6533b85ffe1ef96bd12c27f9

RESEARCH PRODUCT

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

Philip Van DammePascal LaforêtBenedikt SchoserBarry J. ByrneLoren D.m. PenaRichard J. BarohnOzlem Goker-alpanKerry Culm-merdekAns T. Van Der PloegVolker StraubKarl Eugen MengelBeth L. ThurbergJean PougetRaheel ShafiKatherine KacenaAlan PestronkPeter YoungJohn VissingShafeeq LadhaClaude DesnuelleJaya Trivedi

subject

Avalglucosidase alfa (neoGAA)0301 basic medicineMaleGLUCOSE TETRASACCHARIDELysosomal acid alpha-glucosidase (GAA) deficiencyCHILDRENPulmonary function testingMOTOR FUNCTION0302 clinical medicineMedicineGenetics (clinical)Late-onset Pompe disease (LOPD)Glycogen Storage Disease Type IIAlglucosidase alfaMOUSE MODELEnzyme replacement therapyMiddle AgedTreatment OutcomeNeurologyTolerabilityEnzyme replacement therapySKELETAL-MUSCLEFemaleLife Sciences & BiomedicineMUSCLE TRAINING RMTGlycogen6-MINUTE WALKmedicine.drugAdultmedicine.medical_specialtyClinical NeurologyGLYCOGEN03 medical and health sciencesFEV1/FVC ratioPharmacokineticsInternal medicineHumansEnzyme Replacement TherapyAdverse effectAlglucosidase alfaScience & Technologybusiness.industryNeurosciencesalpha-GlucosidasesADULTSGlycogen storage disease type IISEVERITY030104 developmental biologyPharmacodynamicsPediatrics Perinatology and Child HealthNeurosciences & NeurologyNeurology (clinical)Glucan 14-alpha-Glucosidasebusiness030217 neurology & neurosurgery

description

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 (t1/2z∼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. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

yearjournalcountryeditionlanguage
2019-03-01Neuromuscular Disorders
10.1016/j.nmd.2018.12.004https://doi.org/10.1016/j.nmd.2018.12.004