This is intended for HCPs practising in Great Britain (England, Scotland and Wales) only.

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Nexviadyme offers all patients with Pompe disease a treatment that is:

Designed for better cellular uptake

Enhancement with 15x M6P, compared with Myozyme (alglucosidase alfa), for improved receptor-mediated uptake into muscle cells and targeting to lysosomes1

Efficacious

Non-inferior differences versus Myozyme in respiratory (FVC, p=0.0074) and motor function (6MWT, nominal improvement p=0.04)1,2

A monotherapy

With fewer serious treatment-related adverse reactions and IARs than Myozyme in the Phase 3 trial1,2

Mechanism of action

Nexviadyme is an ERT enhanced with 15x M6P
compared with Myozyme.

Nexviadyme is designed to replace the deficient GAA enzyme activity in patients with Pompe disease, which results in lysosomal glycogen accumulation in muscles. It is enhanced with fifteen times M6P, compared with Myozyme, for improved receptor-mediated uptake into muscle cells and targeting to lysosomes.1

   a. For illustrative purposes only
   b. Myozyme was the first ERT approved for the treatment of patients with Pompe disease3

Evidence

Nexviadyme may offer patients with LOPD improvement in respiratory function and walking distance from baseline. It was compared with Myozyme in COMET.1,2

Read more about how

Nexviadyme was studied

  • A multicentre, multinational, randomised, double-blinded study to compare the efficacy and safety of bi-weekly infusions of Nexviadyme® and Myozyme in patients with LOPD.

    a. 48 doses are given for the duration of the open-label treatment period (up to week 144).
    b. The assessment schedule includes an open-label treatment period up to week 144 and an additional extended open-label treatment period up to week 238 or until Nexyviadyme is approved in the patients country.

    Outcomes
     

    Primary

    Change from baseline in FVC (% predicted) in the upright position.

    Secondary

    Change from baseline in 6MWT, MIP, MEP, HHD (lower extremity muscle strength), QMFT, SF-12, and safety.

    Key inclusion criteria

     

    • Treatment-naïve patients, ≥3 years old.

    • Confirmed GAA enzyme deficiency and/or two confirmed GAA variants.

    • Upright FVC ≥30% and ≥85% predicted.

    • Able to walk ≥40 m without stopping or assistive device

  • A multicentre, multinational, open-label, ascending dose study of Nexviadyme in ERT-experienced and -naïve patients with LOPD.

    Outcomes
     

    Primary

    Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy.

    Key inclusion criteria
     
    • ≥18 years old.
    • Confirmed GAA enzyme deficiency and/or two confirmed GAA variants.
    • Upright FVC ≥50% predicted.
    • Able to walk ≥50 m without stopping or assistive device.

  • A multicentre, multinational, open-label study of Nexviadyme in ERT-experienced and -naïve patients with LOPD.

    Outcomes
     

    Primary

    Long-term safety and pharmacokinetics.

    Secondary

    Long-term effect of Nexviadyme® on pharmacodynamic and exploratory efficacy variables, and the time-course of response.

    Key inclusion criteria
     
    • Participated in NEO1 Phase 1 study.

  • A multicentre, multinational, open-label study of Nexviadyme in ERT-experienced and -naïve patients with LOPD.

    Outcomes
     

    Primary

    Safety

    Secondary

    Pharmacokinetics and preliminary efficacy (GMFM-88, GMFCS-E&R, Pompe-PEDI Functional Skills Scale: Mobility Domain, QMFT, ECHO endpoints [LVMI and LVM z-score], eyelid position measurement [IPFD, MRD1, MPD], and CK).

    Key inclusion criteria
     
    • <18 years old and previously treated with Myozyme.
    • Confirmed GAA enzyme deficiency.
    • Cohorts 1 and 2: clinical decline in at least one of respiratory function, motor skills, and/or cardiac parameters.
    • Cohort 3: sub-optimal clinical response in at least one of respiratory function, motor skills, and/or new onset of ptosis.

COMET trial

  • 2.89% LS mean improvement with Nexviadyme vs 0.46% with Myozyme (Δ 2.43% [95% CI –0.13 to 4.99], non-inferiority p=0.0074; superiority not demonstrated p=0.063)2.

  • 32.21 m LS mean improvement from baseline in 6MWT with Nexviadyme vs 2.19 m with Myozyme (Δ 30.01 m [95% CI 1.33 to 58.69], nominal p=0.040 without multiplicity adjustment), at 12 months (49 weeks)2.

    Patients treated with Nexviadyme showed Δ = 4.40 and Δ = 2.51 greater LS mean changes from baseline vs patients treated with Myozyme in MIP and MEP, respectively2

    Patients treated with Nexviadyme showed Δ = 106.97 and Δ = 2.08 greater LS mean changes from baseline vs patients treated with Myozyme in HHD (lower extemity strength) and QMFT (motor function), respectively2

    Patients treated with Nexviadyme showed Δ = 0.77 and Δ = 2.12 greater LS mean changes from baseline vs patients treated with Myozyme in SF-12 PCS and SF-12 MCS, respectively2

    It has been suggested that urinary Hex4 (Glc4) could serve as a valuable biomarker adjunct to clinical endpoints for monitoring the efficacy of therapeutic interventions in patients with Pompe disease.8 In treatment-naïve LOPD patients aged 16 to 78, the mean percentage (SD) change in Hex4 from baseline for patients treated with Nexviadyme 20 mg/kg every other week for 49 weeks was -53.90% (24.03) whereas for patients treated with Myozyme the change was -10.8% (32.33).2,9 Absolute mean (SD) changes (mmol/mol creatinine) were from 12.71 (10.10) to 4.85 (3.38) and from 8.74 (5.04) to 7.82 (6.15), with Nexviadyme and Myozyme, respectively.

NEO1/NEO-EXT trials

  • Long-term treatment effect of Nexviadyme on FVC and 6MWT has been shown for up to 6 years in an uncontrolled open-label study in patients with LOPD (NEO1/NEO-EXT)1,4,5 . Each line represents an individual patient.

  • Long-term treatment effect of Nexviadyme on FVC and 6MWT has been shown for up to 6 years in an uncontrolled open-label study in patients with LOPD (NEO1/NEO-EXT)1,4,5. Each line represents an individual patient.

Mini-COMET trial

Of 22 included patients with IOPD (1 year of age of older, declining or with sub-optimal response on Myozyme), 16 received Nexviadyme and showed improvement or stabilisation based on secondary outcome measures of preliminary efficacy. The primary outcome measure of Mini-COMET was safety.

This was shown in Mini-COMET across cardiac function, motor function and mobility6.

Cardiac function

Assessed by ECHO-LVM z score

Motor function

Assessed by the GMFM-88 and QMFT

Mobility

Assessed by the Pompe-PEDI

Patients showed stabilisation or improvement in the mobility domain of the Pompe-PEDI.

Patients are represented by separate lines, with the first dot representing the age at inclusion in the trial and last dot at conclusion for this trial period.

Safety

In the COMET trial, there were fewer treatment-related SAEs and IARs with Nexviadyme than with Myozyme. During the 49-week primary analysis period, no patients withdrew from the Nexviadyme arm.2

N values are numbers of patients and not events.

The safety of Nexviadyme has been established in patients older than 6 months of age acrosss both LOPD and IOPD1,6

Across four clinical studies of Nexviadyme, the most frequently reported adverse drug reactions (>5%) were headache, nausea, pruritus, urticaria, rash, fatigue and chills1

Summary of safety information


Please refer to the Summary of Product Characteristics before prescribing

Dosage and Administration

Nexviadyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases. Patients may be pretreated with antihistamines, antipyretics and/or corticosteroids to prevent or reduce allergic reactions. The recommended dose of avalglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks.

Dose modification for IOPD patients

For IOPD patients who experience lack of improvement or insufficient response in cardiac, respiratory, and/or motor function while receiving 20 mg/kg, a dose increase to 40 mg/kg every other week should be considered in the absence of safety concerns (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload). In patients who do not tolerate avalglucosidase alfa at 40 mg/kg every other week (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload), consider decreasing the dose to 20 mg/kg every other week.

Special Populations

Elderly patients

No dose adjustment is required in patients >65 years.

 

Hepatic impairment

The safety and efficacy of avalglucosidase alfa in patients with hepatic impairment have not been evaluated.

Renal impairment

No dose adjustment is required in patients with mild renal impairment. The safety and efficacy of avalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated.

Paediatric population (patients 6 months of age and younger)

The safety and efficacy of avalglucosidase alfa in children 6 months of age and younger have not yet been established. There are no data available in patients 6 months of age and younger.

Contraindications

Life-threatening hypersensitivity to the active substance or to any of the excipients.

Precautions and Warnings

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis, have been reported in Nexviadyme-treated patients. Appropriate medical support measures, including cardiopulmonary resuscitation equipment especially for patients with cardiac hypertrophy and patients with significantly compromised respiratory function, should be readily available when Nexviadyme is administered. If severe hypersensitivity or anaphylaxis occur, Nexviadyme should be discontinued immediately, and appropriate medical treatment should be initiated. The risks and benefits of re-administering Nexviadyme following anaphylaxis or severe hypersensitivity reaction should be considered.

IARs

In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the infusion of Nexviadyme and were more likely with higher infusion rates. Patients with an acute underlying illness at the time of Nexviadyme 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. If severe IARs occur, immediate discontinuation of the administration of Nexviadyme should be considered and appropriate medical treatment should be initiated. The benefits and risks of readministering Nexviadyme following severe IARs should be considered.

Immunogenicity

Treatment emergent ADA were reported in both treatment naïve (95%) and treatment experienced patients (49%). Adverse-event-driven immunologic testing, including IgG and IgE ADA, may be considered for patients who have risk for allergic reaction or previous anaphylactic reaction to alglucosidase alfa.

Risk of acute cardiorespiratory failure

Caution should be exercised when administering Nexviadyme to patients susceptible to fluid volume overload or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusion. Appropriate medical support and monitoring measures should be readily available during Nexviadyme infusion.

Cardiac arrhythmia and sudden death during general anaesthesia for central venous catheter placement

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia, and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation, have been associated with the use of general anaesthesia in IOPD patients with cardiac hypertrophy.

Interactions

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

Fertility and Lactation

There are no available data on the use of Nexviadyme in pregnant women. The potential risk for humans is unknown. Nexviadyme should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the foetus. 

Breast-feeding

There are no available data on the presence of Nexviadyme in human milk or the effects of Nexviadyme on milk production or the breastfed infant.

Adverse reactions

Very common (≥1/10)

Hypersensitivity.

Common (≥1/100 to <1/10)

Anaphylaxis, headache, dizziness, tremor, ocular hyperaemia, hypertension, cough, dyspnoea, nausea, diarrhoea, vomiting, lip swelling, swollen tongue, pruritus, rash, urticaria, erythema, palmer erythema, muscle spasms, myalgia, fatigue, chills, chest discomfort, pain, influenza like illness, infusion site pain, blood pressure increased, and oxygen saturation decreased.

Prescribers should consult the SmPC in relation to other adverse reactions.

Dosing and Administration

Nexviadyme is a monotherapy that does not require a stabiliser. It is administered via intravenous infusion once every 2 weeks.1
 

  • The recommended dose is 20 mg/kg.
  • For patients with IOPD who experience lack of improvement or insufficient response, while receiving 20 mg/kg, a dose increase to 40 mg/kg should be considered in the absence of safety concerns.
  • In patients who do not tolerate Nexviadyme at 40 mg/kg (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload), consider decreasing the dose to 20 mg/kg.
  • For more information, please refer to the Nexviadyme prescribing information.

Resources


Overview of COMET
Download pdf

Overview of Mini-COMET
Download pdf

Overview of Neo-EXT
Download pdf

    6MWT, 6-minute walk test; ADA, anti-drug antibody; CI, confidence interval; CK, creatinine kinase; ECHO, echocardiography; ERT, enzyme replacement therapy; ETP, extended treatment period; FVC, forced vital capacity; GAA, acid alpha-glucosidase; GMFCS-E&R, Gross Motor Function Classification System – Expanded and Revised; GMFM-88, Gross Motor Function Measure-88; GSGC, Gait, Stair, Gower's Maneuver and Chair Test; Hex4, hexose tetrasaccharide; HHD, hand-held dynamometry; HRQoL, health-related quality of life; IARs, infusion-associated reactions; IOPD, infantile onset Pompe disease; IPFD, interpalpebral fissure distance; IV, intravenous; LOPD, late-onset Pompe disease; LS, least-squares; LVM, left ventricular mass; LVMI, left ventricular mass index; M6P, Mannose 6-Phosphate; MCS, mental component summary; MEP, maximum expiratory pressure; MIP, maximum inspiratory pressure; MPD, margin pupil distance; MRD1, margin reflex distance; OLE, open-label extension; PAP, primary analysis period; PCS, physical component summary; Pompe-PEDI, Pompe-specific Paediatric Evaluation of Disability Inventory; QMFT, quick motor function test; qow, every other week; qw, every week; SAEs, serious adverse events; SD, standard deviation; SE, standard error; SF-12, 12-Item Short Form Survey.

    1. Nexviadyme Summary of Product Characteristics. Accessed January 2023

    2. Diaz-Manera J et al. Lancet Neurol. 2021 Dec;20(12):1012–1026

    3. Myozyme Summary of Product Characteristics. Accessed January 2023

    4. Pena LDM et al. Neuromuscul Disord. 2019 Mar;29(3):167–186

    5. Dimachkie MM et al. Neurology. 2022 May;99(5):e536-e548. Online ahead of print

    6. Kishnani PS et al. Genet Med. 2022 Dec;doi: 10.1016/j.gim.2022.10.010. Online ahead of print.

    7. Kishnani PS et al. ePoster presented at the 18th WORLDSymposium™, San Diego, CA, USA, February 7–11, 2022

    8. An Y et al. Mol Genet Metab. 2005 Aug;85(4):247–54.

    9. Diaz-Manera J et al. Lancet Neurol. 2021 Dec;20(12): Supplementary Appendix

MAT-XU-2203480 (v3.0)
Date of preparation: February 2023