2.1 Recommendations Prior to NEXVIAZYME Treatment

• Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)].
• NEXVIAZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.4)].
• Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration.

2.2 Recommended Dosage and Administration

• NEXVIAZYME is administered as intravenous infusion. For patients weighing:
  • 30 kg or more- the recommended dosage is 20 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.6)]
  • Less than 30 kg- the recommended dosage is 40 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.6)]
• 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 (2.6)]. If one or more doses are missed, restart NEXVIAZYME treatment as soon as possible, maintaining the 2 week interval between infusions thereafter.

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

• In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue NEXVIAZYME administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, [see Warnings and Precautions (5.1, 5.2)].
• In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 30 minutes or slowing the infusion rate by 50% [see Dosage and Administration (2.6)] and initiating appropriate medical treatment [see Warnings and Precautions (5.1, 5.2)].
  • If symptoms persist for longer than 30 minutes despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion on the same day when symptoms subside at 50% of the rate at which the reaction occurred with appropriate pretreatment.
  • If symptoms subside after holding the infusion, resume infusion at 50% of the rate at which the reaction occurred, and subsequently increase the infusion rate every 15 to 30 minutes by 50% as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete the infusion at the reduced rate as tolerated.
  • Starting with the next infusion, increase the infusion rate until the infusion rate at which the reaction occurred is reached. Consider continuing to increase the infusion rate in a stepwise manner until reaching the recommended infusion rate. Closely monitor the patient.

2.4 Reconstitution and Dilution Instructions

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

2.5 Storage Instructions for the Reconstituted and Diluted Product

2.6 Administration Instructions

1. If the diluted solution was refrigerated, allow solution to equilibrate to room temperature for 30 minutes prior to infusion.
2. It is recommended to use an in-line, low protein-binding, 0.2 micron filter during administration.
3. 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 initial recommended infusion rate is 1 mg/kg/hour (see Table 2). If there are no signs of hypersensitivity or 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 to 5 hours.

   Table 2: Recommended Infusion Rates at 20 mg/kg Dose

   Dose	Step 1	Step 2	Step 3	Step 4	Step 5
   Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion every 30 minutes until completion (total time approximately 4 to 5 hours).
   20 mg/kg	1 mg/kg/hour	3 mg/kg/hour	5 mg/kg/hour	7 mg/kg/hour	Continue 7 mg/kg/hour

   
   When the recommended dose is 40 mg/kg
   • Initial Infusion: The initial recommended infusion rate is 1 mg/kg/hour (see Table 3). If there are no signs of hypersensitivity or 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 initial recommended infusion rate is 1 mg/kg/hour (see Table 3) with gradual increase in infusion rate every 30 minutes if there are no signs of hypersensitivity or 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.

   Table 3: Recommended Infusion Rates at 40 mg/kg Dose

   Dose		Step 1	Step 2	Step 3	Step 4	Step 5
   Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion every 30 minutes until completion. Total time for initial infusion approximately 7 hours and can optionally increase rate of subsequent infusions to decrease total duration to 5 hours.
   40 mg/kg	Initial infusion rate	1 mg/kg/hour	3 mg/kg/hour	5 mg/kg/hour	7 mg/kg/hour	Continue 7 mg/kg/hour
   	Subsequent infusions (optional)	1 mg/kg/hour	3 mg/kg/hour	6 mg/kg/hour	8 mg/kg/hour	Continue 10 mg/kg/hour

4. After the infusion is complete, flush the intravenous line with 5% Dextrose Injection.
5. Do not infuse NEXVIAZYME in the same intravenous line with other products.

5.1 Hypersensitivity Reactions Including Anaphylaxis

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in NEXVIAZYME-treated patients. In NEXVIAZYME clinical studies, 67 (48%) NEXVIAZYME-treated patients experienced hypersensitivity reactions, including 6 (4%) patients who reported severe hypersensitivity reactions and 3 (2%) patients who experienced anaphylaxis; 2 (1%) patients who experienced anaphylaxis discontinued from the study. Some of the hypersensitivity reactions were IgE mediated. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included chest discomfort, erythema, generalized edema, hypotension, hypoxia, rash, respiratory distress, tongue edema, and urticaria.

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

• If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering NEXVIAZYME following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates at a dosage lower than the recommended dosage. In patients with severe hypersensitivity reaction, desensitization measures to NEXVIAZYME may be considered. If the decision is made to readminister NEXVIAZYME, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage.
• If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3)].

5.2 Infusion-Associated Reactions

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 all clinical studies. In these studies, 5 (4%) NEXVIAZYME-treated patients reported 10 severe IARs including symptoms of chest discomfort, decreased or increased blood pressure, dysphagia, erythema, generalized edema, hypoxia, nausea, respiratory distress, tongue edema, and urticaria. 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, respiratory distress, and urticaria. Increased incidence of IARs was observed in patients with higher ADA titers [see Adverse Reactions (6.1)].

Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. However, IARs may still occur in patients after receiving pretreatment.

If a severe IAR occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. Consider the benefits and risks of readministering NEXVIAZYME following a severe IAR. Patients may be rechallenged using slower infusion rates at a dosage lower than the recommended dosage. Once the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage.

If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3)].

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.

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 aged 1 year 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 13 patients 65 to 74 years of age and 4 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) that degrades glycogen to glucose in the lysosome. GAA deficiency 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 the major component, glucose tetrasaccharide (Glc4). 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 ERT-naïve LOPD patients in Study 1, the baseline mean (SD) urinary Glc4 concentration was 12.7 mmol/mol (10.10) and 8.7 mmol/mol (5.04) in NEXVIAZYME and alglucosidase alfa treatment groups, respectively [see Clinical Studies (14.1)]. At Week 145, the mean urinary Glc4 concentration was 4.32 mmol/mol (4.28) in patients who continued with NEXVIAZYME and 5.25 mmol/mol (7.48) in patients who switched from alglucosidase alfa to NEXVIAZYME.

For patients who started on NEXVIAZYME, the mean percentage (SD) change in urinary Glc4 concentration from baseline was -54% (24), at Week 49 and -53% (73) at Week 145. For patients who started on alglucosidase alfa and switched to NEXVIAZYME at Week 49, the mean percentage (SD) change in urinary Glc4 concentration from baseline was -11% (32) at Week 49, and -48% (42) at Week 145.

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 greater than or equal to 30 kg or 0.125 to 0.5 times the approved recommended dosage in LOPD patients weighing less than 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 greater than or equal to 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 less than 30 kg are expected to have similar AUC following intravenous infusion of 40 mg/kg of NEXVIAZYME every two weeks.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of NEXVIAZYME or of other avalglucosidase alfa products.

Table 5 presents the incidence of anti-avalglucosidase alfa-ngpt antibodies (referred to as ADA) in NEXVIAZYME-treated patients with Pompe disease [see Clinical Studies (14.1)]. In ERT-naïve LOPD patients who received NEXVIAZYME 20 mg/kg every two weeks for up to 436.2 weeks (with mean of 204.7 weeks), 95% (59/62) of patients developed ADA. The median time to seroconversion was 8 weeks.

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

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 treatment-naïve patients with LOPD. One hundred patients (51 in NEXVIAZYME and 49 in alglucosidase alfa) were randomized in a 1:1 ratio based on baseline forced vital capacity ([FVC] % predicted; <55% or ≥55%), sex, age (<18 years or ≥18 years), and country (Japan or not-Japan) to receive 20 mg/kg of NEXVIAZYME or alglucosidase alfa administered intravenously once every two weeks for 49 weeks. After 49 weeks, all randomized patients in Study 1 had the option to enter an open-label extension treatment period to receive NEXVIAZYME and continue treatment up to at least Week 145.

How Supplied

NEXVIAZYME (avalglucosidase alfa-ngpt) for injection is supplied as a sterile, white to pale-yellow lyophilized powder in a single-dose vial. Each vial contains 100 mg of avalglucosidase alfa-ngpt. NEXVIAZYME is available as:

One single-dose vial in a carton (NDC 58468-0426-1)

Storage and Handling

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

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

Advise the patient and caregiver that reactions related to the infusion may occur during and after NEXVIAZYME treatment, including life-threatening hypersensitivity reactions, including anaphylaxis, and IARs. Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.2)].

Risk of Acute Cardiorespiratory Failure

Advise the patient and caregiver 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 and should seek medical care should signs and symptoms occur [see Warnings and Precautions (5.3)].

NEXVIAZYME Exposure During Pregnancy or Lactation

Advise a pregnant or lactating woman exposed to NEXVIAZYME to report NEXVIAZYME exposure to her healthcare provider and by calling 1-800-633-1610, option 1 [see Use in Specific Populations (8.1., 8.2)].

Pompe Registry

Inform the patient and/or caregiver that there is a Pompe Registry to better understand the variability and progression of Pompe disease and to monitor and evaluate long-term effects of NEXVIAZYME. Encourage the patient and/or caregiver to enroll in the Pompe Registry and state that participation is voluntary and may involve long-term follow-up. For more information regarding the registry program, direct the patient and caregiver to visit www.registrynxt.com or call 1-800-745-4447, extension 15500.