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WARNING
SEVERE HYPERSENSITIVITY REACTIONS, INFUSION-ASSOCIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS
Patients treated with NEXVIAZYME have experienced life-threatening hypersensitivity reactions, including anaphylaxis. 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. In patients with severe hypersensitivity reaction, a desensitization procedure to NEXVIAZYME may be considered [see WARNINGS AND PRECAUTIONS].
Patients treated with NEXVIAZYME have experienced severe IARs. 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. Patients with an acute underlying illness at the time of NEXVIAZYME infusion may 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 [see WARNINGS AND PRECAUTIONS].
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 NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion in such patients [see WARNINGS AND PRECAUTIONS].
Avalglucosidase alfa-ngpt is a hydrolytic lysosomal glycogen-specific recombinant human α-glucosidase enzyme conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P)-tetra-mannose glycans resulting in approximately 15 moles of M6P per mole of enzyme (15 M6P) and is produced in Chinese hamster ovary cells (CHO). Avalglucosidase alfa-ngpt has a molecular weight of approximately 124 kDa.
NEXVIAZYME (avalglucosidase alfa-ngpt) for injection is a sterile white to pale-yellow lyophilized powder for intravenous use after reconstitution and dilution. Each single-dose vial contains 100 mg of avalglucosidase alfa-ngpt, glycine (200 mg), L-Histidine (10.7 mg), L-Histidine HCl monohydrate (6.5 mg), mannitol (200 mg), and polysorbate 80 (1 mg). After reconstitution with 10 mL of Sterile Water for Injection, USP, the resultant concentration is 100 mg/10 mL (10 mg/mL) with a pH of approximately 6.2.
NEXVIAZYME is indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).
Reconstitute and dilute NEXVIAZYME in the following manner. Use aseptic technique during preparation.
Administer the diluted solution without delay. The recommended infusion duration is between 4 to 7 hours [see DOSAGE AND ADMINISTRATION]. Discard any unused diluted solution after 9 hours.
Table 1: Projected Intravenous Infusion Volume for NEXVIAZYME Administration According to Actual Body Weight
| Patient Actual Body Weight Range (kg) | Total Infusion Volume (mL) for 20 mg/kg | Total Infusion Volume (mL) for 40 mg/kg |
| 5 to 9.9 kg | N/A | 100 mL |
| 10 to 19.9 kg | N/A | 200 mL |
| 20 to 29.9 kg | N/A | 300 mL |
| 30 to 34.9 kg | 200 mL | N/A |
| 35 to 49.9 kg | 250 mL | N/A |
| 50 to 59.9 kg | 300 mL | N/A |
| 60 to 99.9 kg | 500 mL | N/A |
| 100 to 119.9 kg | 600 mL | N/A |
| Patient Actual Body Weight Range (kg) | Total Infusion Volume (mL) for 20 mg/kg | Total Infusion Volume (mL) for 40 mg/kg |
| 120 to 140 kg | 700 mL | N/A |
Table 2: Recommended Infusion Rates at 20 mg/kg Dose
| Dose | Step 1 | Step 2 | Step 3 | Step 4 | Step 5 |
| 20 mg/kg | 1 mg/kg/hour | 3 mg/kg/hour | 5 mg/kg/hour | 7 mg/kg/hour | Continue 7 mg/kg/hour |
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).
Table 3: Recommended Infusion Rates at 40 mg/kg Dose
| Dose | Step 1 | Step 2 | Step 3 | Step 4 | Step 5 | |
| 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 | |
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.
For injection: 100 mg of avalglucosidase alfa-ngpt as a white to pale-yellow lyophilized powder in a single-dose vial for reconstitution.
NEXVIAZYME (avalglucosidase alfa-ngpt) for injection is supplied as a sterile, white to paleyellow 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)
Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not use NEXVIAZYME after the expiration date on the vial.
Manufactured by: Genzyme Corporation, Cambridge, MA 02141, SANOFI COMPANY, U.S. License Number: 1596. Revised: Sep 2023
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
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.
The pooled safety analysis from 4 clinical trials in the Pompe disease population (including Study 1) with a mean exposure of 26 months and up to 85 months of treatment included a total of 141 NEXVIAZYME-treated patients (118 adult and 23 pediatric patients [see Clinical Studies].
Adverse reactions were similar across both adult and pediatric populations.
Serious adverse reactions reported in 2 or more NEXVIAZYME-treated patients were respiratory distress, chills, and pyrexia.
A total of 4 NEXVIAZYME-treated patients in clinical trials permanently discontinued NEXVIAZYME due to adverse reactions, including 3 patients who discontinued the treatment because of a serious adverse reaction.
The most frequently reported adverse reactions (>5%) in the pooled safety population were abdominal pain, arthralgia, chills, diarrhea, dizziness, dyspnea, erythema, fatigue, flushing, headache, hypertension, hypotension, myalgia, nausea, pruritus, pyrexia, rash, vomiting, and urticaria.
Hypersensitivity reactions were reported in 67 (48%) NEXVIAZYME-treated patients, including 6 (4%) patients who reported severe hypersensitivity reactions. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included chest discomfort, erythema, generalized edema, hypotension, hypoxia, rash, respiratory distress, tongue edema, and urticaria. IARs were reported in 48 (34%) NEXVIAZYME-treated patients. Six (4%) NEXVIAZYMEtreated patients reported 13 severe IARs including symptoms of chest discomfort, decreased or increased blood pressure, dysphagia, erythema, generalized edema, hypoxia, nausea, respiratory distress, tongue edema, and urticaria. IARs reported in more than 1 patient included chest discomfort, cyanosis, decreased or increased blood pressure, diarrhea, dizziness, erythema, fatigue, feeling hot or cold, generalized edema, headache, hyperhidrosis, hypoxia, influenza-like illness, nausea, pain, pruritus, pyrexia, rash, respiratory distress, tachycardia, throat irritation, tongue edema, tremor, urticaria, and vomiting.
In Study 1, 100 patients aged 16 to 78 years of age with LOPD (naive to enzyme replacement therapy) were treated with either 20 mg/kg of NEXVIAZYME (n=51) or 20 mg/kg of alglucosidase alfa (n=49) given every other week as an intravenous infusion for 49 weeks followed by an open-label extension period [see Clinical Studies].
During the double-blind active-controlled period of 49 weeks, serious adverse reactions were reported in 1 (2%) patient treated with NEXVIAZYME and in 3 (6%) patients treated with alglucosidase alfa. The most frequently reported adverse reactions in (>5%) NEXVIAZYMEtreated patients were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria.
IARs were reported in 13 (25%) of the NEXVIAZYME-treated patients. IARs reported in more than 1 patient on NEXVIAZYME were mild to moderate and included headache, diarrhea, pruritus, urticaria, and rash. None of them were severe IARs. IARs were reported in 16 (33%) patients treated with alglucosidase alfa. IARs reported in more than 1 patient on alglucosidase alfa were mild to severe and included dizziness, flushing, dyspnea, nausea, pruritis, rash, erythema, chills, and feeling hot. Severe IARs were reported in 2 patients treated with alglucosidase alfa.
Table 4 summarizes the adverse reactions that occurred in at least 3 NEXVIAZYME-treated patients (≥6%) in Study 1. Study 1 was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions in the NEXVIAZYME and the alglucosidase alfa treatment groups.
Table 4: Adverse Reactions Reported in at Least 6% of NEXVIAZYME-Treated Patients with LOPD in Study 1
| Adverse Reaction | NEXVIAZYME (N=51) n (%) |
Alglucosidase Alfa (N=49) n (%) |
| Headache | 11 (22%) | 16 (33%) |
| Fatigue | 9 (18%) | 7 (14%) |
| Diarrhea | 6 (12%) | 8 (16%) |
| Nausea | 6 (12%) | 7 (14%) |
| Arthralgia | 5 (10%) | 8 (16%) |
| Dizziness | 5 (10%) | 4 (8%) |
| Myalgia | 5 (10%) | 7 (14%) |
| Pruritus | 4 (8%) | 4 (8%) |
| Vomiting | 4 (8%) | 3 (6%) |
| Dyspnea | 3 (6%) | 4 (8%) |
| Erythema | 3 (6%) | 3 (6%) |
| Paresthesia | 3 (6%) | 2 (4%) |
| Urticaria | 3 (6%) | 1 (2%) |
In enzyme replacement therapy (ERT)-naive NEXVIAZYME-treated patients (mean of 47 months, up to 100 months of treatment), the incidence of [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] IARs was 69% (9/13) in patients with an anti-drug antibody (ADA) peak titer ≥12,800, compared with incidences of 27% (12/44) in those with ADA peak titer <12,800 and 33% (1/3) in those who were ADA-negative.
In ERT-experienced adult patients, the incidence of IARs and hypersensitivity reactions were higher in patients who developed ADA compared to patients who were ADA-negative [see CLINICAL PHARMACOLOGY].
In adults, one ERT-naive patient (ADA peak titer 3,200) and 2 ERT-experienced patients (peak ADA titers; 800 and 12,800, respectively) developed anaphylaxis. One ERT-experienced pediatric patient (peak ADA titer 6,400) developed anaphylaxis [see WARNINGS AND PRECAUTIONS].
No Information provided
Included as part of the PRECAUTIONS section.
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.
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].
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].
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.
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.
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].
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].
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].
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.
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.
Available data from case reports of NEXVIAZYME use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, available data from postmarketing reports and published case reports on alglucosidase alfa (another hydrolytic lysosomal glycogen-specific enzyme replacement therapy) use in pregnant women have not identified a drug-associated risk of adverse pregnancy outcomes. The continuation of treatment for Pompe disease during pregnancy should be individualized to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women (see Clinical Considerations).
Embryo-fetal toxicity studies performed in pregnant mice resulted in maternal toxicity related to an immunologic response (including an anaphylactoid response) and embryo-fetal loss at 17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for LOPD patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg. Avalglucosidase alfa-ngpt did not cross the placenta in mice, therefore, the adverse effects were likely related to the immunologic response in the mothers. Embryo-fetal toxicity studies performed in pregnant rabbits showed no adverse effects on the fetuses at exposure up to 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pregnant women exposed to NEXVIAZYME, or their healthcare providers, should report NEXVIAZYME exposure by calling 1-800-633-1610, option 1.
Disease-Associated Maternal And/Or Embryo-Fetal Risk
Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women.
Animal Data
The majority of reproductive toxicity studies in mice included the pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions. The effects of NEXVIAZYME were evaluated based on comparison with a control group treated with DPH alone. Rabbits tested in reproductive toxicity studies were not pretreated with DPH because hypersensitivity reactions were not observed.
Embryo-fetal toxicity studies performed in pregnant mice at doses of 0, 10, 20, or 50 mg/kg/day administered intravenously once daily on gestational days 6 through 15 resulted in an immunologic response, including an anaphylactoid response, in some dams 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 LOPD patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Increased postimplantation loss and mean number of late resorptions were observed in this group. Placental transfer studies determined that avalglucosidase alfa-ngpt was not transported from the maternal to the fetal circulation in mice, suggesting that the embryo-fetal effects were due to maternal toxicity relating to the immunologic response. The maternal no observed adverse effect level (NOAEL) was 50 mg/kg/day intravenously (17 times the human AUC) and the developmental NOAEL was 20 mg/kg/day intravenously (4.8 times the human AUC).
Embryo-fetal toxicity studies performed in rabbits at doses of 0, 30, 60, and 100 mg/kg/day administered intravenously once daily on gestational days 6 through 19 resulted in no adverse effects in the fetuses at the highest dose (100 mg/kg/day; 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Furthermore, the administration of NEXVIAZYME intravenously every other day in mice from gestational day 6 through postpartum day 20 did not produce adverse effects in the offspring at the highest dose of 50 mg/kg (maternal exposure not evaluated).
There are no data on the presence of avalglucosidase alfa-ngpt in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Available published literature suggests the presence of alglucosidase alfa (another hydrolytic lysosomal glycogenspecific enzyme replacement therapy) in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEXVIAZYME and any potential adverse effects on the breastfed infant from NEXVIAZYME or from the underlying maternal condition.
Lactating women exposed to NEXVIAZYME, or their healthcare providers, should report NEXVIAZYME exposure by calling 1-800-633-1610, option 1.
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]. 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.
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].
No Information provided
None.
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.
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]. 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.
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 alfangpt 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.
The volume of distribution of avalglucosidase alfa-ngpt was 3.4 L in LOPD patients.
The mean total body clearance of avalglucosidase alfa-ngpt was 0.9 L/hour and the mean plasma elimination half-life of avalglucosidase alfa-ngpt was 1.6 hours in LOPD patients.
The protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides by catabolic pathways.
Population pharmacokinetic analyses indicated that age, which ranged from 1 to 78 years in the clinical trials, and sex did not significantly influence the pharmacokinetics of avalglucosidase alfa-ngpt in patients with Pompe disease.
In 16 patients aged 1 to 12 years with Pompe disease, following a 4-hour intravenous infusion of NEXVIAZYME 20 mg/kg every two weeks and 7-hour intravenous infusion of NEXVIAZYME 40 mg/kg every two weeks, the mean Cmax ranged from 175 to 189 μg/mL and 250 to 403 μg/mL, respectively. The mean AUClast ranged from 805 to 923 μg•hr/mL for 20 mg/kg every two weeks and 1,720 to 2,630 μg•hr/mL for 40 mg/kg every two weeks.
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]. In ERTnaïve 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 crossreactive to alglucosidase alfa.
In Study 1, the avalglucosidase alfa-ngpt exposure (e.g., AUC) in the two ADA-negative NEXVIAZYME-treated patients was within the range of patients who developed ADA. Among the patients who developed ADA, the median AUC was similar between Week 1 and Week 49 irrespective of titer values and neutralizing activities of the ADA. There was no identified clinically significant effect of ADA on pharmacokinetics. [see CLINICAL PHARMACOLOGY].
In Study 1, a trend toward decreased pharmacodynamic response as measured by percent change of urinary glucose tetrasaccharides from baseline was observed in NEXVIAZYME-treated patients with an ADA peak titer ≥12,800 compared to those with a lower ADA peak titer.
Increased incidence of IARs was observed in NEXVIAZYME-treated patients with higher ADA peak titers (>12,800) compared to those with lower ADA peaks. The incidence of hypersensitivity reactions was higher in ERT-experienced adult patients who developed ADA compared to those who were ADA-negative [see ADVERSE REACTIONS]. In ERT-naïve patients, hypersensitivity reactions occurred irrespective of ADA development and peak ADA titer. In Study 1, there was no identified clinically significant effect of ADA on efficacy.
Table 5: Incidence of Anti-Avalglucosidase Alfa-ngpt Antibodies in NEXVIAZYMEtreated Patients with Pompe Disease up to 100 months
| ERT-Naive Patients | ERT-Experienced Patients | |||
| Adult and Pediatric Patients* 20 mg/kg every two weeks (N=62)† n (%) |
Adults 20 mg/kg every two weeks (N=58) n (%) |
Pediatric Patients 20 mg/kg every two weeks (N=6) n (%) |
Pediatric Patients 40 mg/kg every two weeks (N=16) n (%) |
|
| ADA at baseline | 2 (3%) | 43 (74%) | 1 (17%) | 2 (13%) |
| ADA after NEXVIAZYME treatment | 59 (95%) | 36 (62%) | 1 (17%) | 9 (56%) |
| Neutralizing Antibody (NAb) After NEXVIAZYME Treatment | ||||
| Both NAb types | 14 (23%) | 5 (9%) | 0 | 0 |
| Inhibition of enzyme activity | 19 (31%) | 11 (19%) | 0 | 0 |
| Inhibition of enzyme cellular uptake | 26 (42%) | 20 (34%) | 0 | 2 (13%) |
| * Includes two pediatric patients † ERT-naïve: patients only treated with NEXVIAZYME ‡ ERT-experienced: patients previously treated with alglucosidase alfa within a range of 0.9-9.9 years for adult patients and 0.6-11.8 years for pediatric patients before they received NEXVIAZYME. |
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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.
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). The racial groups for the patients consisted of 94 White (94%), 3 Black or African American (3%), and 3 Asian (3%). Fifteen patients were Hispanic/Latino (15%), 76 non-Hispanic/Latino (76%) and 9 were not reported. Five patients (all in the alglucosidase alfa arm) discontinued the study prior to Week 49: four due to adverse events (acute myocardial infarction, arthritis, dyspnea, and urticaria), and one due to withdrawal of consent. All 95 patients who did not discontinue the study prior to Week 49 entered the open-label period (51 from the NEXVIAZYME arm and 44 from the alglucosidase alfa arm). Of the 95 patients, 77 patients had follow-up data on FVC (% predicted) at Week 145 (44 from the NEXVIAZYME arm and 33 from the alglucosidase alfa arm) and 80 patients had follow-up data on 6MWT at Week 145 (45 from the NEXVIAZYME arm and 35 from the alglucosidase alfa arm). Fourteen (14%) patients (7 in each group) discontinued during the Extension Treatment period (5 for adverse event, 1 for poor compliance to protocol and 8 for other reason).
The primary endpoint of Study 1 was the change in FVC (% predicted) in the upright position from baseline to Week 49. At Week 49, the least squares (LS) mean change in FVC (% predicted) for patients treated with NEXVIAZYME and alglucosidase alfa was 2.9% and 0.5%, respectively. The estimated treatment difference was 2.4% (95% CI: -0.1, 5.0) favoring NEXVIAZYME (see Table 6). Figure 1 presents the LS mean change from baseline in FVC (% predicted) over time by treatment group up to Week 49.
Table 6: Summary Results of FVC (% predicted) in Upright Position in ERT-Naïve Patients with LOPD (Study 1)*
| NEXVIAZYME (n=51) |
Alglucosidase Alfa (n=49) |
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| Pretreatment baseline | Mean (SD) | 62.5 (14.4) | 61.6 (12.4) |
| Week 49 | Mean (SD) | 65.5 (17.4) | 61.2 (13.5) |
| Estimated change from baseline to week 49 | LS mean (SE) | 2.9† (0.9) | 0.5† (0.9) |
| Estimated difference between groups in change from baseline to week 49 | LS mean (95% CI) | 2.4†,‡ (-0.1, 5.0) | |
| * All randomized patients † Estimated using a mixed model for repeated measures (MMRM) including baseline FVC (% predicted, as continuous), sex, baseline age (years), treatment group, visit, and treatment-by-visit interaction term as fixed effects. ‡ Noninferiority margin of 1.1% (p=0.0074). Statistical superiority of NEXVIAZYME over alglucosidase alfa was not achieved (p=0.06). |
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Figure 1: Plot of LS Mean (SE) Change from Baseline of FVC (% predicted) in Upright Position over Time in ERT-Naïve Patients with LOPD (Study 1)*
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* All randomized patients
For patients who continued to receive NEXVIAZYME after Week 49 the mean change from baseline to Week 145 in FVC (% predicted) was 1.7 (SD=8.6, 95% CI: -0.9, 4.2), and the mean change from Week 49 to Week 145 was -0.8 (SD=6.2, 95% CI: -2.7, 1.0). For patients who switched from alglucosidase alfa to NEXVIAZYME after Week 49 the mean change from baseline to Week 145 was 0.5 (SD=8.3, 95% CI: -2.3, 3.4), and the mean change in FVC (% predicted) from Week 49 to Week 145 was 0.8 (SD=6.9) (95% CI: -1.6, 3.1).
The key secondary endpoint of Study 1 was change in total distance walked in 6 minutes (6- Minute Walk Test, 6MWT) from baseline to Week 49. At Week 49, the LS mean change from baseline in 6MWT for patients treated with NEXVIAZYME and alglucosidase alfa was 32.2 meters and 2.2 meters, respectively. The estimated treatment difference was 30 meters (95% CI: 1.3, 58.7) favoring NEXVIAZYME (Table 7). Figure 2 presents the LS mean change from baseline in 6MWT distance over time by treatment group.
Table 7: Summary Results of 6-Minute Walk Test in ERT-Naïve Patients with LOPD (Study 1)*
| NEXVIAZYME (n=51) |
Alglucosidase Alfa (n=49) |
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| Pretreatment baseline | Mean (SD) | 399.3 (110.9) | 378.1 (116.2) |
| Week 49 | Mean (SD) | 441.3 (109.8) | 383.6 (141.1) |
| Estimated change from baseline to week 49 | LS mean (SE) | 32.2† (9.9) | 2.2† (10.4) |
| Estimated difference between groups in change from baseline to week 49 | LS mean (95% CI) | 30.0†‡ (1.3, 58.7) | |
| * All randomized patients † The MMRM model for 6MWT distance adjusts for baseline FVC (% predicted), baseline 6MWT (distance walked in meters), baseline age (years), sex, treatment group, visit, and treatment-by-visit interaction as fixed effects. ‡ p-value at nominal level, without multiplicity adjustment (p=0.04). |
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Figure 2: Plot of LS Mean (SE) Change from Baseline of 6MWT (distance walked, in meters) over Time in ERT-Naïve Patients with LOPD (Study 1)*
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* All randomized patients
For patients who continued to receive NEXVIAZYME after Week 49 the mean change from baseline to Week 145 in 6MWT was 24.9 (SD=68.6, 95% CI: 4.8, 44.9), and the mean change from Week 49 to Week 145 was -11.0 (SD=33.5, 95% CI: -20.8, -1.2). For patients who switched from alglucosidase alfa to NEXVIAZYME after Week 49 the mean change from baseline to Week 145 in 6MWT was -4.1 (SD=90.4, 95% CI: -34.1, 25.8), and the mean change from Week 49 to Week 145 was -7.7 (SD=50.3, 95% CI: -24.4, 9.0).
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].
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].
Pregnant or lactating women exposed to NEXVIAZYME, or their healthcare providers, should report NEXVIAZYME exposure by calling 1-800-745-4447, extension 15500.
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.
