Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study

NEO1 Investigator Group

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4 Citations (Scopus)

Abstract

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

Original languageEnglish (US)
JournalNeuromuscular Disorders
DOIs
StatePublished - Jan 1 2019

Fingerprint

Glycogen Storage Disease Type II
Enzyme Replacement Therapy
Pharmacokinetics
Safety
Therapeutics
Glucosidases
Quadriceps Muscle
human GAA protein
Late Onset Disorders
Glycogen
Area Under Curve
Thorax
Lung
Acids
Antibodies

Keywords

  • Alglucosidase alfa
  • Avalglucosidase alfa (neoGAA)
  • Enzyme replacement therapy
  • Glycogen storage disease type II
  • Late-onset Pompe disease (LOPD)
  • Lysosomal acid α-glucosidase (GAA) deficiency

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

Cite this

@article{831b7f7984b84e0fa7639b4eccd7e6a2,
title = "Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-na{\"i}ve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study",
abstract = "This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa na{\"i}ve (Na{\"i}ve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50{\%} predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Na{\"i}ve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Na{\"i}ve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Na{\"i}ve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Na{\"i}ve groups and over time. Baseline quadriceps muscle glycogen was low (∼6{\%}) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.",
keywords = "Alglucosidase alfa, Avalglucosidase alfa (neoGAA), Enzyme replacement therapy, Glycogen storage disease type II, Late-onset Pompe disease (LOPD), Lysosomal acid α-glucosidase (GAA) deficiency",
author = "{NEO1 Investigator Group} and Pena, {Loren D.M.} and Barohn, {Richard J.} and Byrne, {Barry J.} and Claude Desnuelle and Ozlem Goker-Alpan and Shafeeq Ladha and Pascal Lafor{\^e}t and Mengel, {Karl Eugen} and Alan Pestronk and Jean Pouget and Benedikt Schoser and Volker Straub and Trivedi, {Jaya R} and {Van Damme}, Philip and John Vissing and Peter Young and Katherine Kacena and Raheel Shafi and Thurberg, {Beth L.} and Kerry Culm-Merdek and {van der Ploeg}, {Ans T.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.nmd.2018.12.004",
language = "English (US)",
journal = "Neuromuscular Disorders",
issn = "0960-8966",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease

T2 - A phase 1, open-label, multicenter, multinational, ascending dose study

AU - NEO1 Investigator Group

AU - Pena, Loren D.M.

AU - Barohn, Richard J.

AU - Byrne, Barry J.

AU - Desnuelle, Claude

AU - Goker-Alpan, Ozlem

AU - Ladha, Shafeeq

AU - Laforêt, Pascal

AU - Mengel, Karl Eugen

AU - Pestronk, Alan

AU - Pouget, Jean

AU - Schoser, Benedikt

AU - Straub, Volker

AU - Trivedi, Jaya R

AU - Van Damme, Philip

AU - Vissing, John

AU - Young, Peter

AU - Kacena, Katherine

AU - Shafi, Raheel

AU - Thurberg, Beth L.

AU - Culm-Merdek, Kerry

AU - van der Ploeg, Ans T.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

AB - This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

KW - Alglucosidase alfa

KW - Avalglucosidase alfa (neoGAA)

KW - Enzyme replacement therapy

KW - Glycogen storage disease type II

KW - Late-onset Pompe disease (LOPD)

KW - Lysosomal acid α-glucosidase (GAA) deficiency

UR - http://www.scopus.com/inward/record.url?scp=85061300190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061300190&partnerID=8YFLogxK

U2 - 10.1016/j.nmd.2018.12.004

DO - 10.1016/j.nmd.2018.12.004

M3 - Article

C2 - 30770310

AN - SCOPUS:85061300190

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

ER -