean of 26 months, up to 85 months of treatment), the incidence of IAR was 62% (8/13) in those with an ADA peak titer ≥12,800, compared with incidences of 19% (8/43) in those with ADA peak titer <12,800 and 33% (1/3) in those who were ADA-negative [see Warnings and Precautions (5.2)]. Increased incidence of hypersensitivity reactions was observed in patients with higher ADA titers (4/13, 31%) compared to lower ADA titers (2/14, 14%). In enzyme replacement therapy (ERT)–experienced adult patients, the occurrences of IARs and hypersensitivity reactions were higher in patients who developed ADA compared to patients who were ADA-negative. One (1) treatment-naive patient (ADA peak titer 3,200) and 2 treatment-experienced patients (ADA peak titers; 800 and 12,800, respectively) developed anaphylaxis [see Warnings and Precautions (5.1)].

The median time to seroconversion was 8 weeks. No clear trend of ADA impact on pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. A trend toward decreased pharmacodynamic response as measured by percent change of urinary glucose tetrasaccharides from baseline was observed in patients with ADA peak titer ≥12,800. The development of ADA did not have an apparent impact on clinical efficacy.

ADA cross-reactivity studies showed that antibodies to avalglucosidase alfa-ngpt were cross-reactive to alglucosidase alfa.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of NEXVIAZYME for the treatment of late-onset Pompe disease have been established in pediatric patients 1 year of age and older. Use of NEXVIAZYME for this indication is supported by evidence from two clinical studies which included adults with LOPD, and 1 pediatric patient with LOPD (16 years of age) and from safety experience in 19 pediatric patients with infantile-onset Pompe disease (IOPD) (1 to 12 years of age) treated with NEXVIAZYME [see Clinical Studies (14.1)]. NEXVIAZYME is not approved for the treatment of IOPD.

The safety profile of NEXVIAZYME in pediatric patients 1 to 12 years old with Pompe disease was similar to the safety profile of NEXVIAZYME in older pediatric and adult patients with LOPD. The safety and effectiveness of NEXVIAZYME have not been established in pediatric patients younger than 1 year of age.

8.5 Geriatric Use

Clinical studies with NEXVIAZYME included 14 patients 65 to 74 years of age and 3 patients 75 years of age and older. The recommended dosage in geriatric patients is the same as the recommended dosage in younger adult patients [see Adverse Reactions (6.1)].

12.1 Mechanism of Action

Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II) is an inherited disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA), which results in intralysosomal accumulation of glycogen in various tissues.

Avalglucosidase alfa-ngpt provides an exogenous source of GAA. The M6P on avalglucosidase alfa-ngpt mediates binding to M6P receptors on the cell surface with high affinity. After binding, it is internalized and transported into lysosomes where it undergoes proteolytic cleavage that results in increased GAA enzymatic activity. Avalglucosidase alfa-ngpt then exerts enzymatic activity in cleaving glycogen.

12.2 Pharmacodynamics

In patients with Pompe disease, excess of glycogen is degraded to hexose tetrasaccharide (Hex4) which is then excreted in urine. The urinary Hex4 assay measures its major component, glucose tetrasaccharide (Glc4). In clinical studies, treatment with NEXVIAZYME resulted in reductions of urinary Glc4 concentrations (normalized by urine creatinine and reported as mmol Glc4/mol creatinine) in patients with Pompe disease.

In Study 1, the baseline mean urinary Glc4 concentration was 12.7 mmol/mol and 8.7 mmol/mol in NEXVIAZYME and alglucosidase alfa treatment groups, respectively, in treatment-naive LOPD patients [see Clinical Studies (14.1)]. The mean percentage (SD) change in urinary Glc4 concentrations from baseline to Week 49 was -54% (24) and -11% (32) in the NEXVIAZYME and alglucosidase alfa treatment groups, respectively.

12.3 Pharmacokinetics

The avalglucosidase alfa-ngpt exposure increases in an approximately proportional manner with increasing doses over a range from 5 to 20 mg/kg (0.25 to 1 time the approved recommended dosage in LOPD patients weighing ≥30 kg or 0.125 to 0.5 times the approved recommended dosage in LOPD patients weighing <30 kg). No accumulation was observed following every two weeks dosing. Following intravenous infusion of 20 mg/kg of NEXVIAZYME every two weeks in LOPD patients weighing ≥30 kg, the mean ± SD plasma Cmax of avalglucosidase alfa-ngpt at Week 1 and Week 49 was 259 ± 72 µg/mL and 242 ± 81 µg/mL, respectively; the mean ± SD plasma AUC of avalglucosidase alfa-ngpt at Week 1 and Week 49 was 1,290 ± 420 µg∙h/mL and 1,250 ± 433 µg∙h/mL, respectively. Patients weighing <30 kg are expected to have similar AUC following intravenous infusion of 40 mg/kg of NEXVIAZYME every two weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential or studies to evaluate mutagenic potential have not been performed with avalglucosidase alfa-ngpt.

Intravenous administration of avalglucosidase alfa-ngpt every other day at doses up to 50 mg/kg (exposure not evaluated) had no adverse effects on fertility in male or female mice.

14.1 Clinical Trial in Patients with Late-Onset Pompe Disease

Study 1 (NCT02782741) was a randomized, double-blinded, multinational, multicenter trial comparing the efficacy and safety of NEXVIAZYME to alglucosidase alfa in 100 treatment-naive patients with LOPD. Patients were randomized 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 administered intravenously once every two weeks for 49 weeks. The trial included an open-label, long-term, follow-up phase of up to 5 years, in which patients in the alglucosidase alfa arm were switched to NEXVIAZYME treatment. Of the 100 randomized patients, 52 were males, the baseline median age was 49 years old (range from 16 to 78), median baseline weight was 76.4 kg (range from 38 to 139 kg), median length of time since diagnosis was 6.9 months (range from 0.3 to 328.4 months), mean age at diagnosis was 46.4 years old (range from 11 to 78), mean FVC (% predicted) at baseline was 62.1% (range from 32 to 85%), and mean 6MWT at baseline was 388.9 meters (range from 118 to 630 meters).

Refrigerate vials of NEXVIAZYME at 36°F to 46°F (2°C to 8°C ). Do not use NEXVIAZYME after the expiration date on the vial.

Hypersensitivity Reactions (Including Anaphylaxis) and Infusion-Associated Reactions (IARs)

Advise the patients and caregivers that reactions related to the infusion may occur during and after NEXVIAZYME treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and IARs. Inform patients of the signs and symptoms of hypersensitivity reactions and IARs and have them seek medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.2)].

Risk of Acute Cardiorespiratory Failure

Advise patients and caregivers that patients with underlying respiratory illness or compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure from volume overload during NEXVIAZYME infusion [see Warnings and Precautions (5.3)].

NEXVIAZYME Exposure During Pregnancy or Lactation

Pregnant or lactating women exposed to NEXVIAZYME, or their healthcare providers, should report NEXVIAZYME exposure by calling 1-800-745-4447, extension 15500.

Pompe Registry

Inform patients and their caregivers that the Pompe Registry has been established in order to better understand the variability and progression of Pompe disease, and to continue to monitor and evaluate long-term effects of NEXVIAZYME. Patients and their caregivers should be encouraged to participate in the Pompe Registry and advised that their participation is voluntary and may involve long-term follow-up. For more information regarding the registry program, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.