PracticeUpdate Conference Series_WORLDSymposium 2019

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

15TH ANNUAL WORLDSymposium 4–8 FEBRUARY 2019 • ORLANDO, FLORIDA, USA

THE BEST OF WORLDSymposium 2019 Early-Onset Pompe Disease Linked to c.-32-13TNG Variant • Neuroimaging Demonstrates Complications in Newborns With MPS I • Transition From Pediatric to Adult Care in Patients With MPS Needs to Be Flexible and Comprehensive • Gene Therapy Using SB-913 Shown to Be Safe and Well Tolerated in MPS II

DYSPHAGIA 1

MUSCLE PAIN 1

PROXIMAL MUSCLE WEAKNESS 1

RESPIRATORY INSUFFICIENCY 1

EXERCISE INTOLERANCE 3

FATIGUE 3

GAIT ABNORMALITIES 1

UNKNOWN CAUSE OF HYPERCKEMIA 2

FREQUENT FALLS 1

IT’S NOT IN YOUR PATIENT’S HEAD

SLEEP APNOEA 3

IT’S IN THEIR MUSCLES

If your patients have discussed experiencing any of these symptoms or test results with you, it’s time to consider Late-Onset Pompe Disease (LOPD). Pompe Disease affects approximately 1 in every 40,000 people, and is a progressive disease that gets worse over time. 1,4 Like many conditions, Pompe Disease can be managed and treated if it is diagnosed early. Test your patients for Late-Onset Pompe Disease using the Dried Blood Spot (DBS) Testing Kit, fully funded by Sanofi Genzyme.

Request your free DBS Testing Kit and Pompe Patient Booklet today by emailing: DBSkits@sanofi.com

For more information on Pompe Disease, please visit: https://sanofigenzymeonline.com.au/pompe-disease References: 1. Kishnani PS, et al. Gen Med 2006; 8: 267–88. 2. Lukacs Z, et al. Neurology 2016; 87: 295–8. 3. Chan J, et al. Mol Genet Metab 2017; 120:163–72. 4. American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve 2009; 40: 149–60. sanofi-aventis Australia pty ltd trading as Sanofi Genzyme ABN 31 008 558 807.Talavera Corporate Centre,Building D, 12–24 Talavera Road,Macquarie Park,NSW 2113.GZANZ.MYOZ.16.08.0142a.Date of Preparation March 2018.AM7338.

CONTENTS WORLDSymposium 2019 • 4–8 February 2019 • Orlando, Florida, USA BY THE PRACTICEUPDATE EDITORIAL TEAM

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3 Early-Onset Pompe Disease Linked to c.-32-13TNG Variant 4 Biochemical Change Corresponds With Clinical Manifestation of Neurologic Response in Patients With MPS I-H 5 Algorithm That Incorporates Facial Features Helps Identify Mucopolysaccharidoses 6 Neuroimaging Demonstrates Complications in Newborns With MPS I 7 Enzyme Therapy Reduces Paraprotein Levels in Type 1 Gaucher Disease

8 Long-Term Migalastat Therapy Benefits Renal Function and Cardiac Mass in Patients With Fabry Disease 10 Tripeptidyl Peptidase 1 Assay for Dried Blood Specimens Helps Diagnose CLN2 Disease Inexpensively 11 RNA Reprogramming Procedure Generates Induced Pluripotent Stem Cells of Patients With Fabry Disease 12 Elosulfase α Improves Outcomes Long Term in Patients With MPS IVA 14 Transition From Pediatric to Adult Care in Patients With MPS Needs to Be Flexible and Comprehensive

16 Velaglucerase α Maintains Improvement Long Term in Patients With Gaucher Disease 17 Patients With MPS II Without Cognitive Impairment Still Markedly Affected by Somatic Symptoms 18 Gene Therapy Using SB-913 Shown to Be Safe and Well Tolerated in MPS II 20 Gammopathies More Common in Patients >50 Years With Gaucher Disease

The production of this publication is sponsored by Sanofi Genzyme. The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing.

WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 1

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PracticeUpdate ® is a registered trademark of Elsevier Inc. ©2019 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Sanofi Genzyme. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Sanofi Genzyme. All content printed in this publication can be found on PracticeUpdate.com SALES Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja ISSN 2208-150X (Print) • ISSN 2208-1518 (Online)

Michael H. Kroll MD Professor of Medicine; Chief, Section of Benign Hematology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas

Associate Editors

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Early-Onset Pompe Disease Linked to c.-32-13TNG Variant Careful evaluation of symptoms is needed in patients with the variant.

T he onset of symptoms, including gross motor delay, swallow/feeding difficulties and sleep apnea, in the first 2 years of life is not uncom- mon in individuals with late-onset Pompe disease, conclude results of a retrospective chart review. Stephanie Austin, MD, of Duke University in Durham, North Carolina, and colleagues set out to identify patients diagnosed clinically (as opposed to through newborn screening). The charts of a cohort of 84 patients with late-onset Pompe disease with the c.-32-13TNG variant were reviewed. Their symptom onset was documented clinically within the first 2 years of life. Four patients experi- enced early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included gross motor delay, swallow/feeding difficul- ties and sleep apnea. Early deviations in skeletal muscle posture and move- ment were identified in all subjects. Age at diagnosis ranged from 10 to 26 months. Median age at the initiation of enzyme replacement therapy was 23.5 months. Despite enzyme replacement therapy, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lor- dosis, scapular winging, and trunk/lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, Peabody Developmental Motor Scales-2, Bruininks-Oseretsky Test of Motor Proficiency (second edition), and 6-minute walk test. Dr. Austin explained that individuals with late-onset Pompe disease and the common c.-32-13TNG variant are widely thought to suffer from milder, adult-onset disease. Reports of late-onset Pompe disease in children have not included a description

of the early-onset phenotype. This description of subtle signs and symptoms is important to facilitate prompt identification and appropriate treatment in symptomatic children. The leaky c.-32-13TNG variant is the most frequent mutation in late-onset Pompe disease. The variant gives rise to alternatively spliced transcripts, including a deletion of the frst coding exon, but still allows the production of a low amount of normally processed mRNA. The c.-32-13TNG mutation has been found in over 40% of patients of Caucasian origin. A 2012 study of a large cohort of patients with a similar genotype – c.-32-13TNG in combination with a second null mutation – unexpectedly showed a signifcant variability in the age of disease onset, suggesting the role of secondary modifying factors on the clinical course. A possible factor responsible for the wide clinical variability is the deletion/deletion polymorphism in the gene coding for the angiotensin-converting enzyme, which is known to increase the number of type II fbers and influence muscle properties, is associated with earlier onset, higher creatine kinase levels, muscle pain, and more severe progression of the disease in patients with adult form. Dr. Austin concluded that the onset of symptoms, including gross motor delay, swallow/feeding difficul- ties and sleep apnea, in the first 2 years of life is not uncommon in individuals with late-onset Pompe disease and the c.-32-13TNG variant. Careful evaluation for specific gross motor posture and movement in patients with this variant is nec- essary to identify early-onset disease. Increased awareness of the early-onset signs and symptoms will enable early identification of disease onset in children diagnosed through newborn screening.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 3

Biochemical Change Corresponds With Clinical Manifestation of Neurologic Response in Patients With MPS I-H This is the first evidence of a link between a biomarker and intelligence.

R epresenting the frst evidence of a link between a biomarker and intelligence in patients with mucopolysaccharidosis (MPS) I-H, a biochemical change has been found to correspond with a clinical manifestation of neurologic response. This fnding of a prospective study was reported at the WORLDSymposium 2019. Troy C. Lund, MD, PhD, of the University of Minnesota in Minneapolis, and colleagues set out to determine whether intrathecal enzyme replacement therapy + intravenous enzyme replacement therapy and hematopoietic stem cell transplantation is associated with attenuation of cerebrospinal fluid abnormalities and whether this change exhibits clinical correlates. A total of 24 patients with MPS I-H received intrathecal enzyme replacement therapy at four time points in the peritransplant period. At these times, cerebrospinal fluid opening pressure, heparin sulfate, non-reducing ends (NRE I0S0 and I0S6), heparin cofactor II thrombin complex, and in ammatory markers were measured. Neurocognitive functioning (that is, infant IQ) was quantified at baseline, and 1 and 2 years after hematopoietic stem cell transplantation. No adverse events due to the administration of intrathecal enzyme replacement therapy were observed. An association between attenuated cerebrospinal fluid biomarkers and IQ change following transplant was examined. Significant reductions in cerebrospinal fluid abnormalities were seen between time points 1 and 2, that is, prior to hematopoietic stem cell transplantation, for cerebrospinal fluid opening pressure, NRE I0S0 and I0S6, and heparin cofactor II thrombin complex (P = .036, .001, .006, and 0.026, respectively). Reductions were seen across time points 1 through 4 for NRE I0S0 and I0S6, heparin sulfate, and heparin cofactor II thrombin complex (P < .001 for all four biomarkers). Percent decrease in non-reducing ends from the first to fourth dose was significantly associated with a percent increase in IQ from baseline to 2 years post-hematopoietic stem cell transplantation (mean ft slope 0.703; 95% CI 0.232–1.175; P = .003). Intrathecal enzyme replacement therapy is associated with attenuation of abnormal cerebrospinal fluid biomarkers in MPS I-H, with maximal attenuation following the combination of intrathecal/intravenous enzyme replacement therapy and hematopoietic stem cell transplantation. Dr. Lund explained that abnormal cerebrospinal uid characteristics have been reported in children with severe MPS I-H (Hurler syndrome), a progressive lysosomal storage disease associated with rapid neurocognitive decline, worsening multisystem organ dysfunction, and early death. MPS I-H is the most severe form of MPS I. MPS I-H is characterized by high concentrations of the mucopolysaccharides dermatan and heparan sulfates in the urine. Symptoms frst become evident at 6 months to 2 years of age with developmental delay, recurrent urine and upper respiratory infections, noisy breathing, and persistent nasal discharge. Hydrocephalus is common after age 2–3 years. Other physical manifestations may include clouding of the cornea, an unusually large tongue, misaligned teeth, the devel- opment of a curved spine, and severe joint stiffness with claw-like hands. Mental development usually reaches a peak at approximately 2 years of age with progressive mental retardation thereafter. Dr. Lund concluded that the results offer the first evidence of a biochemical change that corresponds with a clinical manifestation of neurologic response, specifically, improvement in IQ, in patients with MPS I-H.

" Significant reductions in cerebrospinal fluid abnormalities were seen… prior to hematopoietic stem cell transplantation for cerebrospinal fluid opening pressure, NRE I0S0 and I0S6, and heparin cofactor II thrombin complex. "

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PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 4

Algorithm That Incorporates Facial Features Helps Identify Mucopolysaccharidoses The approach could be valuable in countries where access to diagnosis is limited. A n algorithm incorporating frontal facial images has suc- ceeded in suggesting mucopolysaccharidosis (MPS) as a possible diagnosis. This outcome of an evaluation of the algorithm was reported at the WORLDSymposium 2019.

Roberto Giugliani, MD, of the Hospital de Clínicas de Porto Alegre and the Universidade Federal do Rio Grande do Sul in Porto Alegre, Brazil, and col- leagues set out to determine whether a tool for facial recognition could identify patients with MPS III and IV. Dr. Giugliani told Elsevier’s PracticeUp- date , “New technologies like this one are needed to identify patients earlier,

Dr. Roberto Giugliani

especially in locations where medical resources are scarce. Such tools, easy to apply and requiring only a smartphone, are helpful diagnostic aids in the feld of rare diseases." The investigators took the wide spectrum of clinical manifesta- tions of mucopolysaccharidoses into consideration and explored the benefits of noninvasive phenotypic characterization using frontal pictures. The team evaluated version 18.1.14 of the algorithm with pictures from 25 known patients with MPS IIIB, n=16, or IVA, n=9. A deidentified case was created with frontal pictures of each patient, including date of birth, height, weight and head circumference. The phenotype was refined with the following descriptors: coarse facial features, hepatomegaly, short stature, intellectual disability, psychomotor deterioration, abnormal heart valve morphology, cardiomyopathy, hernia, hearing impairment, kyphosis, sple- nomegaly, genu valgum, corneal opacity, dysostosis multiplex, respiratory distress, and pectus carinatum, according to the clinical examination. Face2Gene scores were classified as exhibiting low, medium, and high similarity. Overall, 1 patient (4%) was scorable for MPS, 9 patients (36%) scored lowest, 14 (56%) medium, and one (4%) highest. Among patients with MPS IIIB, 15 (94%) were suggested to suffer from MPS within the top fve syndromes. Ten (62%) were sug- gested to suffer from MPS IIIB as one of the top fve suggested diagnoses. Among patients with MPS IVA, all were suggested as harboring a MPS. None, however, was suggested. Other than MPS, the most common suggested diagnoses were: Angelman, DiGeorge, and Williams-Beuren syndrome. Dr. Giugliani explained that the Face2Gene algorithm extracts mathematical facial descriptors from patients’ frontal pictures and compares them with syndrome gestalts with the goal of suggesting potential diagnoses.

Deep learning algorithms build syndrome-specifc, computational- based classifers (syndrome gestalts). Proprietary technology converts a patient photo into de-identifed mathematical facial descriptors (facial descriptors). The patient’s facial descriptor is compared with syndrome gestalts to quantify similarity (gestalt scores), resulting in a prioritized list of syndromes with similar morphology. Artifcial intelligence suggests likely phenotypic traits and genes to assist in feature annotation and syndrome prioritization. Dr. Giugliani concluded that the algorithm incorporating frontal facial images succeeded in suggesting MPS as a possible diag- nosis in most patients based on frontal images only with minimal clinical data and without testing. Nonetheless, improvements are still necessary. The approach could be valuable in low-income countries where access to diagnosis is limited.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 5

Neuroimaging Demonstrates Complications in

Newborns With MPS I Abnormalities have been shown in infants <6months of age with the disease.

N euroimaging assessments of infants <6 months of age with muco- polysaccharidosis (MPS) I have demonstrated abnormalities. Recognition of such features could be a useful tool for assessing severity, report fndings pre- sented at the WORLDSymposium 2019. Elizabeth Braunlin, MD, of the University of Minnesota in Minneapolis, and colleagues reviewed MRI images from 12 infants <6 months of age with known severe MPS I for features known to be present in severe MPS I. These included perivascular space enlargement, enlarged extra-axial spaces, white matter lesions, ventriculomegaly, bony abnormalities of the skull and cer- vical spine, cervical cord stenosis, and odontoid capping. Additionally, dilated optic nerve sheaths and mastoid uid were noted when present. Six male infants were studied at a median of 76 (21–185) days. A total of 6 infants had begun enzyme replacement therapy a median of 13 (range 2–87) days prior to imaging. No infant exhibited a normal scan. Bony abnormalities of the skull (12/12), the presence of mastoid uid (12/12) and enlarged perivascular spaces (10/12) were the most common findings. Enlarged extra-axial spaces (8/12) and cervical spi- nal canal stenosis (8/12), enlarged optic nerves (6/11), ventriculomegaly (7/12), and odontoid capping (7/12) occurred in 50% of infants.

White matter lesions (0/12) and cortical atrophy 0/12) were not identified. Infants <6 months of age with severe MPS I exhibit neuroimaging findings known to be present in older children with MPS I, most commonly bony abnormalities of the skull and enlarged perivascular spaces. Evaluation of a comparable group of infants with attenuated MPS I infants will be crucial before employing these find- ings as part of the assessment of disease severity in unknown mutations. Dr. Braunlin explained that newborn screening for MPS I allows for initiation of early treatment for infants with known mutations. In those with unknown mutations, treat- ment strategies become complicated as early enzyme replacement therapy may alter clinical findings subtly, preventing the identification of infants with severe muta- tions requiring hematopoietic stem cell transplantation. Recognizing features of severe mutations by neuroimaging could be a useful tool for classifying severity.

Dr. Braunlin also examined the hypothe- sis that with implementation of newborn screening for MPS I in the US, hemato- poietic stem cell transplantation may now occur earlier than 1–2 years of age and cardiac issues might be fewer. She and her team reviewed their records for any MPS I-H infant who underwent hematopoietic stem cell transplantation at ≤6 months of age. Pre- and (most recent) post-hematopoi- etic stem cell transplantation cardiac echocardiograms and clinical courses were reviewed in all infants with MPS I-H undergoing hematopoietic stem cell transplantation at ≤6 months of age. Overall, 7 infants with MPS I-H (4 males) were diagnosed at median MEDRNG 14 (range 3–22) days of life by newborn screening (n=2) or because an older sibling suffered from MPS I-H (n=5), and began enzyme replacement therapy at MEDRNG 48 (range 7–62) days of life.

" …early cardiac evaluation will identify cardiac features; however, increased awareness of the anatomic and functional differences of all organ systems related to young age will be necessary for optimal outcomes in patients with MPS I-H. "

PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 6

Enzyme Therapy Reduces ParaproteinLevels inType 1 Gaucher Disease Patients with Gaucher disease 1 may respond to enzyme replacement therapy. F urther evidence has been provided that altering levels of lysolipid accumulation in patients with Gaucher disease 1 and monoclonal gammopathy of undeter- mined significance may attenuate malignancy risk. This outcome of a retrospective chart reviewwas reported at theWORLDSymposium 2019. Graeme A.M. Nimmo, MD, MBBS, MSc, MPH, of the Hospital for Sick Children in Toronto, Ontario, Canada, reviewed the charts of 85 patients with Gaucher disease 1. A total of 12 patients harboredmonoclonal gammopathy of undetermined significance (incidence 14%), including 4 patients who received enzyme replacement therapy. Enzyme replacement therapy resulted in an improvement in markers of disease activity (including chitotriosidase, ferritin, glucosylsphingosine) and in reduction of the monoclonal protein. The response was sustained in the majority of patients. One patient demonstrated a transient reduction in paraprotein with enzyme replace- ment therapy but progressed to smoldering myeloma with an immunoglobulin G-κ monoclonal component. Dr. Nimmo explained that individuals with Gaucher disease I are at a 25- to 50-fold increased risk of developing monoclonal gammopathy of undetermined significance and its postcursor, multiple myeloma vs the general population. Multiple myeloma is a major contributor to morbidity and mortality in patients with Gaucher disease with up to 8.0% of patients progressing to a malignant gammopathy. Chronic immune activation and pathogenic accumulation of lysolipids in Gaucher disease are hypothesized to contribute to this increased risk. The response of monoclonal gammopathy of undetermined significance to enzyme replacement therapy and/or an alteration in the risk of progression to multiple myeloma on treatment is not clear, however. Gaucher disease is an autosomal-recessive lysosomal storage disorder caused by deficient activity of β-glucocerebrosidase. Glucocerebroside accumulates in cells and certain organs. The disorder is char- acterized by bruising, fatigue, anemia, low platelet count, and liver and spleen enlargement. Glucocerebroside accumulates, particularly in leukocytes and espe- cially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow. Skeletal disorders and bone lesions may be painful. Severe neurological compli- cations, swelling of the lymph nodes, and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, and yellow fatty deposits on the sclera are also features. Patients affected seriously may also bemore susceptible to infection. Both clinical features and response to treatment are heterogeneous. Skeletal dis- ease is complex, and a proportion of patients do not respond or progress despite Gaucher-specific therapy. Determinants of skeletal response are not known. The disease is characterized by polyclonal gammopathy and monoclonal gammopathy of undetermined significance. Dr. Nimmo concluded that monoclonal gammopathy of undetermined significance may respond to enzyme replacement therapy. Further evidence has been provided that altering levels of lysolipid accumulation in patients with Gaucher disease I with monoclonal gammopathy of undetermined significance may attenuate the risk of progression to malignancy.

First pre-hematopoietic stem cell trans- plant echocardiography was performed at MEDRNG 45 (range 0–88) days of life. Hematopoietic stem cell transplantation (n=6 cord blood, n=1 related) occurred at MEDRNG 131 (range 105–183) days of life with most recent echocardiography at MEDRNG 408 (range 10–1897) days after hematopoietic stem cell transplantation. Mitral regurgitation occurred in 2 infants before hematopoietic stem cell transplan- tation and remained present thereafter. Patent foramen ovale was common. Left ventricular hypertrophy occurred after hematopoietic stem cell transplantation. One infant suffered from severely decreased function at initial echocardiog- raphy and requiredmanagement in the ICU. One infant died unexpectedly 69 days after hematopoietic stem cell transplantation. Dr. Braunlin explained that hematopoietic cell transplantation is accepted therapy for severe MPS I-H. Newborns and young infants with severe MPS I presenting for hematopoietic stem cell transplantation suffer from unique medical issues related to their age. Dr. Braunlin concluded that early cardiac evaluation will identify cardiac features; however, increased awareness of the anatomic and functional differences of all organ systems related to young age will be necessary for optimal outcomes in patients with MPS I-H.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 7

Long-TermMigalastat Therapy Benefits Renal Function and Cardiac Mass in Patients With Fabry Disease Subanalysis of the ATTRACT trial points to better outcomes with the therapy.

L ong-term therapy with migalastat has been shown to benefit renal function and cardiac mass in patients with Fabry disease, outcome of a subanalysis of the phase III, randomized, enzyme replacement therapy-controlled ATTRACT trial shows. Nina Skuban, MD, of Amicus Therapeutics in Cranbury, New Jersey, and colleagues set out to evaluate the long-term effects of migalastat on α-galactosidase A activity and clinical outcomes in enzyme replacement therapy-experienced patients enrolled in ATTRACT. The analysis focused on 5 patients (3 females, 2 males) whose GLA variants, when tested with the in vitro migalastat amenability assay, resulted in a relatively low response of α-galactosidase A activity (an increase of ≥3% to <6% of wild type) but still met amenable criteria (≥1.2-fold relative increase over baseline and ≥3% absolute increase of wild-type activity). These 5 patients, after an average of 2.2 years of migalastat treatment, achieved stabilization in renal function and a reduction in cardiac mass. Their glo- botriaosylsphingosine levels also remained stable, consistent with the overall population. White blood cell α-galactosidase A activity (assessed in 2 males only) was very low at baseline in this subset and achieved sustained increases during migalastat treatment, maintaining absolute

increases of 4.6% (1.7-fold) and 7.2% (16.9-fold) of normal at last assessment, respectively. Every-other-day dosing resulted in consistent lev- els of migalastat exposure in these patients. Dr. Skuban explained that Fabry disease is a rare, X-linked disorder of α-galactosidase A deficiency caused by mutations in the GLA gene. The def- ciency results in substrate accumulation and multiorgan deterioration. Migalastat is a first-in-class, oral, small-molecule pharmacological chaperone that binds to and sta- bilizes endogenous α-galactosidase A, leading to increased lysosomal activity and reduced substrates in patients with amenable GLA variants, as deter- mined by an in vitro migalastat amenability assay. Dr. Skuban concluded that in patients with amenable GLA variants with low α-galactosidase A responses in the in vitro migalastat amenability assay, long- term migalastat therapy benefits renal function and cardiac mass in patients with Fabry disease.

" …given the uncertainty in the origin of plasma globotriasosylceramide and differences in the biodistribution and mechanism of action among the current treatment options, plasma globotriasosylceramide should not be interpreted as a stand-alone biomarker. " PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 8

Dr. Skuban’s team also evaluated the effect of long-term migalastat treatment on plasma globotria- sosylceramide levels in ATTRACT and its open-label extension study. They examined globotriasosylcer- amide profiles in patients with migalastat-amenable GLA mutations in the trial. They measured plasma globotriasosylceramide levels at baseline and at various subsequent time points. At baseline, defined as the start of migalastat treatment, median globotria- sosylceramide level was lower in females (5.8 nmoL/L minimum, maximum 0.8, 14.7 [n=26]) than in males (10.5 nmoL/L minimum, maximum 0.8, 59.1 [n=18]). Median globotriasosylceramide levels remained low and stable with long-termmigalastat treatment. Median changes from baseline to month 60 were –2.5 nmoL/L in males (n=4) and 0.4 nmoL/L in females (n=6). Assay-to-assay variability of the globotriasosylcer- amide quantification assay is approximately 20%. This variability which may have contributed to visit- to-visit changes.

Dr. Skuban explained that Fabry disease is associated with a pathological accumulation of substrates, including globotriasosylceramide and globotriaosylsphingosine. Though the clinical relevance of globotriasosyl- ceramide as a biomarker for monitoring treatment effect in Fabry remains uncertain, globotriasosyl- ceramide is used widely as a diagnostic indicator of Fabry disease. Dr. Skuban concluded that the data validated primary trial results, but given the uncertainty in the origin of plasma globotriasosylceramide and differences in the biodistribution and mechanism of action among the current treatment options, plasma globotriasosylceramide should not be interpreted as a stand-alone biomarker. Further research is warranted, and clinical out- comes should be considered when assessing treatment efficacy.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 9

Tripeptidyl Peptidase 1 Assay for Dried Blood Specimens Helps Diagnose CLN2 Disease Inexpensively The test can be applied withminor modi cations for mass throughput. A tripeptidyl peptidase 1 assay for dried blood specimens may be used to diagnose CLN2 disease. The test has been shown to be reliable, convenient and inexpensive.

quality of samples and for CLN2 simultaneously, they measured the activities of two additional lysosomal enzymes as controls. These were palmitoyl peptidase 1 and ß-galactosidase. Of all samples, 1.7% were excluded from the study because of sub- normal activity of more than one enzyme. For all samples with subnormal tripeptidyl peptidase 1 activity and good sample quality, they reviewed clinical information. Consequently, they obtained adequate clinical and molecular genetic data for 51 patients. All had doubtless evidence of CLN2 disease, including 7 atypical patients, as shown by symptoms of progressive brain disease and the presence of known path- ogenic CLN2 variants. The test’s sensitivity could not be evaluated directly. The investi- gators’ neuronal ceroid lipofuscinose clinic is a major reference center for these disorders, however, and the team has never received feedback that a patient with normal tripeptidyl pepti- dase 1 activity who received the test of dried blood specimens was diagnosed later with CLN2 disease. Their success rate constitutes convincing circumstantial evidence of high sensitivity. Dr. Lukacs explained that CLN2 disease is a lysosomal storage disorder that belongs to the neuronal ceroid lipofuscinoses class and leads progressively to dementia, blindness and early death. It is caused by a deficiency of the lysosomal enzyme tripeptidyl peptidase 1. The disease has gained recent interest as enzyme replacement therapy has become available. Diagnosis must be timely for the therapy to be effective. Signs and symptoms of CLN2 disease typically begin between ages 2 and 4 years. Initial features usually include recurrent seizures and ataxia. Affected children also develop myoclonus and vision loss. CLN2 disease affects motor skills and speech development. This condition also causes developmental regression, intellectual disa- bility that worsens gradually, and behavioral problems. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Some children with CLN2 disease do not develop symptoms until later in childhood, typically after age 4 years. These indi- viduals tend to suffer from milder features overall than children diagnosed earlier, but with more severe ataxia. They tend to survive into adulthood. Dr. Lukacs concluded that the tripeptidyl peptidase 1 test of dried blood specimens was shown to be reliable, convenient, and inexpensive as a first diagnostic step for suspected CLN2 disease. The test can be applied with minor modifications for mass throughput, as are newborn screening programs. He noted, “Our assay can provide a convenient tool for identify- ing CLN2 disease in the newborn. Furthermore, new substrates for mass spectrometry may also allow for multiplexed testing of CLN2 and other lysosomal diseases.”

This fnding of a controlled evaluation was reported at the WORLDSymposium 2019. Zoltan Lukacs, PhD, of the Hamburg University Medical Center in Germany, and colleagues set out to investigate the diagnostic reliability of a test for tripepti- dyl peptidase 1 deficiency in dried blood specimens. Dr. Lukacs’s team developed the assay to detect CLN2 disease.

Dr. Zoltan Lukacs

Dr. Lukacs told Elsevier’s PracticeUpdate , “CLN2 disease is important, particularly because therapy has become available recently. Therapy allows patients to develop normally rather than face dementia and death. In the longer term, we expect newborn screening to be an option for detecting this disorder.” Over a 12-year period, they have received 3882 dried blood specimens for testing tripeptidyl peptidase 1 activity. To check for

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PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 10

RNA Reprogramming Procedure Generates Induced Pluripotent Stem Cells of Patients With Fabry Disease The procedure could be used widely to help reveal the pathogeneticmechanismof various lysosomal diseases. A n RNA reprogramming procedure has been shown to generate induced pluripotent stem cells of patients with Fabry disease. Such RNA The latter then accumulate in body fluids and in the lysosomes of a variety of cell types, including capillary endothelial cells, renal cells (podocytes and tubular, glomerular endothelial, mesangial, and interstitial cells), cardiac cells (cardiomyocytes and fbroblasts), eye cells, and nerve cells.

reprogramming could be useful in uncovering the pathogenesis of numerous lysosomal diseases, fnds a controlled comparative evaluation of the procedure. Mohammad Arif Hossain, PhD, of the Advanced Clinical Research Center in Kawasaki, Kanagawa, Japan, and colleagues focused on reprogramming of RNA. Skin fibroblasts from control patients and those with Fabry disease were transfected with reprogram- ming factors (Oct4, Sox2, Klf4, cMyc, Nanog, Lin28), interferon factors (B18, E3, K3), RNA, and microRNA. Formed induced pluripotent stem cell colonies were obtained after several cell passages and studied morphologically and biochemically. Using this RNA reprogramming method, neither virus nor feeder cells are used. Induced pluripotent stem cells can be obtained efficiently and quickly. Using this method, induced pluripotent stem cells were established successfully from healthy human skin fbroblasts and fbroblasts from patients with Fabry disease. Surface markers and undifferentiated markers were expressed in these induced pluripotent stem cells, as demonstrated by immunostaining and reverse-tran- scriptase polymerase chain reaction. Dr. Hussain explained that Fabry disease is a lyso- somal metabolic disorder with X-linked inheritance caused by a deficiency of α-galactosidase. The deficiency leads to accumulation of globotriao- sylceramide in various organs. Clinical features of Fabry disease are renal, cardiac, and central nerv- ous system involvement. Slow growth (mean height/ weight <50th percentile) in pediatric males affected with Fabry disease is another documented feature of the condition. Patients with partial or complete deficiency of α-galactosidase are unable to effectively degrade glycosphingolipids, globotriaosylceramide, and glycosphingolipid-related compounds, such as gal- abiosylceramide and globotriaosylsphingosine. " Surface markers and undifferentiated markers were expressed in these induced pluripotent stem cells… "

Clinical manifestations in classically affected homozy- gotes with Fabry disease include onset of symptoms during childhood or adolescence, such as pain and paresthesia in the extremities, vessel ectasia (angiokeratoma) in the skin and mucous membranes, hypo- or anhidrosis, abdominal pain, hearing impair- ment, and cornea verticillata. With aging, renal and cardiac impairment may appear. Since enzyme replacement therapy was introduced in 2001, the current biweekly intravenous adminis- tration of recombinant human agalsidase α or β has played a major role in providing comfortable lives for patients with a pathologically missing or functionally impaired GAL gene, leading to an α-galactosidase defcit. Though enzyme replacement therapy limits the sever- ity of the disease and irreversible organ damage, the therapy is accompanied by antibody-mediated side effects. Indeed, patients with high antibody titers tend to show signifcantly higher levels of globotriaosyl- ceramide in urinary samples than patients without antibody production. The precise cellular pathogenesis of Fabry disease remains unknown. The induced pluripotent stem cell technology may be useful for the understanding of pathogenetic mechanism of lysosomal storage disease including Fabry disease. Generation of induced pluripotent stem cells has employed the Sendai virus vector or episomal vector, but these technologies require special environmental handling of viruses. Dr. Hussain concluded that generated induced pluri- potent stem cells from this cohort of patients with Fabry disease were confirmed as such cells using various markers of pluripotency. The RNA reprogramming procedure to generate induced pluripotent stem cells could be used widely with the goal of understanding the pathogenetic mechanisms of various lysosomal diseases, in addi- tion to Fabry disease.

www.practiceupdate.com/c/80597

WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 11

Elosulfase α Improves Outcomes Long Term in Patients With MPS IVA The finding is in line with previously reported data.

P atients with mucopolysaccharidosis (MPS) IVA receiving elosulfase α for ≥2 years show stable or improved patient-reported outcomes, in line with previously reported stabilization/improvement of clinical outcomes with the drug. This outcome of a 24-month assessment using sev- eral measurement tools was reported at the meeting. Jacqueline Adam, PhD, BSc, of MPS Commercial in Amersham, UK, and colleagues evaluated and reported baseline and 24-month assessments (20-month assess- ments for the Beck Depression Inventory) of patients with MPS IVA who had a managed access agreement. As of 2018, 36 patients had received treatment in the managed access agreement for ≥2 years (26 initiated treatment in clinical trials, 10 initiated in the managed access agreement). Mean treatment duration was 7 ± 1.4 and 2.1 ± 0.3 years for each group, respectively (range in clinical trial patients 4.1–8.9 years, range in patients initiating treatment in the managed access agreement 0.2–2.2 years). Among patients in the clinical trial, the fve- item EuroQol 5D (n=22) and Mucopolysaccharidosis Health Assessment Questionnaire Caregiver Domain (n=24) remained unchanged from baseline through 24 months (EuroQol 5D 5L, mean change –0.04 ± 0.29, Mucopolysaccharidosis Health Assessment Questionnaire Caregiver Domain 0.38 ± 6.27). Patients initiating treatment in the managed access agreement who completed the EuroQol

5D 5L (n=8) and Mucopolysaccharidosis Health Assessment Questionnaire Caregiver Domain (n=10) also remained unchanged (EuroQol 5D 5L 0.08 ± 0.53, Mucopolysaccharidosis Health Assessment Questionnaire Caregiver Domain –1.3 ± 16.79). From baseline through 20 months, the Beck Depression Inventory remained unchanged for clinical trial patients (n=19, –0.47 ± 2.34). Those initi- ating treatment in the managed access agreement improved (n=4, –5.75 ± 6.85). Patients in the clinical trial (n=11) and those initiating treatment in the managed access agreement (n=9) assessed using the Adolescent Pediatric Pain Tool improved from baseline through 24 months (–3.27 ± 1.62 and –2.33 ± 2.83, respectively). Only 6 patients in the clinical trial were assessed. Brief Pain Inventory results remained unchanged (–0.17 ± 2.23). No patients discontinued treatment due to intolerability or lack of efficacy. Elosulfase α is the only approved treatment for MPS IVA. In England, access to treatment is granted on a conditional basis through a managed access agreement. One criterion to continue treatment is stabilization/ improvement in quality of life/activities of daily living as assessed by patient-reported outcomes. Patient-reported outcomes assessed quality of life/activities of daily living (EuroQol 5D 5L and/ or Mucopolysaccharidosis Health Assessment

PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 12

Questionnaire Caregiver Domain, Beck Depression Inventory), and pain (Adolescent Pediatric Pain Tool or Brief Pain Inventory). Dr. Adam concluded that in the managed access agreement, patients receiving elosulfase α for ≥2 years showed stable or improved patient-reported outcomes, in line with previously reported sta- bilization/improvement of clinical outcomes with elosulfase α. Dr. Adam’s team, while collecting these patient- reported outcomes, undertook their own research to capture changes reported by patients. Patients (or parents of patients under 18 years of age) were asked to describe, in their own words, any changes they noticed after 4, 8 and 12 months on treatment and then yearly thereafter (enzyme replacement therapy-naive patients) or yearly from entry to the managed access agreement (patients who received enzyme replacement therapy previ- ously in a clinical trial). Testimonies were collected for 42 patients age 1–58 years. At 4 months, the most commonly reported changes among treatment-naive patients were: energy levels (10/49, 20%), walking/movement (9/49, 18%) and pain (8/49, 16%). At 8 months, the most commonly reported changes among treatment-naive patients were: general health (22/79, 28%), walking/movement (17/79, 22%) and energy levels (13/79, 16%).

" The findings may act as a guide to the selection of suitable tools or development of disease-specific measures for use in future studies. "

At 12 months, the most commonly reported changes among treatment-naive patients were: general health (24/95, 25%), energy levels (19/95, 20%), and sleep/ tiredness (16/95, 17%). At 12 months, the most commonly reported changes among patients in clinical trials were: energy levels (11/53, 21%), general health (10/53, 19%), and specific health benefits andwalking/movement (both 7/53, 13%). At 24 months, the most commonly reported changes among patients in clinical trials were: energy levels (4/19, 21%), walking/movement, sleep/tiredness, think- ing/learning, and general health (all 3/19, 16%). Dr. Adam concluded that the study highlights a range of outcomes important to patients’ lives. These out- comes may not be collected via current standard patient-reported outcome tools. The findings may act as a guide to the selection of suitable tools or development of disease-specific measures for use in future studies.

www.practiceupdate.com/c/80587

WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 13

Transition From Pediatric to Adult Care in Patients With MPS Needs to Be Flexible and Comprehensive Patients need to be given sufficient time to learn how the systems differ.

C omprehensive strategies are needed when transferring patients with mucopolysaccha- ridosis (MPS) from pediatric to adult care, concludes a case review. Christian J. Hendriksz, MD, MBChB, MSc, of the University of Pretoria in South Africa, and col- leagues reviewed challenges in transitioning patients with MPS from pediatric to adult care. They used case studies to highlight challenges that have emerged in such transitions. They shared best practice strategies to optimize the transition. “We were keen,” Dr. Hendriksz told Elsevier’s PracticeUpdate , “to take real life cases and illus- trate why transition in this group of patients can be more challenging than in patients with more common disorders.”

Dr. Christian J. Hendriksz

He continued, “The real issues for these patients are that most are diagnosed after a prolonged diagnostic odyssey. By the time they are diag- nosed, their trust in the medical system is low. Then suddenly they fnd an expert who understands their disorder and they get very attached. They then become experts in their disorder. They often need to educate their clinician to get appropriate care.” " We used this case study format to show both successes and failures, to enable others to learn and adapt. Our patients are diverse, as are our healthcare systems. We hope to learn from each other with the goal of developing digital tools and programs to facilitate that collaboration. Some excellent platforms could help toward this effort and empower our patients as well. "

“This need to inform their physician reinforces their mistrust in the medical profession. Then, suddenly, they are told they need to move to a new team due to their age. Many struggle with this transition. Few physicians who treat adults care for patients with mucopolysaccharidosis, so their struggles start again. Their new clinician, however, will better manage their common adult healthcare problems. We need to prepare them for this change in their care and establish systems in which our adult care colleagues can learn from us.” Six cases were provided by four leading European metabolic disease centers, including patients with MPS I, II, IIIC, and VI, age 15–18 years at first transi- tion visit (age 16–19 years at transfer to adult care). Transition processes were based on national guide- lines and institutional regulations. Strategies varied in the duration of transition periods, healthcare providers involved, and methods used to support patients and monitor their readiness for transfer to adult care. At one center, adult care was coordinated in a pedi- atric setting. At others, patient care was transferred

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from pediatric to adult care teams in different hos- pital departments or at different sites. Challenges included the attachment to pediatri- cians and the unwillingness to attend appointments with unfamiliar healthcare professionals. Limited knowledge of MPS in adult-care teams also con- cerned patients and parents. Challenges were resolved by preparing for transfer at an early stage, regularly communicating with and reassuring the patient and family, coordinating the process with MPS experts, and including multidisci- plinary input from MPS experts in adult care. Dr. Hendriksz explained that mucopolysacchari- doses are rare disorders associated with enzyme deficiencies, resulting in glycosaminoglycan accu- mulation in multiple organ systems. Improvements in diagnosis and therapy for MPS have allowed patients to survive to adulthood. A smooth transi- tion to adult care is essential. Dr. Hendriksz concluded that the cases highlight strategies needed to manage the transfer from pediatric to adult care in patients with MPS.

Transition plans should be comprehensive but exible to accommodate individual patient needs. Sufficient time should be provided to allow patients to understand the process and how the adult care system differs from the pediatric setting. Effective communication between adult and pediatric teams, as well as between patients and caregivers, is key to ensuring a smooth transition. “We need to start early,” Dr. Hendriksz added, “to reinforce that this change is an extension of their medical team, and that as they get older, their gen- eral medical needs become larger, which is why this transition is essential.” “We used this case study format to show both successes and failures, to enable others to learn and adapt. Our patients are diverse, as are our healthcare systems. We hope to learn from each other with the goal of developing digital tools and programs to facilitate that collaboration. Some excellent platforms could help toward this effort and empower our patients as well.”

www.practiceupdate.com/c/80421

WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 15