NEXVIAZYME

Avalglucosidase alfa, or NeoGAA, is a drug for enzyme replacement therapy specifically designed for Pompe disease, a rare inherited neuromuscular disorder caused by the deficiency of the alpha-glucosidase (GAA) enzyme.

GAA is an essential enzyme that hydrolyzes glycogen into free glucose for use in cellular functions.

In Pompe disease, the GAA enzyme is missing and patients are unable to properly break down glycogen, resulting in the accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells.

Pompe disease is characterized by progressive muscle weakness and loss of motor function, including respiratory muscle weakness, which leads to premature death and debilitating effects on people's lives.

Avalglucosidase alfa is a recombinant form of GAA that restores deficient enzyme levels.

First developed by Sanofi

Genzyme, avalglucosidase alfa is a chemically modified version of alglucosidase alfa, where synthetic bis-phosphorylated oligosaccharides were attached to the structure to improve cellular uptake of the drug and better muscle targeting.

On August 6, 2021, avalglucosidase alfa-ngpt was approved by the FDA under the market name Nexviazyme to treat patients one year of age and older with late-onset Pompe disease.

Pompe disease is associated with a range of debilitating physical symptoms, such as progressive muscle weakness, including respiratory muscle weakness, and loss of motor function.

In clinical trials, avalglucosidase alfa improved lung function in patients with Pompe disease.

Avalglucosidase alfa was approved by Health Canada on November for the treatment of patients older than six months of age with late-onset Pompe disease.

The EMA approved the drug on

June 24, 2022.

Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase deficiency). 3, 7, 8 In the US, it is approved in patients one year of age and older.

Avalglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme that catalyzes hydrolysis of glycogen.

In clinical trials, avalglucosidase alfa reduced the levels of glycogen excreted in the urine of patients with Pompe disease, indicating that it effectively cleaved excess glycogen.

Avalglucosidase alfa has significantly higher binding affinity for cation-independent mannose-6-phosphate receptor (CI-MPR) for cellular uptake and better muscle targeting than alglucosidase alfa.

In GAA-deficient mice, avalglucosidase alfa reduced glycogen with more efficacy than alglucosidase alfa at an equivalent dose.

The avalglucosidase alfa-ngpt exposure increases in an approximately proportional manner with increasing doses over a range from 5-20 mg/kg. Following intravenous infusion of 20 mg/kg every two weeks in patients with late-onset Pompe disease, the mean ± SD plasma C max of avalglucosidase alfa-ngpt was 259 ± 72 µg/mL at week one and 242 ± 81 µg/mL at week 49.

The mean ± SD plasma AUC of avalglucosidase alfa-ngpt was 1,290 ± 420 µg∙h/mL at week one and 1,250 ± 433 µg∙h/mL at week 49.

The volume of distribution of avalglucosidase alfa-ngpt was 3.4 L in patients with late-onset Pompe disease. weeks-dosing schedules.

The metabolic pathway of avalglucosidase alfa-ngpt has not been characterized.

The protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides and amino acids via catabolic pathways.

There is limited information on drug elimination.

The mean avalglucosidase alfa-ngpt plasma elimination half-life was 1.6 hours in patients with late-onset Pompe disease.

The mean avalglucosidase alfa-ngpt clearance was 0.9 L/hour in patients with late-onset Pompe disease.

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There is limited information on the overdose profile and LD 50 values of avalglucosidase alfa.

Consider administering antihistamines, antipyretics, and/or corticosteroids prior to NEXVIAZYME administration to reduce the risk of IARs.

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. <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.

See the full prescribing information for dosage modifications due to hypersensitivity reactions or IARs.

Must be reconstituted and diluted prior to use.

For instructions on storage and administration, see full prescribing information. 2.1 Recommendations Prior to NEXVIAZYME Treatment Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids.

NEXVIAZYME must be reconstituted and diluted prior to use.

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 Less than 30 kg.

• the recommended dosage is 40 mg/kg (of actual body weight) every two weeks 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) .

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, .

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% and initiating appropriate medical treatment.

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 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.

Reconstitute the Lyophilized Powder Determine the number of NEXVIAZYME vials to be reconstituted based on actual body weight in kg and the recommended dose.

Round the number of vials up to the next whole number.

Remove the required number of

NEXVIAZYME vials from the refrigerator and allow the vials to sit for 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use.

Reconstitute each vial by injecting 10 mL of Sterile Water for Injection, down the inside wall of each vial.

Avoid adding the Sterile Water for

Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming.

Gently tilt and roll each vial to enhance the dissolution process.

Do not invert, swirl, or shake the vial.

Allow the solution to become dissolved.

Each vial will yield a concentration of 100 mg/10 mL (10 mg/mL) of avalglucosidase alfa-ngpt.

Visually inspect the reconstituted solution in the vials for particulate matter and discoloration.

The reconstituted solution should be clear, colorless to pale-yellow.

Discard if particles are present or the solution is discolored.

Select an appropriate size 5% Dextrose Injection infusion bag and prepare by removing a volume equal to the required NEXVIAZYME volume and any overfill to achieve a fixed total volume per Table 1 based on actual body weight.

Slowly withdraw the required volume of reconstituted solution from the NEXVIAZYME vial(s).

Discard any unused reconstituted solution remaining in the vial.

Gently inject the

NEXVIAZYME reconstituted solution into the port of the 5% Dextrose Injection bag.

Avoid foaming or agitation of the infusion bag and avoid introducing air into the infusion bag.

Gently invert the infusion bag to mix the solution.

Do not shake.

After dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of avalglucosidase alfa-ngpt.

Administer the diluted solution without delay.

The recommended infusion duration is between to 7 hours.

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 to 9.9 kg N/A 100 mL to 19.9 kg N/A 200 mL to 29.9 kg N/A 300 mL to 34.9 kg 200 mL N/A to 49.9 kg 250 mL N/A to 59.9 kg 300 mL N/A to 99.9 kg 500 mL N/A to 119.9 kg 600 mL N/A to 140 kg 700 mL N/A 2.5 Storage Instructions for the Reconstituted and Diluted Product Storage of the Reconstituted Solution Dilute the reconstituted solution without delay.

If the reconstituted solution is not diluted immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

Do not freeze.

If the diluted solution is not used immediately, refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

The diluted solution must be infused within 9 hours after removal from the refrigerator, inclusive of infusion time, or discarded.

Once the diluted solution is removed from the refrigerator, it must not be restored back into the refrigerator.

Do not freeze. 2.6 Administration Instructions If the diluted solution was refrigerated, allow solution to equilibrate to room temperature for 30 minutes prior to infusion.

It is recommended to use an in-line, low protein-binding, 0.2 micron filter during administration.

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.

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 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 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion every 30 minutes until completion (total time approximately 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.

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.

The initial recommended infusion rate is 1 mg/kg/hour 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 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 After the infusion is complete, flush the intravenous line with 5% Dextrose Injection.

Do not infuse

NEXVIAZYME in the same intravenous line with other products.

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.

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Do not use

NEXVIAZYME after the expiration date on the vial.

Risk Summary 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.

Pompe disease may result in worsening disease symptoms in pregnant women.

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.

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.

Data 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 post-implantation 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).

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.

NEXVIAZYME is not approved for the treatment of IOPD.

The safety profile of

NEXVIAZYME in pediatric patients to 12 years old with Pompe disease was similar to the safety profile of NEXVIAZYME in older pediatric and adult patients with LOPD.

NEXVIAZYME have not been established in pediatric patients younger than 1 year of age.

Clinical studies with

NEXVIAZYME included 13 patients 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.