Introduction: Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked lysosomal storage disorder. It results from a deficiency of the enzyme iduronate-2-sulfatase (I2S), leading to the accumulation of glycosaminoglycans (GAGs) in various tissues and organs. Clinical manifestations include skeletal abnormalities, facial coarsening, organ enlargement, and developmental delays.

Objectives: 1) To identify neuronopathic MPS II-specific biomarkers to discriminate the neuronopathic form of the disease from healthy controls; 2) To use liquid chromatography-high-resolution time-of-flight mass spectrometry (LCMS) based untargeted metabolomic approaches to identify these potential biomarkers; 3) To better understand how the disease may affect the metabolome of patients.

Methods: Urine and plasma samples from 21 untreated neuronopathic MPS II patients with severe clinical manifestations were compared to 23 age- and gender-matched healthy controls using a Xevo G2-XS QTOF MS (Waters Corp.).

Results: Using a comprehensive metabolomic workflow and multivariate statistical analyses, metabolites consistently elevated in MPS II patients were targeted, including acylaminosugars, dipeptides, specific amino acids, and derivatives. Development/validation of quantitative MS methods will be done using tandem mass spectrometry. Reference values will be established with an age- and gender-matched control group.

Conclusions: Future perspectives include expanding the study by comparing samples from untreated MPS II patients with the non-neuronopathic form to those with the neuronopathic form. According to our preliminary results, identifying biomarkers associated with the central nervous system in MPS II patients would help detect the neuronopathic form of the disease early, provide treatment, and enable the evaluation of the effectiveness of novel therapeutic strategies.

Mucopolysaccharidoses (MPS) are a group of rare inherited lysosomal storage diseases (LSDs) characterized by the paucity of specific enzymes that result in the accumulation of glycosaminoglycans (GAGs) causing progressive, multi-system organ dysfunction. Although GAG accumulation is the primary metabolic derangement seen in the MPS, there is interest in the role of secondary metabolic processes in the progression of symptoms. Recent transcriptome analysis has demonstrated perturbed sphingolipid metabolism that may influence the pathogenesis of MPS and course of disease. Sphingolipids, a complex class of lipids, are known to regulate various cellular functions, such as cell growth, differentiation, and apoptosis. The role of sphingolipids as a possible biomarker in MPS disorders is a focus in our lab. Given the importance of reliable analytical procedures for accurate sphingolipid measurements, control values are essential for an adequate evaluation. Therefore, the main objective of this study is to obtain reference values of specific sphingolipid families for our current and future studies. To accomplish our research objective, we developed a targeted quantification method encompassing optimised techniques for extracting, purifying and quantifying ceramides and sphingomyelins from human plasma samples, a two-phase organic/aqueous extraction which ensures high recovery rates and reproducibility. 120 samples from healthy individuals (carrier and non-carrier of various rare diseases such as GA type 1, X-ALD, MPS IIIA, etc.) are used. The extracted samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and we will present this data.

Introduction: Pompe disease is a rare, progressive, neuromuscular genetic disorder caused by the deficiency of the enzyme acid -glucosidase (GAA gene) leading to abnormal accumulation of glycogen. Urinary tetrasaccharides (Glc4) are biomarkers used in the monitoring and follow-up of patients undergoing treatment. Urine Glc4 has been very helpful in the diagnosis of IOPD, monitoring of disease, yet Glc4 are not always elevated due to marked phenotypic/genotypic variations of the disease.

Objectives: A) To discover new biomarkers in biological fluids (urine and plasma) of patients with Pompe disease (infantile and late-onset forms) using a semi-targeted metabolomic approach; B) To develop and validate analytical methods to quantify these biomarkers by tandem mass spectrometry; and C) To assess correlations of these biomarkers with clinical manifestations and disease progression, as well as the monitoring of treatment efficiency.

Methodology: A semi-targeted metabolomic approach evaluating saccharides and lipids will be used. Extracted samples from untreated patients will be analysed and compared to control samples using time-of-flight mass spectrometry. Statistical and computational tools will be used to discriminate and confirm potential biomarkers. Quantitative analytical methods for the targeted biomarkers will be developed/validated using tandem mass spectrometry. Reference values will be established with healthy controls. Biomarkers will be analysed to establish correlations with clinical manifestations and disease progression.

Results and Perspectives: This biomarker study might provide effective monitoring and follow-up for treated Pompe patients, assessing disease progression and treatment efficacy for both forms of the disease. Reliable biomarkers might also facilitate high-risk screening of this disease.

Biallelic pathogenic variants in GNPTAB are responsible for both mucolipidosis type II and type III alpha/beta (ML II and ML III), caused by a defect in lysosomal enzyme phosphorylation and localization. Phenotypes associated with ML II include developmental delay, severe skeletal abnormalities, and cardiorespiratory insufficiency; ML III is an attenuated form of the disease. Here, we present a male who presented before age 2 years with skeletal abnormalities and a dysplastic aortic valve. Molecular testing revealed a single likely pathogenic donor splice site variant in GNPTAB, but a second variant in this gene was not detected. Enzyme testing showed elevations in beta-glucosidase and beta-hexosaminidase, in support of a GNPTAB-related disorder. A urine mucopolysaccharide screen was normal while oligosaccharides in the urine were abnormal. By age 14 years, his cardiac presentation had progressed to severe aortic insufficiency. The proband was enrolled in the Care4Rare Canada research program and RNA sequencing (RNA-Seq) was performed to investigate the possibility of a second causative variant in GNPTAB. From these analyses, a cryptic exon was detected, and further investigation revealed that this resulted from a deep intronic variant. Segregation in the parents confirmed that the GNPTAB variants were biallelic. Overall, this individuals clinical presentation overlaps with ML III and through RNA-Seq, we were able to identify a second causative variant in GNPTAB. This study highlights the benefits of RNA-Seq in obtaining a diagnosis for patients where there is strong suspicion of a causative gene but lack of a molecular diagnosis.

The mucopolysaccharidoses are a group of 12 rare genetic disorders each caused by the absence or reduced function of lysosomal enzymes resulting in progressive cellular damage and organ system dysfunction. Historically, care has depended primarily on supportive care and hematopoietic stem cell transplantation (HSCT). Since 2003, remarkable progress has been made with regulatory approval of intravenous enzyme replacement therapy (ERT) for MPS I, II, IVa, VI, and VII. Although effective in treating many somatic symptoms, IV administered enzyme does not treat CNS disease. We will discuss new strategies and the promise of new therapies which give hope for families in the coming decade. Progress forward depends on partnership between investigator, sponsor, families/patients, advocacy groups and regulatory agencies.

Introduction: Fabry Disease is an X-linked lysosomal storage disorder caused by a deficiency of the -galactosidase A enzyme. The overall incidence of Fabry disease is reported to be between 1:1,600 and 1:117,000 live births.

Objectives: 1) To develop and validate a robust and highly selective tandem mass spectrometry plasma analysis for Gb3 and related isoforms; 2) To establish normal reference values and evaluate Gb3 levels of treated male and female Fabry patients; 3) To investigate the global profile of Gb3 and isoforms for genotype and phenotype correlations.

Methods: 92 Fabry patient plasma specimens and 50 healthy controls were processed using a liquid-liquid extraction (water/methanol/methyl tert-butyl ether). Gb3 isoforms were analyzed using an Acquity H-Class+/Xevo TQ-S micro system (Waters Corp.).

Results: Gb3 and 6 isoforms were validated according to FDA guidelines. Our results show an efficient differentiation between Fabry patients and controls. High sensitivity and good resolution allowed the detection of low quantities of Gb3 and isoforms. Interday and intraday assays show biases at <15%. Short term stability for 72 hours at 4C and 22C was good with a bias of <9%. The overall profile of biomarkers shows that C16:0 accounts for 50% of Gb3, C24:1 for 25%, C22:0 for 10%, and the remaining 3 isoforms contribute to 15%. As expected, men have higher concentrations than women.

Conclusions: These results demonstrate the efficiency of our validated technique for separating and identifying low levels of Gb3 isoforms. This method might be used for early detection, monitoring, and follow-up of Fabry patients.

Background: Agalsidase beta is dosed biweekly and infusion rates can be increased based on tolerability. The present study will evaluate safety and tolerability of agalsidase beta at approved dose and increased infusion rate with reduced infusion volume.

Methods: This ongoing Phase 4 study will enroll 18 participants (2 to 65 years) with confirmed diagnosis of Fabry disease into five cohorts. The primary endpoints are percentage reduction of infusion duration from prestudy mean of recent three infusions and from initial 120 minutes along with shortest infusion duration each participant can tolerate. Here we present data from Cohort 1, with three agalsidase beta-experienced female patients (30 kg).

Results: Three female patients aged 22, 19, and 49 years (mean body weight, 70.7 kg) were enrolled. The duration of previous agalsidase beta treatment was 132, 60, 58 months and the prestudy mean duration of three most recent infusions was 133, 136, 120 minutes, respectively. The initial duration for first infusion in all three patients was 120 minutes. In four subsequent infusions, the infusion time was gradually reduced to 20 minutes without experiencing any infusion associated reaction (IAR). The plasma lyso-GL3 remained low and stable and antidrug antibodies to agalsidase beta remained negative in all three patients throughout the study.

Conclusion: Agalsidase beta infusion was given safely at a final time of 20-minute infusion duration in ERT-experienced female patients without IAR. Further findings from this study will help in establishing a protocol to reduce duration of agalsidase beta infusion and minimize the treatment burden.

Understanding neurocognitive functioning in patients with lysosomal diseases requires moving beyond traditional metrics such as IQ. Although measures of intellectual ability have historically been central to neurocognitive evaluations, they often fail to capture the complexities of these disorders or the broader impacts on everyday life. Emerging research underscores the need for more comprehensive approaches that consider the full range of neurocognitive and functional challenges associated with lysosomal diseases.

This presentation explores the evolving landscape of neurocognitive assessment in lysosomal diseases, with a focus on patients with MPS. Traditional neurocognitive endpoints, such as IQ, though informative, provide a limited perspective. Expanding the scope of assessment to include domains like attention, memory, executive functioning, and adaptive functioning reveals a more nuanced understanding of disease impact. Factors such as fatigue, chronic pain, and psychosocial challenges further complicate the clinical picture and merit integration into neurocognitive evaluations.

Case studies, recent research findings, and preliminary data will be used to illustrate the need for patient-centered approaches that extend beyond IQ. These approaches aim to provide a more holistic understanding of neurocognitive functioning and its influence on quality of life, disease progression, and treatment outcomes. This presentation will emphasize innovative strategies for neuropsychological evaluation that better reflect the complexities faced by patients with MPS, ultimately advancing both clinical care and research efforts.

Background: Due to the rarity of mucopolysaccharidoses (MPS), there is a paucity of evidence on which to base treatment decisions. The rigorous collection of standardized longitudinal health outcomes within a patient registry can facilitate research to enhance understanding of natural history and evaluate intervention effectiveness. The Canadian MPS Society and the INFORM RARE research network co-developed the first non-industry led/product focused MPS registry in Canada, The Canadian MPS Registry.

Methods: The patient registry is hosted on the National Organization for Rare Disorders IAMRARE(r) Platform and is available in English and French. Eligible participants are individuals aged 18 years diagnosed with MPS receiving care in Canada; expansion to adult populations is a priority. Phased data collection is informed by a core outcome set. Following consent and confirmation of eligibility, patient/caregiver-reported demographic and quality of life questionnaires (including the Patient-Reported Outcome Measurement Information System; PROMIS) are collected. Questionnaires on adaptive functioning, pain, mobility, sleep, and caregiver/family impact will be added. In phase II, clinician-reported data will be integrated into the registry and linked, with participant consent and site-specific research ethics board approvals, to phase I data.

Results: Launched on May 2, 2024, to date, 17 participants across six provinces enrolled in the registry. Descriptive statistics about registry participants will be presented at the time of the conference, including demographic characteristics and health-related quality of life.

Conclusions: The Canadian MPS Registry is a milestone achievement towards the generation of high-quality natural history data to support research to improve care for patients with MPS.

In this symposium, the speakers will discuss the patient perception of disease burden, monitoring and management of Fabry disease with an emphasis on mental health impacts of the disease.

Speakers will also share their experience and provide insights on ways to incorporate patient perspectives in clinical decision-making to adopt a holistic patient-care approach. The presentation will include case studies and will end with a Q&A session.

Sponsored by Chiesi Global Rare Diseases

Background: Enzyme replacement therapy (ERT) is an established treatment for Fabry disease. Infusion time varies by product and this can be a factor in patient decisions around therapy. Shorter infusion time as low as 45 minutes for agalsidase beta has been tried in Italy with success in small numbers of patients. While the initial Canadian Fabrazyme Product Monograph in 2004 stated for patients weighing 30 kg, the infusion duration should not be less than 2 hours, this was changed to 1.5 hours in the 2023 monograph. We implemented a quality assurance program in the Nova Scotia Fabry Disease Program to decrease infusion time of agalsidase beta from 120 to 90 minutes. We report evaluation of this change in infusion time.

Methods: Adults with Fabry disease in the Fabry disease program at the QE II HSC Halifax receiving agalsidase beta 1.0 mg/kg EOW i.v. were consented for decreased infusion time. Patients had to meet inclusion criteria of ERT for at least 1 year and stable on ERT without current infusion associated reactions (IAR). All patients received ERT either in their home via an infusion nurse or in a commercial infusion centre. Infusion reports were reviewed and patients evaluated in clinic on an annual basis. Other Fabry clinics in Canada were queried as to ERT infusion times.

Results: There are currently 131 Fabry disease patients receiving agalsidase beta in Canada; 26 are being treated via the QE II HSC clinic. Twenty patients met criteria (77.1%) and all agreed to shortened infusion time. Two patients did not meet criteria due to current IAR and four were new ERT starts. This change was well tolerated in all including three patients with prior IARs and low to intermediate anti-drug antibody titres; no patients went back to the longer infusion time. In the rest of Canada, agalsidase beta infusion times remain at 120+ minutes in 93.5% of 62 patients surveyed to date.

Conclusion: Shortened infusion time of agalsidase beta ERT to 90 minutes in selected adults with Fabry disease in Canada is well tolerated. Only 7.7% of these ERT patients were excluded due to current IARs. There is potential to decrease agalsidase beta infusion time in additional Fabry patients in Canada.

Introduction: Fabry disease (FD) is caused by a mutation in the GLA gene impairing the catabolism of glycosphingolipids. Enzyme replacement therapy (ERT) and pharmacological chaperone therapy are currently approved for FD treatment. The ex vivo gene therapy (GT) approach is also promising. The worlds first GT clinical trial for FD was initiated in Canada in 2016. The objective was to determine the safety and toxicity of lentivirus-galactosidase A transduced autologous CD34+ cells in FD adult males. Biomarker analyses were needed as part of the evaluation of this new therapy.

Objective: The objective of the current project was to evaluate a profile of FD-related biomarkers in participants from this GT clinical trial.

Methods: All participants (n=5) were treated with ERT at baseline. ERT was stopped 1 month before GT and restarted 1-month post-GT, except for one participant. ERT was paused after at least 6 months post-GT if clinical endpoints were reached. Plasma and urinary Gb3 and lyso-Gb3 isoforms and analogues were measured repeatedly by LC-MS/MS for a 5-year surveillance period.

Results: Urine and plasma lyso-Gb3 and analogues, and urine Gb3 levels were lower after GT and while treated with ERT compared to baseline. Three participants ceased ERT after GT. Two of them had lower urine and plasma lyso-Gb3 and analogue levels compared to baseline. An increase of urine Gb3 was observed when ERT was discontinued post-GT.

Conclusions: This glycosphingolipid biomarker profile evaluation was useful to monitor the biochemical response to GT in this cohort of five patients with FD.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME) and Farber Lipogranulomatosis (FL) are rare allelic, autosomal-recessive diseases caused by mutations in theN-acylsphingosine amidohydrolase (ASAH1) gene.ASAH1encodes for acid ceramidase a lysosomal enzyme which hydrolyzes ceramide into sphingosine. Clinically, SMA-PME presents with progressive limb weakness followed by epileptogenesis. By contrast, FL is defined by painful joint deformation, development of sub-cutaneous nodules and a hoarse cry. Based on clinical, genetic, and biochemical overlap, it has been proposed that both diseases lie on a continuum.There are no approved treatments for these disorders, nor available animal models recapitulating the epileptiform feature of the SMA-PME phenotype. We tackled these issues through independentin vitroand anin vivoapproaches. We first sought to define the clinical/biochemical spectrum of these disorders and determine if aberrant lipid metabolism could be normalized via enzyme replacement in patient-derived fibroblasts. We also employed a battery of behavioural tests to assess the development of an SMA-PME-like phenotype in CRISPR-Cas9 knock-in mice carrying mutations mimicking the genotype of the first reported SMA-PME Canadian patient. We found unique lipidomic signatures discriminating FL SMA-PME and successfully conducted enzyme replacement therapy on SMA-PME patient cells. In addition, our mouse model shows a mixed FL/SMA-PME phenotype defined by reduced survival, failure to thrive, organ hyperplasia, impaired coordination and strength, increased seizing sensitivity and an altered sphingolipid metabolism. These findings allow for a better understanding of the pathomechanisms underlyingthe FL/SMA-PME continuum and provide opportunities to investigate potential treatments in a pre-clinical context.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lipidosis caused by a deficiency of the lysosomal hydrolase, arylsulfatase A (ARSA). Biochemically, the enzymatic defect enables intralysosomal accumulation of the ARSA substrate, galactosylceramide I3-sulfate (sulfatide), a major sphingolipid of myelin in glial cells and neurons. MLD presents predominantly as a central nervous system (CNS) condition with myelin degeneration, however as sulfatide accumulates and the disease progresses, a clear peripheral nervous system disease becomes apparent. Children affected by MLD begin to display progressive neurological symptoms around 2-3 years of age. Symptoms such as ataxia, seizures, and quadriplegia culminate in decerebration and eventual death around 10 years. To date, none of the therapeutic efforts examined address both the central and peripheral manifestations.

Sulfatide accumulation in the ARSA-/- mouse is apparent beyond the age of 6 months (6.1pmol/ug) compared with that of a WT mouse (0.32 pmol/ug), prompting our inclusion of only aged mice in our study. To demonstrate widespread efficacy, we designed and administered an intravenous (IV) therapeutic, AAV99 using an EF1-alpha promoter that overexpresses ARSA (AAV9-hARSA) in an established (10-12 month old) KO mouse model of MLD.

Following IV injections of AAV9-hARSA in the aged mouse cohorts demonstrated reduced sulfatide accumulation in the cerebellum (p=0.007), spinal cord (p=0.00001) and sciatic nerve (p=0.03) at 3 months post-injection.Data presented represents a novel study whereby the viral vector success is based on the efficacy of treating both the CNS and PNS disease pathologies associated with symptomatic MLD.

Background: Gene therapy is a promising treatment for Fabry disease. Lentiviral vector mediated gene therapy may allow for larger cDNA delivery than AAV vectors without issue of prior immunity. We report the renal outcomes at 5-year follow up in a phase I trial of lentivirus-mediated gene therapy in Fabry disease (NCT02800070)(Khan et al 2021).

Methods: 5 adult males, mean age 38.4 years with Fabry disease and classical phenotype received standard dose enzyme replacement therapy (ERT). Each received an infusion of autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express human alpha-galactosidase A (-gal A) plus low dose Melphalan 100 mg/m2 to allow bone marrow engraftment. ERT was stopped 60 days prior to the autologous stem cell transplant and resumed at 30 days post in 4 of 5 patients. ERT could be withdrawn if patients were stable.

Results: All patients had stable polyclonal engraftment with increased a-gal A activity in plasma and WBC above baseline that persisted through 5 years. Gb3 and lysoGb3 levels initially fell in urine and plasma in all subjects. In 3 of 5 patients ERT was stopped (at days -41, +214, +548). eGFR slopes ranged from +0.09 to -5.2, mean SD -1.58 1.92 ml/min/1.73m2. Patient #2 with chronic kidney disease (CKD) at baseline had declining eGFR with change from CKD stage IIIa to IIIb by year 3; thereafter eGFR slope stabilized at +0.1 ml/min/1.73m2/yr. CKD stage was unchanged in the other 4 patients, at stage I or II. Proteinuria fell or remained stable in all with a mean of 0.45 0.39 g/day; patient #2 had a fall in proteinuria from peak of 4.77 to 1.07 g/day.

Conclusion: Lentivirus-mediated gene therapy for Fabry disease is a safe and efficacious treatment with kidney disease stabilization over 5 years. eGFR slopes were mainly stable or improved with decreasing proteinuria suggesting possible renal uptake of endogenous -gal A.

Support: This work was supported by Canadian Institutes of Health Research (CIHR grant #119187), the Kidney Foundation of Canada, the MACC Fund. and Avrobio, Inc

Mucopolysaccharidosis type 1 (MPS-1) is a lysosomal storage disorder characterized by a loss in function of the -iduronidase (IDUA) enzyme. Patients with dysfunctional enzyme activity can begin to show signs of the condition before 1-year of age, with symptoms including developmental delays, hepatosplenomegaly, skeletal deformities, and other musculoskeletal issues. Currently, most newborn screening (NBS) programs screen for MPS-1 employing enzymatic assays to measure the activity of -IDUA, before proceeding with sequencing of the IDUA gene. However, a significant portion of samples with seemingly lower enzyme activity end up being reported as false positives upon genetic testing, due to the presence of pseudo deficiencies and variants of uncertain significance. Many studies have tested a second-tier analysis prior to genetic testing that involves measuring the presence of glycosaminoglycans (GAGs) in the NBS dried blood spots (DBS). This study involves optimizing an existing method for incorporation into the Newborn Screening Ontario (NSO) program. The endogenous disaccharide method was employed due to its ability to differentiate disease and non-disease. We measured the MPS-1 markers UA-HNAc (1S) and UA-HNAc-UA (1S) in positive and negative quality control DBS samples and optimized the liquid-chromatography mass-spectrometry settings and workflow according to NSO guidelines. The final method has since been tested on 11 patient samples with pseudo deficiency alleles, with GAG concentrations results that vary accordingly. This study endorses the use of the endogenous disaccharide method for MPS-1 NBS in Ontario, to lessen the burden of genetic testing on families and improve the positive-predictive value for NBS for MPS-1.

Pegunigalsidase alfa (PA) is a PEGylated enzyme replacement therapy (ERT) approved for adults with Fabry disease (FD). PEGylation of PA could mask epitopes, which may reduce incidence of infusion-related reactions (IRRs) by modulating immunogenicity of PA.

The occurrence of IRRs in ERT-switch and ERT-naive patients administered PA 1 mg/kg every other week was evaluated. IRRs occurring from infusion start up to 2 hours post-infusion (IRR-2H) and 24 hours post-infusion (IRR-24H; IRR-24H includes IRR-2H) are described.

This analysis included 111 adults (70M:41F; mean age: 43.4 years); among those, 94 switched from agalsidase alfa (n=22, 19.8%) or agalsidase beta (n=72, 64.9%) and 17 (15.3%) were ERT-naive. In ERT-switch patients, IRR-2H and IRR-24H occurred in 22/94 (35 events; rate (per 100 infusions)=0.6) and 28/94 (51 events; rate=0.8) patients, respectively; in ERT-naive patients, IRR-2H and IRR-24H occurred in 4/17 (17 events; rate=1.5) and 4/17 (20 events; rate=1.8) patients, respectively. Most events were mild/moderate in severity, regardless of prior ERT experience (ERT-switch: 92.2%; ERT-naive: 95.0%). Four severe and serious IRRs leading to discontinuation were reported in 4 patients (type I hypersensitivity n=2, hypersensitivity n=1, and bronchospasm n=1), all were resolved. Most IRRs occurred during the first year of treatment (ERT-switch: 40/51 78.4%; ERT-naive: 19/20 95.0%).

IRRs were observed in less than a third of either ERT-nave or ERT-switch patients with FD treated with PA 1 mg/kg. Most IRRs were mild/moderate in severity and occurred within 2 hours of PA administration. IRRs were observed predominantly in the first year after PA initiation.

Pegunigalsidase alfa (PA) is an enzyme replacement therapy (ERT) approved for adults with Fabry disease (FD). ERTs can cause infusion-related reactions (IRRs) that occur more frequently at higher doses.

We present integrated analyses from 7 clinical trials/extensions of IRR incidence from infusion start up to 2 hours (IRR-2H) and 24 hours post-infusion (IRR-24H; includes IRR-2H) with 2 PA doses (1 mg/kg every other week; 2 mg/kg every 4 weeks).

Of 141 adults (94M:47F), 111 received PA 1 mg/kg and 30 received PA 2 mg/kg. Of patients receiving 1 mg/kg, 26/111 (23.4%, 52 events) and 32/111 (28.8%, 71 events) experienced IRR-2H and IRR-24H, respectively; of those receiving 2 mg/kg, 6/30 (20.0%, 38 events) experienced IRR-2H and IRR-24H. At either dose, 90/109 IRRs occurred up to 2 hours post-infusion and were more frequent in males (31/94 33.0% IRR-24H) vs females (7/47 14.9% IRR-24H). Baseline anti-drug antibody positive (ADA+) patients (36M:1F; 18/37 48.6% IRR-24H) had higher IRR frequency than ADA- patients (58M:46F; 12/83 14.5% IRR-24H). IRRs predominantly occurred during the first year of treatment. Baseline premedication use, as prescribed for prior ERT, decreased over time in both dosing groups. Four severe and serious IRRs leading to discontinuation occurred in 4 patients (type I hypersensitivity n=2; baseline IgG-, hypersensitivity n=1; baseline IgG+, and bronchospasm n=1; baseline IgG-), with no deaths.

Less than a third of patients receiving PA experienced IRRs, with no increased IRR incidence with higher dose. IRRs were more frequent in males and baseline ADA+ patients, regardless of dose.