Molecular Genetics and Metabolism 114 (2015) 156–160
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Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome☆ Young Bae Sohn a, Sung Yoon Cho b, Jieun Lee b, Yonghee Kwun b, Rimm Huh b, Dong-Kyu Jin b,⁎ a b
Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 8 July 2014 Received in revised form 26 August 2014 Accepted 26 August 2014 Available online 30 August 2014 Keywords: Idursulfase beta Enzyme replacement therapy Hunter syndrome Mucopolysaccharidosis II Children
a b s t r a c t Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5 mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%) experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by −35.1 ± 30.6 mg GAG/g creatine from baseline (P = 0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare Xlinked lysosomal storage disorder caused by a deficiency of iduronate2-sulfatase (I2S), which is responsible for the catabolism of glycosaminoglycan (GAG) [1]. IDS deficiency causes lysosomal accumulation of undegraded GAG, leading to cellular damage and tissue dysfunction. The clinical course of Hunter syndrome is progressive and involves multiple organs [2,3]. The clinical phenotype is classified into attenuated and severe forms by the presence of neurologic deficit. However, the attenuated and severe phenotypes are considered the two ends of the continuous clinical spectrum [3].
☆ Clinical Trials.gov Identifier: NCT01645189. ⁎ Corresponding author at: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-ku, Seoul 135710, Republic of Korea. Fax: +82 2 3410 0043. E-mail address: [email protected] (D.-K. Jin).
http://dx.doi.org/10.1016/j.ymgme.2014.08.009 1096-7192/© 2014 Elsevier Inc. All rights reserved.
After the introduction of enzyme replacement therapy (ERT), the treatment of Hunter syndrome by human recombinant idursulfase (Elaprase®, Shire Human Genetic Therapies, Lexington, MA) has been available since 2009 in Korea. Subsequently, a successful clinical trial [4] led to the approval of idursulfase beta (Hunterase®, Green Cross Corp., Yongin, Korea) by the Korean Ministry of Food and Drug Safety. Since 2012, ERT with idursulfase beta has been available for Hunter syndrome patients aged 6 years or older in Korea. However, the previous clinical trial included only patients aged 6 years and older. Therefore, the ERT is more challenging in younger patients. Recently, the age at diagnosis is getting younger because many clinicians are paying more attention to the diagnosis of Hunter syndrome, which is treatable following the approval of ERT. The development of prenatal diagnosis techniques and some pivotal studies of newborn screening also enable early diagnosis [5–7]. In addition, sibling studies have demonstrated that early commencement of ERT is more effective than delayed therapy [8–10]. However, there have been few studies of ERT in young children with Hunter syndrome, with only case series published [11,12]. Recently, a phase IV clinical trial of the safety and effectiveness of ERT with idursulfase in young children aged 1.4–7.5 years reported
Y.B. Sohn et al. / Molecular Genetics and Metabolism 114 (2015) 156–160
that its safety and efficacy profile was similar to that observed in older patients [13]. The present clinical trial aimed to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome patients younger than 6 years. 2. Methods 2.1. Patients Six male patients younger than 6 years who had clinically and biochemically confirmed Hunter syndrome were enrolled. Patients who had undergone a bone marrow transplantation previously or who had a history of hypersensitivity or an anaphylaxis reaction to idursulfase beta were excluded. All parents or guardians of patients provided written informed consent prior to enrollment. All patients were treated with a 0.5 mg/kg/week dose of idursulfase. The mean previous ERT duration was 1.7 ± 1.2 years.
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were performed at weeks 1, 13, 25, 37, and 53. Immunogenicity was evaluated by measuring antidrug antibodies and neutralizing antibodies. Anti-idursulfase beta antibody was measured by the bridge ELISA method. Briefly, 96-well microplates were coated with idursulfase beta, which then binds antibodies to idursulfase beta present in serum samples. The antibodies were detected using idursulfase beta-HRP and the colorimetric reagent 3,3′,5,5′-tetramethylbenzidine. The other secondary endpoint was the efficacy of the drug evaluated by the mean change of urine GAG in 53 weeks from baseline. Spot morning void urine samples for GAG analysis were collected at every cycle from baseline. The amount of GAG in urine samples obtained from the calibration curve was corrected with the creatinine value from the same sample and the unit of the final results was mg GAG/g creatinine. GAG concentration was measured by a commercial Blyscan assay kit (Sulfated glycosaminoglycan assay, Biocolor, Carrickfergus, UK) according to the assay kit protocol. 2.6. Exploratory variables
2.2. Study design This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). The study was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. As all eligible patients had been treated with idursulfase, the previous treatment with idursulfase was ceased for 2 weeks prior to the first infusion of the study drug (washout period). After 2 weeks of washout, study drug infusions were administered weekly. The study period comprised 13 cycles, with each cycle consisting of 4 weeks. After completion of 52 weeks of treatment, the closing visit was done at week 53. 2.3. Idursulfase beta infusion Idursulfase beta was produced from the CHO cell line by genetic engineering yielding a glycosylated protein analogous to the native human enzyme [4,14] All study infusions were administered in the Department of Pediatrics, Samsung Medical Center. The appropriate drug dosage (0.5 mg/kg) was calculated at each visit and diluted with normal saline to yield a volume of 100 mL. The drug was administered by continuous intravenous infusion for 3–4 h. The patients were closely monitored during each infusion. If a patient developed any infusion-related reaction, including chills, fever, headache, flushing, or a skin rash, the infusion rate was decreased, and medical intervention was provided as needed. 2.4. Primary endpoint The primary endpoint was the safety of the drug evaluated by the assessment of collected adverse events (AEs). The AEs were monitored and recorded at every visit. The types of events were categorized as AE, adverse drug reaction (ADR), serious AE (SAE), and serious ADR. An SAE was defined as any event resulting in death, life-threatening AE, hospitalization, persistent disability, congenital anomaly, or birth defect. An infusion-related reaction was defined as an AE with a causal relationship to the infusion determined by the investigator. The relation of AEs to the test drug was assessed by the study investigator. The severity of AEs was rated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (grades 1–5) [15]. 2.5. Secondary endpoints One of the secondary endpoints was the safety of the drug evaluated by the assessment of vital signs, physical examinations, electrocardiogram, laboratory tests, and immunological tests. At every visit, vital signs were monitored, and physical examinations were performed. Electrocardiograms were checked at weeks 1, 29, and 53. Laboratory testing (hematology, chemistry, urinalysis) and immunological testing
Exploratory variables, including growth indices, body weight, and head circumference, were measured on day 1 of every cycle. Routine developmental milestones were assessed with the Denver developmental screening test (DDST) II [16]. Personal/social, adaptive fine motor, language, and gross motor domains were assessed. DDSTs were performed at baseline, week 29, and week 53. The results of the DDST were presented as the average of calculated quotients (the observed scores/expected scores for age) for each of the four domains in the test. 2.7. Statistical analysis All values were expressed as mean standard deviation. A paired t-test and one sample t-test were used to evaluate changes in urinary GAG excretion from baseline. Descriptive statistics were used for the other exploratory variables. All analyses were performed with SAS, Version 9.2 (Cary, NC). 3. Results Six male Hunter syndrome patients younger than 6 years were screened and enrolled. Baseline demographics and clinical characteristics are shown in Table 1. The mean age was 3.6 ± 0.8 years. The mean age at diagnosis was 2.1 ± 1.4 years. The mean weight and height at baseline were 23.2 ± 4.6 kg and 106.3 ± 1.5 cm, respectively. The mean urine GAG at diagnosis was 900.2 ± 467.1 cerylpyridinium chloride (CPC) unit/g creatinine (reference range: b175 CPC unit/g creatinine) which was measured by the CPC precipitation method [4]. The mean duration of previous ERT at baseline was 1.7 ± 1.2 years (Table 1). Of the six patients, one discontinued the study after 12 cycles (48 weeks) of infusion due to withdrawal of consent. The other five patients completed all treatment, without any missing infusions. All six patients were included in the safety and efficacy analysis population. 3.1. Primary outcome: safety assessed by AEs All reported AEs are shown in Table 2. During 52 weeks of infusion, all six patients experienced at least one AE. A total of 109 AEs were reported. There was one SAE in one patient: hospitalization due to acute gastroenteritis that was considered to be unrelated to the drug. There were no deaths or life-threatening AEs. The severity of all reported AEs was Grade 1 or 2, and there were no Grade 3, 4, or 5 AEs according to the CTCAE Version 4. The most frequently reported AEs were infections (67 cases in 6 patients, 100%), including upper respiratory tract infection (46 cases in 6 patients, 100%), gastroenteritis (6 cases in 5 patients, 83.3%), bronchitis (4 cases in 4 patients, 66.7%), sinusitis (4 cases in 4 patients, 66.7%), and otitis media (7 cases in 3 patients,
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Table 1 Demographics and clinical characteristics of patients at baseline.
Age at diagnosis (years) Urine GAG at diagnosisa (CPC unit/g creatinine) ERT duration before enrollment (years) Age at enrollment (years) Height at baseline (cm)/percentile Weight at baseline (kg)/percentile Urine GAG at baseline (mg GAG/g creatine) IDS enzyme activity (leukocyte, nmol/4 h/mg protein) Phenotype Genotype
S01
S02
S03
S04
S05
S06
1.7 1032.5 3.2 5.6 105.8/b5th 22.8/75th 156.8 0.2 Severe c.596_599delAACA (Lys199Argfs*13)
1.2 1120.9 2.0 3.3 106.8/N95th 24.5/N95th 215.7 0.13 Severe c.768delT (p.P256fs*24)
2.9 659.1 1.3 4.3 107.3/50–75th 19.8/75–90th 141.4 0.05 Attenuated c.1327C N T (p.Arg443*)
3.8 284.9 0.5 4.7 108.2/50th 31.5/N95th 144.1 Not detected Severe IDS–IDS2 recombination
3.2 671.6 0.3 3.4 104/75–90th 22.3/N95th 199.5 Not detected Severe IDS–IDS2 recombination
0.2 1632 2.8 3.2 105.8/N95th 18.3/95th 156.5 0.13 Attenuated c.1402delC (p.R468Gfs*17)
SDS, standard deviation score. CPC, cerylpyridinium chloride. a The GAG measurement at diagnosis was performed by CPC precipitation method [4].
50%). Respiratory problems including cough (5 cases in 1 patient, 16.7%) and rhinorrhea (3 cases in 3 patients, 50%) were followed. A skin rash (3 cases in 1 patient, 16.7%) and urticaria (5 cases in 1 patient, 16.7%) were also reported. Among the 109 cases of AEs, 11 (five cases of cough and six cases of urticaria) cases occurred in one patient (16.7%) and were considered infusion-related ADRs. These were easily controlled with antihistamine administration. The patient who had these ADRs (S05) had a history of infusion-related reactions during the previous ERT before enrollment. There was no severe ADR.
3.2. Secondary outcome: safety and efficacy
3.3. Exploratory variables Compared to the baseline, height was significantly increased 5.6 ± 2.4 cm (P = 0.002). Weight was also significantly increased 2.83 ± 1.3 kg (P = 0.003). Head circumference was not significantly changed (P = 0.129). Height, weight, and head circumference were recorded and compared with the normal growth curve of Korean male children (Fig. 2). At baseline, the mean DDST II quotients of the six patients were 0.6 ± 0.3, demonstrating developmental delay. Four patients had severe developmental delay, with a quotient of b 0.5. The other two patients with the attenuated phenotype had a within normal development quotient of N0.9. The mean DDST II quotient of the six patients was 0.6 ± 0.3 at week 29 and 0.5 ± 0.3 at week 53. Therefore, the results of DDST II demonstrated no significant changes in developmental milestones during the study period.
There were no clinically significant changes in vital signs, laboratory parameters, and echocardiograms. Of the six patients, four had IgG antibodies on at least one occasion during the study (Table 3). At baseline, four patients (S01, S02, S03 and S05) had antidrug antibodies or neutralizing antibodies. The antidrug antibodies of S01 disappeared at weeks 25 and 37, but were detected again with low titer at week 53. S03 showed sero-negative state from week 13. However, IgG antibodies persisted throughout the study in the other two patients (S02 and S05). S05 had antidrug IgG antibodies with a high titer compared to the other three antibody-positive patients. Two patients (S04 and S06), who did not have antidrug antibodies at baseline, never developed the antibodies. Therefore, there was no newly developed antibody after idursulfase beta treatment. The change of urine GAG was analyzed as an efficacy variable. The baseline urine GAG was 169.0 ± 31.0 mg GAG/g creatine. The mean urine GAG was decreased at cycle 1 (week 5), and the reduction remained throughout the 53 weeks. At week 53, the urine GAG was 133.9 ± 37.7 mg GAG/g creatine, which was reduced compared to baseline by −35.1 ± 30.6 mg GAG/g creatine (P = 0.038) (Fig. 1). The percentile change was − 20.6 ± 20.7%, which was not statistically significant (P = 0.058).
The primary aim of this study was to evaluate the safety of idursulfase beta in the treatment of young children (b6 years) with Hunter syndrome. During 52 weeks of infusion, all six patients experienced at least one AE. Eleven of the reported 109 AEs occurred in one patient (16.7%) and were considered ADRs. The severity of the reported AEs, including ADRs, was mild and tolerable. Although the population in this study is small, the rate of ADRs is consistent with that reported previously (10%) in Hunter syndrome patients aged 6 years and older treated with 0.5 mg/kg/week of idursulfase beta ERT [4]. In addition, a previous case series [11] and a recent clinical trial of idursulfase treatment in young children [13] reported a similar safety profile to this study. All the patients in this study had a mean 1.7 ± 1.2 years of ERT, and four (66.7%) had anti-drug antibodies and neutralizing antibodies at baseline. This finding is consistent with a previous study, which
Table 2 Summary of adverse events.
Table 3 Immunologic evaluation.
AE ADR SAE Death
Patients (%)
Case
Comment
6 (100) 1 (16.7) 1 (16.7) 0
109 11 1 0
Urticaria (6), cough (5) Hospitalization due to acute gastroenteritisa
AE, adverse event. ADR, adverse drug reaction. SAE, serious adverse event. a Considered not related with the drug.
4. Discussion
S01 S02 S03 S04 S05 S06
Previous ERT duration (month)
Week 1
Week 13
Week 25
Week 37
Week 53
38 24 16 6 3 34
4 (+) 4 (+) 4 (+) – 12 (+) –
2 (+) 4 (+) – – 32 (+) –
– 5 (+) – – 48 (+) –
– 7 (+) – – 40 (+) –
2 (+) 5 (−) – – 45 (+) –
Antidrug antibody titer (neutralizing antibody).
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Fig. 1. Reduction of urine GAG. Urine GAG was reduced after cycle 1 (week 5), and the decrease was maintained throughout the 53 weeks. At week 53, the urine GAG was significantly reduced compared to baseline by −35.1 ± 30.6 mg GAG/g creatine (P = 0.038).
reported a detection rate of 67.9% for IgG antibody and 53.6% for neutralizing antibody in children who underwent ERT with idursulfase [13]. In terms of efficacy, the 0.5 mg/kg/week treatment of idursulfase beta in patients under 6 years significantly reduced urine GAG by − 35.1 ± 30.6 mg GAG/g creatine at week 53 (P = 0.038). In a previous clinical trial of idursulfase beta in patients aged 6 years and older, the % reduction of urine GAG was − 29.5 ± 15.5% [4]. However, in the present study, the % change was − 20.6 ± 20.7% although it was not statistically significant (P = 0.058) in this study. It might be influenced by the small study population and the patient who had high titer of anti-drug antibodies and also neutralizing antibodies. Unlike adult patients, growth and development should be carefully monitored when treating children with Hunter syndrome. Studies have shown that the natural growth pattern of untreated Hunter syndrome patients tends to be within the normal range and that they may be tall for their age until approximately 5 years; from approximately 8–10 years, they become shorter than normal children [17–21]. The findings of this study are consistent with the literature, with the patients' heights and weights within the normal range or greater than the 97th percentile at baseline compared to the standard growth curve of Korean boys. Significant increases in height and weight observed during the study were regarded as normal growth velocity in this age population. Previous studies reported a positive effect of ERT in children with Hunter syndrome [22,23]. However, continuous follow-up is needed to evaluate the long-term effects of ERT on the growth of Hunter syndrome children. Our study population was young, and it was not clear whether they had neurological involvement. However, four patients in our study population had a severe phenotype because they already showed developmental delay. The calculated DDST II quotients of these four patients were 0.4 ± 0.3, and there were no significant changes in the DDST II quotients after 53 weeks of ERT. As the neurologic deterioration of the Hunter syndrome is progressive, neurologic function should be monitored for extended period. The limitation of this study is the small number of patients in the study population. However, Hunter syndrome is a rare disease, and the diagnosis of the syndrome in children younger than 6 years is very rare. In addition, despite the 2-week washout period, all the patients had a history of ERT. Therefore, the influence of the previous treatment should be considered in the interpretation of the results. Further studies in treatment-naive patients are warranted.
Fig. 2. Growth chart. The growth chart of the height (A), weight (B), and head circumference (C) during study period. The dotted lines represent 5th, 50th, and 95th percentiles of standard growth curve of normal Korean boys, respectively.
In conclusion, although the study population was small, the safety and efficacy profile of 0.5 mg/kg/week of idursulfase beta infusion was similar to that reported previously for Hunter syndrome patients aged 6 years and older. This result is valuable as it demonstrates that ERT with idursulfase beta can be initiated and maintained tolerably in pediatric patients under 6 years with close monitoring of AEs.
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Conflict of interest All of the authors have nothing to disclose. Acknowledgments This study was supported by grant (#PHO1121123) from Green Cross Corp. (Yongin, Korea) and Samsung Medical Center grant (#GFO1140061). References [1] F.N.M.J. Neufeld (Ed.), The Metabolic and Molecular Basis of Inherited Disease, 8th editionMcGraw-Hill, New York, 2001. [2] R. Martin, M. Beck, C. Eng, R. Giugliani, P. Harmatz, V. Munoz, J. Muenzer, Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome), Pediatrics 121 (2008) e377–e386. [3] J.E. Wraith, M. Scarpa, M. Beck, O.A. Bodamer, L. De Meirleir, N. Guffon, A. Meldgaard Lund, G. Malm, A.T. Van der Ploeg, J. Zeman, Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy, Eur. J. Pediatr. 167 (2008) 267–277. [4] Y.B. Sohn, S.Y. Cho, S.W. Park, S.J. Kim, A.R. Ko, E.K. Kwon, S.J. Han, D.K. Jin, Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome), Orphanet J. Rare Dis. 8 (2013) 42. [5] K. Nakamura, K. Hattori, F. Endo, Newborn screening for lysosomal storage disorders, Am. J. Med. Genet. C: Semin. Med. Genet. 157C (2011) 63–71. [6] G.J. Ruijter, D.A. Goudriaan, A.M. Boer, J. Van den Bosch, A.T. Van der Ploeg, L.H. Elvers, S.S. Weinreich, A.J. Reuser, Newborn Screening for Hunter Disease: A Small-Scale Feasibility Study JIMD reports, 2013. [7] S. Tomatsu, T. Fujii, M. Fukushi, T. Oguma, T. Shimada, M. Maeda, K. Kida, Y. Shibata, H. Futatsumori, A.M. Montano, R.W. Mason, S. Yamaguchi, Y. Suzuki, T. Orii, Newborn screening and diagnosis of mucopolysaccharidoses, Mol. Genet. Metab. 110 (2013) 42–53. [8] M. Furujo, T. Kubo, M. Kosuga, T. Okuyama, Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI, Mol. Genet. Metab. 104 (2011) 597–602. [9] J.J. McGill, A.C. Inwood, D.J. Coman, M.L. Lipke, D. de Lore, S.J. Swiedler, J.J. Hopwood, Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age — a sibling control study, Clin. Genet. 77 (2010) 492–498. [10] J. Muenzer, Early initiation of enzyme replacement therapy for the mucopolysaccharidoses, Mol. Genet. Metab. 111 (2014) 63–72.
[11] National Cancer Institute, Common terminology criteria for adverse events v4.0, NIH Publication #09-74732009. [12] C. Lampe, A. Atherton, B.K. Burton, M. Descartes, R. Giugliani, D.D. Horovitz, S.O. Kyosen, T.S. Magalhaes, A.M. Martins, N.J. Mendelsohn, J. Muenzer, L.D. Smith, Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age JIMD Reports, 2014. [13] R. Giugliani, W.L. Hwu, A. Tylki-Szymanska, D.A. Whiteman, A. Pano, A multicenter, open-label study evaluating safety and clinical outcomes in children (1.4–7.5 years) with Hunter syndrome receiving idursulfase enzyme replacement therapy, Genet. Med. Off. J. Am. Coll. Med. Genet. 16 (2014) 435–441. [14] Y.K. Chung, Y.B. Sohn, J.M. Sohn, J. Lee, M.S. Chang, Y. Kwun, C.H. Kim, J.Y. Lee, Y.J. Yook, A.R. Ko, D.K. Jin, A biochemical and physicochemical comparison of two recombinant enzymes used for enzyme replacement therapies of hunter syndrome, Glycoconj. J. 31 (2014) 309–315. [15] E. Nii, M. Urawa, T. Nshimura, H. Kitou, S. Ikegawa, S. Shimizu, H. Taneda, A. Uchida, N. Niikawa, Acrodysostosis with unusual iridal color changing with age, Am. J. Med. Genet. B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet. 144B (2007) 824–825. [16] W.K. Frankenburg, J. Dodds, P. Archer, H. Shapiro, B. Bresnick, The Denver II: a major revision and restandardization of the Denver Developmental Screening Test, Pediatrics 89 (1992) 91–97. [17] I.V. Schwartz, M.G. Ribeiro, J.G. Mota, M.B. Toralles, P. Correia, D. Horovitz, E.S. Santos, I.L. Monlleo, A.C. Fett-Conte, R.P. Sobrinho, D.Y. Norato, A.C. Paula, C.A. Kim, A.R. Duarte, R. Boy, E. Valadares, M. De Michelena, P. Mabe, C.D. Martinhago, J.M. Pina-Neto, F. Kok, S. Leistner-Segal, M.G. Burin, R. Giugliani, A clinical study of 77 patients with mucopolysaccharidosis type II, Acta paediatrica (Oslo, Norway: 1992), Supplement 962007. 63–70. [18] J.E. Wraith, M. Beck, R. Giugliani, J. Clarke, R. Martin, J. Muenzer, Initial report from the Hunter Outcome Survey, Genet. Med. Off. J. Am. Coll. Med. Genet. 10 (2008) 508–516. [19] I.D. Young, P.S. Harper, Mild form of Hunter's syndrome: clinical delineation based on 31 cases, Arch. Dis. Child. 57 (1982) 828–836. [20] I.D. Young, P.S. Harper, The natural history of the severe form of Hunter's syndrome: a study based on 52 cases, Dev. Med. Child Neurol. 25 (1983) 481–489. [21] A. Rozdzynska, A. Tylki-Szymanska, A. Jurecka, J. Cieslik, Growth pattern and growth prediction of body height in children with mucopolysaccharidosis type II, Acta paediatrica (Oslo, Norway: 1992), 1002011. 456–460. [22] S.Y. Cho, R. Huh, M.S. Chang, J. Lee, Y. Kwun, S.H. Maeng, S.J. Kim, Y.B. Sohn, S.W. Park, E.K. Kwon, S.J. Han, J. Jung, D.K. Jin, Impact of enzyme replacement therapy on linear growth in Korean patients with mucopolysaccharidosis type II (Hunter syndrome), J. Korean Med. Sci. 29 (2014) 254–260. [23] G. Schulze-Frenking, S.A. Jones, J. Roberts, M. Beck, J.E. Wraith, Effects of enzyme replacement therapy on growth in patients with mucopolysaccharidosis type II, J. Inherit. Metab. Dis. 34 (2011) 203–208.
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome☆ Young Bae Sohn a, Sung Yoon Cho b, Jieun Lee b, Yonghee Kwun b, Rimm Huh b, Dong-Kyu Jin b,⁎ a b
Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 8 July 2014 Received in revised form 26 August 2014 Accepted 26 August 2014 Available online 30 August 2014 Keywords: Idursulfase beta Enzyme replacement therapy Hunter syndrome Mucopolysaccharidosis II Children
a b s t r a c t Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5 mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%) experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by −35.1 ± 30.6 mg GAG/g creatine from baseline (P = 0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare Xlinked lysosomal storage disorder caused by a deficiency of iduronate2-sulfatase (I2S), which is responsible for the catabolism of glycosaminoglycan (GAG) [1]. IDS deficiency causes lysosomal accumulation of undegraded GAG, leading to cellular damage and tissue dysfunction. The clinical course of Hunter syndrome is progressive and involves multiple organs [2,3]. The clinical phenotype is classified into attenuated and severe forms by the presence of neurologic deficit. However, the attenuated and severe phenotypes are considered the two ends of the continuous clinical spectrum [3].
☆ Clinical Trials.gov Identifier: NCT01645189. ⁎ Corresponding author at: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-ku, Seoul 135710, Republic of Korea. Fax: +82 2 3410 0043. E-mail address: [email protected] (D.-K. Jin).
http://dx.doi.org/10.1016/j.ymgme.2014.08.009 1096-7192/© 2014 Elsevier Inc. All rights reserved.
After the introduction of enzyme replacement therapy (ERT), the treatment of Hunter syndrome by human recombinant idursulfase (Elaprase®, Shire Human Genetic Therapies, Lexington, MA) has been available since 2009 in Korea. Subsequently, a successful clinical trial [4] led to the approval of idursulfase beta (Hunterase®, Green Cross Corp., Yongin, Korea) by the Korean Ministry of Food and Drug Safety. Since 2012, ERT with idursulfase beta has been available for Hunter syndrome patients aged 6 years or older in Korea. However, the previous clinical trial included only patients aged 6 years and older. Therefore, the ERT is more challenging in younger patients. Recently, the age at diagnosis is getting younger because many clinicians are paying more attention to the diagnosis of Hunter syndrome, which is treatable following the approval of ERT. The development of prenatal diagnosis techniques and some pivotal studies of newborn screening also enable early diagnosis [5–7]. In addition, sibling studies have demonstrated that early commencement of ERT is more effective than delayed therapy [8–10]. However, there have been few studies of ERT in young children with Hunter syndrome, with only case series published [11,12]. Recently, a phase IV clinical trial of the safety and effectiveness of ERT with idursulfase in young children aged 1.4–7.5 years reported
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that its safety and efficacy profile was similar to that observed in older patients [13]. The present clinical trial aimed to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome patients younger than 6 years. 2. Methods 2.1. Patients Six male patients younger than 6 years who had clinically and biochemically confirmed Hunter syndrome were enrolled. Patients who had undergone a bone marrow transplantation previously or who had a history of hypersensitivity or an anaphylaxis reaction to idursulfase beta were excluded. All parents or guardians of patients provided written informed consent prior to enrollment. All patients were treated with a 0.5 mg/kg/week dose of idursulfase. The mean previous ERT duration was 1.7 ± 1.2 years.
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were performed at weeks 1, 13, 25, 37, and 53. Immunogenicity was evaluated by measuring antidrug antibodies and neutralizing antibodies. Anti-idursulfase beta antibody was measured by the bridge ELISA method. Briefly, 96-well microplates were coated with idursulfase beta, which then binds antibodies to idursulfase beta present in serum samples. The antibodies were detected using idursulfase beta-HRP and the colorimetric reagent 3,3′,5,5′-tetramethylbenzidine. The other secondary endpoint was the efficacy of the drug evaluated by the mean change of urine GAG in 53 weeks from baseline. Spot morning void urine samples for GAG analysis were collected at every cycle from baseline. The amount of GAG in urine samples obtained from the calibration curve was corrected with the creatinine value from the same sample and the unit of the final results was mg GAG/g creatinine. GAG concentration was measured by a commercial Blyscan assay kit (Sulfated glycosaminoglycan assay, Biocolor, Carrickfergus, UK) according to the assay kit protocol. 2.6. Exploratory variables
2.2. Study design This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). The study was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. As all eligible patients had been treated with idursulfase, the previous treatment with idursulfase was ceased for 2 weeks prior to the first infusion of the study drug (washout period). After 2 weeks of washout, study drug infusions were administered weekly. The study period comprised 13 cycles, with each cycle consisting of 4 weeks. After completion of 52 weeks of treatment, the closing visit was done at week 53. 2.3. Idursulfase beta infusion Idursulfase beta was produced from the CHO cell line by genetic engineering yielding a glycosylated protein analogous to the native human enzyme [4,14] All study infusions were administered in the Department of Pediatrics, Samsung Medical Center. The appropriate drug dosage (0.5 mg/kg) was calculated at each visit and diluted with normal saline to yield a volume of 100 mL. The drug was administered by continuous intravenous infusion for 3–4 h. The patients were closely monitored during each infusion. If a patient developed any infusion-related reaction, including chills, fever, headache, flushing, or a skin rash, the infusion rate was decreased, and medical intervention was provided as needed. 2.4. Primary endpoint The primary endpoint was the safety of the drug evaluated by the assessment of collected adverse events (AEs). The AEs were monitored and recorded at every visit. The types of events were categorized as AE, adverse drug reaction (ADR), serious AE (SAE), and serious ADR. An SAE was defined as any event resulting in death, life-threatening AE, hospitalization, persistent disability, congenital anomaly, or birth defect. An infusion-related reaction was defined as an AE with a causal relationship to the infusion determined by the investigator. The relation of AEs to the test drug was assessed by the study investigator. The severity of AEs was rated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (grades 1–5) [15]. 2.5. Secondary endpoints One of the secondary endpoints was the safety of the drug evaluated by the assessment of vital signs, physical examinations, electrocardiogram, laboratory tests, and immunological tests. At every visit, vital signs were monitored, and physical examinations were performed. Electrocardiograms were checked at weeks 1, 29, and 53. Laboratory testing (hematology, chemistry, urinalysis) and immunological testing
Exploratory variables, including growth indices, body weight, and head circumference, were measured on day 1 of every cycle. Routine developmental milestones were assessed with the Denver developmental screening test (DDST) II [16]. Personal/social, adaptive fine motor, language, and gross motor domains were assessed. DDSTs were performed at baseline, week 29, and week 53. The results of the DDST were presented as the average of calculated quotients (the observed scores/expected scores for age) for each of the four domains in the test. 2.7. Statistical analysis All values were expressed as mean standard deviation. A paired t-test and one sample t-test were used to evaluate changes in urinary GAG excretion from baseline. Descriptive statistics were used for the other exploratory variables. All analyses were performed with SAS, Version 9.2 (Cary, NC). 3. Results Six male Hunter syndrome patients younger than 6 years were screened and enrolled. Baseline demographics and clinical characteristics are shown in Table 1. The mean age was 3.6 ± 0.8 years. The mean age at diagnosis was 2.1 ± 1.4 years. The mean weight and height at baseline were 23.2 ± 4.6 kg and 106.3 ± 1.5 cm, respectively. The mean urine GAG at diagnosis was 900.2 ± 467.1 cerylpyridinium chloride (CPC) unit/g creatinine (reference range: b175 CPC unit/g creatinine) which was measured by the CPC precipitation method [4]. The mean duration of previous ERT at baseline was 1.7 ± 1.2 years (Table 1). Of the six patients, one discontinued the study after 12 cycles (48 weeks) of infusion due to withdrawal of consent. The other five patients completed all treatment, without any missing infusions. All six patients were included in the safety and efficacy analysis population. 3.1. Primary outcome: safety assessed by AEs All reported AEs are shown in Table 2. During 52 weeks of infusion, all six patients experienced at least one AE. A total of 109 AEs were reported. There was one SAE in one patient: hospitalization due to acute gastroenteritis that was considered to be unrelated to the drug. There were no deaths or life-threatening AEs. The severity of all reported AEs was Grade 1 or 2, and there were no Grade 3, 4, or 5 AEs according to the CTCAE Version 4. The most frequently reported AEs were infections (67 cases in 6 patients, 100%), including upper respiratory tract infection (46 cases in 6 patients, 100%), gastroenteritis (6 cases in 5 patients, 83.3%), bronchitis (4 cases in 4 patients, 66.7%), sinusitis (4 cases in 4 patients, 66.7%), and otitis media (7 cases in 3 patients,
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Table 1 Demographics and clinical characteristics of patients at baseline.
Age at diagnosis (years) Urine GAG at diagnosisa (CPC unit/g creatinine) ERT duration before enrollment (years) Age at enrollment (years) Height at baseline (cm)/percentile Weight at baseline (kg)/percentile Urine GAG at baseline (mg GAG/g creatine) IDS enzyme activity (leukocyte, nmol/4 h/mg protein) Phenotype Genotype
S01
S02
S03
S04
S05
S06
1.7 1032.5 3.2 5.6 105.8/b5th 22.8/75th 156.8 0.2 Severe c.596_599delAACA (Lys199Argfs*13)
1.2 1120.9 2.0 3.3 106.8/N95th 24.5/N95th 215.7 0.13 Severe c.768delT (p.P256fs*24)
2.9 659.1 1.3 4.3 107.3/50–75th 19.8/75–90th 141.4 0.05 Attenuated c.1327C N T (p.Arg443*)
3.8 284.9 0.5 4.7 108.2/50th 31.5/N95th 144.1 Not detected Severe IDS–IDS2 recombination
3.2 671.6 0.3 3.4 104/75–90th 22.3/N95th 199.5 Not detected Severe IDS–IDS2 recombination
0.2 1632 2.8 3.2 105.8/N95th 18.3/95th 156.5 0.13 Attenuated c.1402delC (p.R468Gfs*17)
SDS, standard deviation score. CPC, cerylpyridinium chloride. a The GAG measurement at diagnosis was performed by CPC precipitation method [4].
50%). Respiratory problems including cough (5 cases in 1 patient, 16.7%) and rhinorrhea (3 cases in 3 patients, 50%) were followed. A skin rash (3 cases in 1 patient, 16.7%) and urticaria (5 cases in 1 patient, 16.7%) were also reported. Among the 109 cases of AEs, 11 (five cases of cough and six cases of urticaria) cases occurred in one patient (16.7%) and were considered infusion-related ADRs. These were easily controlled with antihistamine administration. The patient who had these ADRs (S05) had a history of infusion-related reactions during the previous ERT before enrollment. There was no severe ADR.
3.2. Secondary outcome: safety and efficacy
3.3. Exploratory variables Compared to the baseline, height was significantly increased 5.6 ± 2.4 cm (P = 0.002). Weight was also significantly increased 2.83 ± 1.3 kg (P = 0.003). Head circumference was not significantly changed (P = 0.129). Height, weight, and head circumference were recorded and compared with the normal growth curve of Korean male children (Fig. 2). At baseline, the mean DDST II quotients of the six patients were 0.6 ± 0.3, demonstrating developmental delay. Four patients had severe developmental delay, with a quotient of b 0.5. The other two patients with the attenuated phenotype had a within normal development quotient of N0.9. The mean DDST II quotient of the six patients was 0.6 ± 0.3 at week 29 and 0.5 ± 0.3 at week 53. Therefore, the results of DDST II demonstrated no significant changes in developmental milestones during the study period.
There were no clinically significant changes in vital signs, laboratory parameters, and echocardiograms. Of the six patients, four had IgG antibodies on at least one occasion during the study (Table 3). At baseline, four patients (S01, S02, S03 and S05) had antidrug antibodies or neutralizing antibodies. The antidrug antibodies of S01 disappeared at weeks 25 and 37, but were detected again with low titer at week 53. S03 showed sero-negative state from week 13. However, IgG antibodies persisted throughout the study in the other two patients (S02 and S05). S05 had antidrug IgG antibodies with a high titer compared to the other three antibody-positive patients. Two patients (S04 and S06), who did not have antidrug antibodies at baseline, never developed the antibodies. Therefore, there was no newly developed antibody after idursulfase beta treatment. The change of urine GAG was analyzed as an efficacy variable. The baseline urine GAG was 169.0 ± 31.0 mg GAG/g creatine. The mean urine GAG was decreased at cycle 1 (week 5), and the reduction remained throughout the 53 weeks. At week 53, the urine GAG was 133.9 ± 37.7 mg GAG/g creatine, which was reduced compared to baseline by −35.1 ± 30.6 mg GAG/g creatine (P = 0.038) (Fig. 1). The percentile change was − 20.6 ± 20.7%, which was not statistically significant (P = 0.058).
The primary aim of this study was to evaluate the safety of idursulfase beta in the treatment of young children (b6 years) with Hunter syndrome. During 52 weeks of infusion, all six patients experienced at least one AE. Eleven of the reported 109 AEs occurred in one patient (16.7%) and were considered ADRs. The severity of the reported AEs, including ADRs, was mild and tolerable. Although the population in this study is small, the rate of ADRs is consistent with that reported previously (10%) in Hunter syndrome patients aged 6 years and older treated with 0.5 mg/kg/week of idursulfase beta ERT [4]. In addition, a previous case series [11] and a recent clinical trial of idursulfase treatment in young children [13] reported a similar safety profile to this study. All the patients in this study had a mean 1.7 ± 1.2 years of ERT, and four (66.7%) had anti-drug antibodies and neutralizing antibodies at baseline. This finding is consistent with a previous study, which
Table 2 Summary of adverse events.
Table 3 Immunologic evaluation.
AE ADR SAE Death
Patients (%)
Case
Comment
6 (100) 1 (16.7) 1 (16.7) 0
109 11 1 0
Urticaria (6), cough (5) Hospitalization due to acute gastroenteritisa
AE, adverse event. ADR, adverse drug reaction. SAE, serious adverse event. a Considered not related with the drug.
4. Discussion
S01 S02 S03 S04 S05 S06
Previous ERT duration (month)
Week 1
Week 13
Week 25
Week 37
Week 53
38 24 16 6 3 34
4 (+) 4 (+) 4 (+) – 12 (+) –
2 (+) 4 (+) – – 32 (+) –
– 5 (+) – – 48 (+) –
– 7 (+) – – 40 (+) –
2 (+) 5 (−) – – 45 (+) –
Antidrug antibody titer (neutralizing antibody).
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Fig. 1. Reduction of urine GAG. Urine GAG was reduced after cycle 1 (week 5), and the decrease was maintained throughout the 53 weeks. At week 53, the urine GAG was significantly reduced compared to baseline by −35.1 ± 30.6 mg GAG/g creatine (P = 0.038).
reported a detection rate of 67.9% for IgG antibody and 53.6% for neutralizing antibody in children who underwent ERT with idursulfase [13]. In terms of efficacy, the 0.5 mg/kg/week treatment of idursulfase beta in patients under 6 years significantly reduced urine GAG by − 35.1 ± 30.6 mg GAG/g creatine at week 53 (P = 0.038). In a previous clinical trial of idursulfase beta in patients aged 6 years and older, the % reduction of urine GAG was − 29.5 ± 15.5% [4]. However, in the present study, the % change was − 20.6 ± 20.7% although it was not statistically significant (P = 0.058) in this study. It might be influenced by the small study population and the patient who had high titer of anti-drug antibodies and also neutralizing antibodies. Unlike adult patients, growth and development should be carefully monitored when treating children with Hunter syndrome. Studies have shown that the natural growth pattern of untreated Hunter syndrome patients tends to be within the normal range and that they may be tall for their age until approximately 5 years; from approximately 8–10 years, they become shorter than normal children [17–21]. The findings of this study are consistent with the literature, with the patients' heights and weights within the normal range or greater than the 97th percentile at baseline compared to the standard growth curve of Korean boys. Significant increases in height and weight observed during the study were regarded as normal growth velocity in this age population. Previous studies reported a positive effect of ERT in children with Hunter syndrome [22,23]. However, continuous follow-up is needed to evaluate the long-term effects of ERT on the growth of Hunter syndrome children. Our study population was young, and it was not clear whether they had neurological involvement. However, four patients in our study population had a severe phenotype because they already showed developmental delay. The calculated DDST II quotients of these four patients were 0.4 ± 0.3, and there were no significant changes in the DDST II quotients after 53 weeks of ERT. As the neurologic deterioration of the Hunter syndrome is progressive, neurologic function should be monitored for extended period. The limitation of this study is the small number of patients in the study population. However, Hunter syndrome is a rare disease, and the diagnosis of the syndrome in children younger than 6 years is very rare. In addition, despite the 2-week washout period, all the patients had a history of ERT. Therefore, the influence of the previous treatment should be considered in the interpretation of the results. Further studies in treatment-naive patients are warranted.
Fig. 2. Growth chart. The growth chart of the height (A), weight (B), and head circumference (C) during study period. The dotted lines represent 5th, 50th, and 95th percentiles of standard growth curve of normal Korean boys, respectively.
In conclusion, although the study population was small, the safety and efficacy profile of 0.5 mg/kg/week of idursulfase beta infusion was similar to that reported previously for Hunter syndrome patients aged 6 years and older. This result is valuable as it demonstrates that ERT with idursulfase beta can be initiated and maintained tolerably in pediatric patients under 6 years with close monitoring of AEs.
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Conflict of interest All of the authors have nothing to disclose. Acknowledgments This study was supported by grant (#PHO1121123) from Green Cross Corp. (Yongin, Korea) and Samsung Medical Center grant (#GFO1140061). References [1] F.N.M.J. Neufeld (Ed.), The Metabolic and Molecular Basis of Inherited Disease, 8th editionMcGraw-Hill, New York, 2001. [2] R. Martin, M. Beck, C. Eng, R. Giugliani, P. Harmatz, V. Munoz, J. Muenzer, Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome), Pediatrics 121 (2008) e377–e386. [3] J.E. Wraith, M. Scarpa, M. Beck, O.A. Bodamer, L. De Meirleir, N. Guffon, A. Meldgaard Lund, G. Malm, A.T. Van der Ploeg, J. Zeman, Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy, Eur. J. Pediatr. 167 (2008) 267–277. [4] Y.B. Sohn, S.Y. Cho, S.W. Park, S.J. Kim, A.R. Ko, E.K. Kwon, S.J. Han, D.K. Jin, Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome), Orphanet J. Rare Dis. 8 (2013) 42. [5] K. Nakamura, K. Hattori, F. Endo, Newborn screening for lysosomal storage disorders, Am. J. Med. Genet. C: Semin. Med. Genet. 157C (2011) 63–71. [6] G.J. Ruijter, D.A. Goudriaan, A.M. Boer, J. Van den Bosch, A.T. Van der Ploeg, L.H. Elvers, S.S. Weinreich, A.J. Reuser, Newborn Screening for Hunter Disease: A Small-Scale Feasibility Study JIMD reports, 2013. [7] S. Tomatsu, T. Fujii, M. Fukushi, T. Oguma, T. Shimada, M. Maeda, K. Kida, Y. Shibata, H. Futatsumori, A.M. Montano, R.W. Mason, S. Yamaguchi, Y. Suzuki, T. Orii, Newborn screening and diagnosis of mucopolysaccharidoses, Mol. Genet. Metab. 110 (2013) 42–53. [8] M. Furujo, T. Kubo, M. Kosuga, T. Okuyama, Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI, Mol. Genet. Metab. 104 (2011) 597–602. [9] J.J. McGill, A.C. Inwood, D.J. Coman, M.L. Lipke, D. de Lore, S.J. Swiedler, J.J. Hopwood, Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age — a sibling control study, Clin. Genet. 77 (2010) 492–498. [10] J. Muenzer, Early initiation of enzyme replacement therapy for the mucopolysaccharidoses, Mol. Genet. Metab. 111 (2014) 63–72.
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