Design of 3 multicenter, phase 3, randomized trials to evaluate efficacy and safety of the enzyme replacement therapy efzimfotase alfa in patients with hypophosphatasia (HICKORY, MULBERRY, CHESTNUT)

Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in functional deficiency of alpha-galactosidase A (α-Gal A); the accumulation of lysosomal α-Gal A substrates can lead to multisystem disease and early death (Germain, 2010; Mehta et al., 2010; Waldek, Patel, Banikazemi, Lemay, & Lee, 2009). Until recently, treatment options were limited to enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta administered via infusion every 2 weeks (Gaggl & Sunder-Plassmann, 2016). Migalastat is a first-in-class, small-molecule pharmacological chaperone that binds to and stabilizes amenable mutant forms of α-Gal A in the endoplasmic reticulum, facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates (Benjamin et al., 2009; Germain et al., 2016; Germain & Fan, 2009; Ishii et al., 2007; Khanna et al., 2010; Yam, Zuber, & Roth, 2005). It is estimated that 35–50% of patients with Fabry disease have migalastat-amenable mutations (Hughes et al., 2017). As of July 23, 2018, the total exposure to migalastat in the Phase 2 and 3 clinical programs was 660 patient-years, with 128 patients exposed ≥1 year (Data on file. Amicus Therapeutics Inc., 2018). The efficacy and safety of migalastat in patients with Fabry disease who have amenable GLA mutations have been established in both placebo and active-controlled clinical trials and long-term open-label extension studies (Germain et al., 2016; Germain et al., 2018; Hughes et al., 2017; Nicholls et al., 2018). Oral migalastat has been approved in the European Union, Switzerland, Australia, Israel, Republic of Korea, and Japan for long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-Gal A deficiency) who have a migalastat-amenable GLA mutation (Amicus Therapeutics Inc., 2018). Migalastat is also approved in the United States and Canada for adults (aged 18 years and older; Amicus Therapeutics U.S., Inc., 2018; Amicus Therapeutics UK Ltd., 2017). We previously reported on Part 1 of the Phase 3 ATTRACT study (AT1001-012; NCT01218659), an 18-month randomized treatment comparison that demonstrated comparable efficacy of migalastat (Cohort 1) and ERT (Cohort 2) in male and female patients with Fabry disease previously treated with ERT for >12 months (Hughes et al., 2017). During Part 2 of the ATTRACT study, patients in both cohorts could receive migalastat for an additional 12 months during the optional open-label extension (OLE). Therefore, both cohorts switched from ERT to migalastat (at baseline for patients randomized at study entry to migalastat [Cohort 1] or month 18 for those randomized to ERT [Cohort 2]). In this article, we assess the safety of switching from ERT to migalastat by evaluating the incidence of adverse events, laboratory assessments, and concomitant medications following switching in both cohorts within the safety population. At study entry, patients ranged in age from 18 to 72 years with a mean age of 49 years; 56% were female (Hughes et al., 2017). Demographics were balanced between cohorts. Mean time since Fabry diagnosis was 11.4 years, and most patients (88%) had multi-organ disease (including nervous system [81%], cardiac [71%], gastrointestinal [61%], and renal/urinary [75%] involvement (Hughes et al., 2017); renal/urinary involvement was defined as having any of the following: a medical history of renal or urinary disorders, decreased estimated glomerular filtration rate (eGFR <90 mL/min/1.73 m2; ~44% of adults aged 40 to 59 have an eGFR below this cutoff [National Kidney Foundation, 2002]), or 24-hr urine protein ≥150 mg). Eight patients had a history of premedication for ERT infusion-associated reactions (IARs; n = 5 in Cohort 1; n = 3 in Cohort 2); 2 patients in Cohort 2 continued IAR prophylaxis during on-study ERT. Fifty-one patients switched from ERT to migalastat: 36 patients in Cohort 1 (Part 1) and 15 patients in Cohort 2 (Part 2/OLE). Most patients continued migalastat treatment until Month 30 (30/36 in Cohort 1 and 12/15 in Cohort 2). Cohort 1 patients switched to migalastat treatment at baseline, by which time most patients had received >2 years of ERT (mean, 3.5 years; Table 1). Prior ERT characteristics were similar between male and female patients. In patients for whom the data were available, migalastat was started 4 to 19 days after their last ERT infusion. The most common treatment-emergent adverse events (AEs) in Cohort 1 (occurring in ≥20% of patients) during the first 18 months were nasopharyngitis (33%) and headache (25%; Table 2), and during the full 30 months were nasopharyngitis (42%), headache (36%), and influenza (27%; Table 2). AEs were generally mild or moderate; no patient discontinued due to an AE. There were no clinically meaningful changes in mean values from baseline for hematology, serum chemistry, urinalysis analysis, and vital signs (Supporting Information Table S1). Thirty-four (94%) Cohort 1 patients started a new medication during months 0–30. The most common new concomitant mediations were amoxicillin (22%), ibuprofen (19%), paracetamol (19%), amoxicillin with clavulanic acid (11%), and temazepam (11%). Only two (6%) patients started a new angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or renin inhibitor. Overall, based on a review of AEs, laboratory measures, and concomitant medications in Cohort 1, migalastat was well tolerated after patients switched from ERT. Cohort 2 patients switched treatment at Month 18, after most patients completed >3 years of ERT (mean, 5.2 years; Table 1). Nasopharyngitis (33%), headache (24%), and cough (24%) were the most common AEs during the 18-month ERT treatment period in Part 1 (Table 3). In patients for whom the data were available, migalastat was started 2 to 14 days after their last ERT infusion. The most common AEs during 12 months of migalastat treatment in Part 2 were nasopharyngitis (33%), diarrhea (27%), vomiting (27%), influenza (20%), and headache (20%; Table 3). Although the percentages of patients experiencing diarrhea or vomiting increased after the switch to migalastat, these reflect changes in only 1–2 patients and the small patient numbers limit interpretation. There were no clinically meaningful changes in mean values from hematology, serum chemistry, urinalysis analysis, and vital signs following the switch from ERT to migalastat (Supporting Information Table S2). Twelve (80%) Cohort 2 patients started a new medication during months 18–30. The most common new concomitant medications were general anesthetics (13%), clindamycin (13%), ibuprofen (13%), naproxen (13%), and paracetamol (13%). Only 1 (7%) patient started a new angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or renin inhibitor. Review of AEs, laboratory measures, and concomitant medications in Cohort 2 did not identify notable safety concerns after switching to migalastat. These data demonstrated a favorable safety profile after patients directly switched to migalastat 150 mg QOD 2 to 19 days following their last ERT infusion. Migalastat was generally well tolerated, and no patients discontinued treatment due to AEs. Reason for discontinuing ERT during 0–18 months was withdrawal by participant (n = 3); reasons for discontinuing migalastat during 0–30 months were withdrawal by participant (n = 4), pregnancy (n = 1), lack of efficacy (n = 1), physician decision unrelated to migalastat (n = 1), and lost to follow-up (n = 1). Limitations of the analysis include the relatively small number of patients who switched from agalsidase beta to migalastat, as most (67%) patients switched from agalsidase alfa because enrollment for ATTRACT coincided with the worldwide shortage of agalsidase beta. Migalastat is the only oral treatment for Fabry disease, which provides a suitable alternative to once-every-2-weeks intravenous ERT in patients with amenable mutations who are ERT-experienced and can also be utilized as a first-line therapy in ERT-naive patients. Although there has not yet been a consensus among physicians who treat patients with Fabry disease on when to choose migalastat over ERT, we have developed some criteria in our clinical practices, which include: age 16 years and older (18 years and older in the United States and Canada), a confirmed amenable mutation, an eGFR > 30 mL/min/1.73 m2, compliance with every-other-day oral administration, and no intention by female patients to become pregnant. Patients' preference and hypersensitivity to ERT are also factors in considering the best treatment option for patients. We suggest having a comprehensive counseling session with the patient to discuss the mechanism of action, clinical data, and approved indication for migalastat, as well as schedule of administration. For patients switching from ERT, migalastat is commonly initiated ~2 weeks after the last dose of ERT based on the infusion interval; however, other practical considerations may influence the exact duration between the last ERT infusion and first dose of migalastat. Migalastat may be safely initiated within days of the last ERT infusion. In conclusion, patients with amenable mutations who have been receiving ERT infusions can be safely switched to migalastat 150 mg QOD, and no special procedure is needed for the switch. The authors would like to thank the patients and clinical investigators who participated in the AT1001-012 study and its open-label extension. Funding for the study was provided by Amicus Therapeutics, Inc. The authors acknowledge the scientific writing services of Brian Zeiler and Hadis Williams. Additional editorial assistance was provided by Lei Bai, PhD, and Cindy Gobbel, PhD, (ApotheCom, Yardley, PA), and was funded by Amicus Therapeutics. The study was designed by the sponsor (Amicus) and a core group of investigators. Data collection and analyses were undertaken by the sponsor (Amicus) in collaboration with investigators. The first draft of the manuscript was written by the first author with medical writing assistance provided by Brian Zeiler. All authors critically reviewed drafts of the manuscript. All authors vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol. All authors made the decision to submit the manuscript for publication. DAH has served as a consultant for and received research funding and honoraria from Amicus, Shire, Sanofi Genzyme, Protalix, and Actelion. KN has served as an advisor for Amicus, Shire, and Sanofi Genzyme, has received research support from Amicus and Shire, and has received travel support from Sanofi Genzyme. GS-P has received personal fees and non-financial support from Amicus and grant funding, personal fees, and non-financial support from Shire and Sanofi Genzyme. AJ has received advisory honoraria and speaker's fees from Amicus, Shire, Biomarin and Sanofi Genzyme. UFR reports other support from Amicus during the conduct of the study, grant support and speaker's honoraria from Amicus, Sanofi Genzyme, and Shire outside the submitted work, and research funding from Novo Nordisk Research Foundation. RS has served as a consultant for and received research funding from Amicus and Protalix Biotherapeutics. RG has received honoraria from Amicus, Biomarin, Sanofi Genzyme, and Shire. CV, JPC, NS, and JAB are employees of and hold stock in Amicus. DGB has received research funding, serves as a consultant, and is on the speaker's bureau for Amicus and Sanofi Genzyme, and has received research funding from Shire. Table S1 Change in Laboratory Measurements and Vital Signs After Switch From ERT to Migalastat in Cohort 1 Table S2. Change in Laboratory Measurements and Vital Signs After Switch From ERT to Migalastat in Cohort 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Long-term outcomes of enzyme replacement therapy for Taiwanese patients with Mucopolysaccharidosis I

Fabry disease is an X-linked disorder resulting from mutations of the gene that encodes the lysosomal hydrolase α -galactosidase A, and leads to progressive lysosomal accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids.[1][1] In classically affected male patients, clinical

Background: Fabry disease is an inherited lysosomal storage disease affecting multiple organs with complications, including cardiomyopathy such as left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) has been the main treatment for Fabry patients since 2001. However, the indications of ERT are not clearly defined. We performed a meta-analysis according to previous studies to review the benefit of ERT for LVH improvement in Fabry patients.Methods: We performed a literature search from the National Center for Biotechnology Information (NCBI) and PubMed database without restriction of years for systematic review purposes. We performed a systematic review of clinical cohort studies and trials using a pooled analysis of proportions. We calculated the pooled proportions and the confidence intervals (CI) for left ventricular mass index (LVMI) for both ERT treatment and ERT treatment-naïve groups. The results for before ERT treatment and after ERT treatment are also investigated.Results: A total of 5 cohort studies and 2 randomized controlled trials (RCTs), involving a total of 552 participants (267 on ERT treatment versus 285 on naïve treatment), met the inclusion criteria. The pooled proportions analysis showed that the difference in means of LVMI between the ERT treatment group and the ERT treatment-naïve group was -0.149 [95% CI: -0.431, 0.132]. Effect differences favored the ERT treatment group over the ERT treatment-naïve group (p = 0.034). Another analysis included 3 cohort studies and 1 RCT with 442 participants (228 on before ERT and 214 on 4 years after ERT). The pooled proportions analysis showed that the difference in means of LVMI between the before ERT treatment group and the after ERT treatment group was -0.448 [95% CI: -0.787, -0.108]. It favored the 4 years after ERT group over the before ERT group (p = 0.037).Conclusions: Based on the currently available data, our meta-analysis showed that there are beneficial effects on LVH improvement with ERT in Fabry disease patients. It is better to start ERT as soon as we have diagnoses in female carriers and atypically affected males. Further research is needed to investigate the role of ERT in LVH improvement.

Background and Aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder in which mutations of the GLA gene cause a decreased or absent activity of the alpha-galactosidase A (α-Gal A) and intracellular accumulation of globotriaosylceramide and other sphingolipids [1]. FD causes a variety of symptoms, including heart and kidneys damage - cardiorenal syndrome (CRS) type 5. In patients with FD, CRS is known to increase the risk of cardiovascular events and death [2]. The aim of our study was to assess renal function and outcomes in patients with FD and CRS receiving enzyme replacement therapy (ERT). Method We performed a retrospective analysis of the medical records of 10 patients (pts) from 7 unrelated families with established diagnosis of FD and cardiac and renal involvement. Pts #1 and #3 are siblings, pt # 10 is their mother; pt #9 is mother of pt #8 (Table 1). The diagnosis was confirmed by DNA diagnostics in all plus levels of α-Gal A enzymatic activity, globotriaosylsphingosine concentrations in some patients. All the patients underwent ERT. Seven out of 10 patients received blockers of the renin-angiotensin-aldosterone system, 3 - did not receive due to contraindications. Results All 10 patients, including 3 women, had left ventricular hypertrophy - left ventricular wall thickness (LVWT) ≥ 1.2 cm. (Table 1). Average LVWT was 1.850 ± 0.097 cm. Two patients had atrial fibrillation. None of the patients had proteinuria 1 g/24 h or higher. In all еGFR was below 60 ml/min/1,73 m2: 4 patients had CKD-G3a, 4 – G3b, 1 – G4 and 1 – G5. Average еGFR was 41,111 ± 8.069 ml/min/1,73 m2 excluding hemodialysis (HD) patient. There were 4 unfavorable outcomes in our group: death occurred in 3 patients from cardiac pathology (congestive heart failure), one patient reached CKD-G5 at 25 years of age and started HD treatment. Patient on HD, brother of deceased pt #1, began receiving ERT after the start of renal replacement therapy. The death of pt #1, who had a very high Lyso-Gb3 level - 118.36 ng/ml (normal 0.05-3.0 ng/ml), appears to be related to the late diagnosis and delayed start of ERT. Conclusion Patients with FD and CRS are likely to have a high risk of cardiovascular complications, loss of kidney function and death, especially with a late start of enzyme replacement and cardio-renoprotective therapy. Early diagnosis of FD and timely initiation of treatment are important in preventing the serious complications and death.

Introduction: Mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes that are responsible for the stepwise degradation of complex carbohydrates, the glycosaminoglycans. Whereas in the past the treatment of MPS consisted mainly of palliative care, enzyme replacement therapy (ERT) is now possible for some MPS disorders, and in the future many other therapeutic options will become available.Areas covered: This review, based on personal experience and the currently available literature, will give an overview on the efficacy and limitations of ERT and will discuss new therapeutic approaches, such as anti-inflammatory drugs, substrate reduction therapy, chaperones and gene therapy.Expert opinion: The therapeutic strategies available nowadays for MPS patients, namely ERT and hematopoietic stem cell transplantation, have their limitations, particularly in regard to the bone and CNS manifestation. Small molecules such as substrate inhibitors or chaperones that are capable of passing the blood–brain barrier are being developed. The use of anti-inflammatory drugs also seems to be an alternative therapeutic option. Before gene therapy can be seen as a routine treatment for MPS disorders, many issues, in particular regarding safety, have to be addressed.

1090. Enzyme Replacement Therapy with Pegylated Adenosine Deaminase (PEG-ADA) Does Not Impede Immune Reconstitution Following Transplantation of Gene-Corrected Bone Marrow Cells in the Murine Model of ADA-SCID

Letter to the Editors: Concerning “CRIM‐negative Pompe disease patients with satisfactory clinical outcomes on enzyme replacement therapy” by Al Khallaf et al

In this issue, Banikazemi and colleagues' landmark trial on Fabry disease provides a crucial path toward lowering the morbidity of this disease. Among other findings, they determined that hemizygou...

Long Term Outcomes of ERT in Children with Gaucher Disease. Spanish Experience

Deterioration of renal function in young adult patients with fabry disease and proteinuria

Pompe disease is a rare lysosomal disorder of muscle glycogen metabolism due to alfa-glucosidase (GAA) deficiency. The prevalence of this disease is estimated to be 1:40.000. Since 2006, Enzyme Replacement Therapy (ERT) became available in Europe and US. So far, there are no officially approved international guidelines about ERT inclusion criteria of patients but they must have a defined diagnosis of Pompe disease confirmed by a biochemical and molecular genetic examinations (1). So far, ERT has been generally prescribed to patients with motor symptoms (muscle weakness) and/or respiratory involvement. Exclusion criteria encompassed a severe associated illness which would be expected to greatly shorten life expectancy. Alglucosidase (Myozyme) is administered biweekly i.v. as 20 mg/kg. Although the high costs of the drug, in several European countries the patients are fully supported by their Ministries of Health. In fact, in Belgium, National guidelines consider every patient with clinical symptoms of muscle and/or respiratory involvement as a candidate for ERT that, on the other hand, should not be started in patients showing neither a clinical impact of the disease or with a limited life expectancy. In the Netherlands, the inclusion criteria are the confirmation of diagnosis via enzyme assay and mutation analysis, and patients should have demonstrable muscle weakness and/or pulmonary function < 80%. In UK, specific guidelines, prepared by a multidisciplinary group (2007), included patients with muscle weakness and/or respiratory compromise leading to an impaired quality of life as candidate for treatment. In France, Pompe disease experts recommend to treat symptomatic patients (muscle weakness and/or respiratory involvement - FVC < 80%). In Germany and in Poland there is a generic recommendation to treat symptomatic patients. In addition, in Brazil there is a recommendation to treat symptomatic patients; mild cases have to be progressively followed by respiratory and /or muscular functional tests and/or by muscle MRI before starting ERT. Because of the high costs of ERT, in several countries Health authorities (and EMA in Europe) request precise data concerning the clinical effects and safety of ERT to reimburse the treatment. Given the data obtained in different cohorts of patients, treated with ERT, there is a clear evidence that alglucosidase improves the walking distance and stabilizes the pulmonary function. A precise monitoring should help to make a decision for initiating or even interrupt ERT Patients should be followed in specialized neuromuscular or metabolic Departments, in connection with a pulmonology unit. Follow-up visits should be organized every 6 months or once a year with clinical evaluations performed by expert physicians and trained physiotherapists; those results should be collected on dedicated data base/registries. To date, there is a need of specific outcome measures to monitor patients before treatment and during the follow up. Across various European countries and US, clinical assessment has been differentially monitored. In fact 6 MWT, MMT, MFM scale, timed tests (i.e. GSGC), WGMS, muscle MRI, SF- 36, have been applied every 3-6 months/1 year to patients. Since 2006, AIFA (Agenzia Italiana del Farmaco) has approved alglucosidase alfa (Myozyme) for the treatment of Pompe disease patients in Italy, either for infantile or late-onset patients. The authorisation to treat patients by ERT has to be given by Centres specialized in rare diseases. Every Centre must assess the diagnosis of Pompe disease with absolute certainty before starting treatment. In 2008, a group of Italian Pompe disease experts reviewed, from a multidisciplinary point of view, the current practices in diagnosis, management and treatment of Pompe disease (2). The main criteria for starting ERT included: 1) confirmed diagnosis; 2) symptoms and clinical signs of muscle weakness and or respiratory insufficiency; 3) in cases of asymptomatic hyperckemia, a 6-months follow up was suggested in an attempt to monitor clinically relevant changes leading to treatment. The standard protocol mainly includes evaluation of muscle strength, respiratory assessment and skeletal muscle MRI that has been applied to 74 patients treated with ERT coming from 18 different Italian Centres, recently described by Angelini et al. (3). Nowadays, general recommendations includes monitoring of limb muscles and respiratory functions every 6 months using timed tests and functional scales. Muscle MRI may constitute an important tool to check the progression of intramuscular fat replacement in the patients (4). Respiratory function should include at least assessment of upright and supine FVC. Other important aspects of the disease to be considered are the cardiac function (ECG once a year) as well as antiRhGAA antibodies (every 3 months) levels, Glc4 (the only available biomarker of muscle glycogenosis type II) and brain MRI if there are symptoms suggestive of CNS involvement. In conclusion, being available the ERT therapy, it is really important to diagnose Pompe disease as soon as possible to avoid respiratory and skeletal muscle degeneration.

Introduction: The effects of ERT (enzyme replacement therapy) on cardiac manifestations in patients with Fabry disease (FD) are ambiguous. We aimed to investigate the response to ERT using diastolic stress echocardiography (DSE). Hypothesis: Diastolic function of FD would be improved after ERT. Methods: 19 patients with FD who underwent ERT were analyzed. All patients had DSE prior to ERT and post ERT at 1 year follow-up. We measured early diastolic (e’) velocity of the mitral annulus at baseline, 25 Watt (W) and peak exercise. The difference of diastolic reserve (ΔDR) between pre and post ERT was calculated. Diastolic reserve is defined as the change of e’ from baseline to 25W or peak of exercise in DSE. Results: Overall diastolic reserve tends to be improved (ΔDR25W: 0.66±1.36, ΔDRpeak 1.47±2.61) after 1 year of the ERT. However, there was no significant change in left ventricular (LV) wall thickness and LV mass index before and after the ERT. When patients were classified into two groups according to ΔDRpeak (Group 1, n=6, ΔDRpeak ≤0; Group 2, n=13, ΔDRpeak &gt;0), group 2 showed more higher pre-ERT MWE (93.6±3.2 vs 84.8±5.0, p&lt;0.01). The pre-ERT longitudinal strain of LV was better in group 2 compared to group 1 (-14.6±2.6 vs -9.9±2.3m p&lt;0.01). LAVI (44.0±12.9 vs 25.5±8.0, p&lt;0.01), LVEDD (50.8±2.8 vs 46.5 ± 3.0, p&lt;0.01) and LV mass index (204.5±57.5 vs 130.4±45.6, p=0.01) of pre ERT were higher in group 1. Conclusions: Diastolic function of FD was improved generally after ERT in FD patients FD patients who have relatively preserved chamber size and mechanical function before starting ERT showed a better response to ERT. In determining the ERT effect, evaluation of diastolic function is more useful than structural evaluation in patients with Fabry cardiomyopathy.

Fabry disease: is there a role for enzyme replacement therapy?