Comparing the efficacy of cipaglucosidase alfa plus miglustat with other enzyme replacement therapies for late-onset Pompe disease: a network meta-analysis utilizing patient-level and aggregate data.

Aim: Late-onset Pompe disease is characterized by progressive loss of muscular and respiratory function. Until recently, standard of care was enzyme replacement therapy (ERT) with alglucosidase alfa. Second-generation ERTs avalglucosidase alfa (aval) and cipaglucosidase alfa with miglustat (cipa+mig) are now available. Without head-to-head trials comparing aval with cipa+mig, an indirect treatment comparison is informative and timely for understanding potential clinical differentiation. Materials & methods: A systematic literature review was performed to identify relevant studies on cipa+mig and aval. Using patient-level and aggregate published data from randomized controlled trials (RCTs) and phase I/II and open-label extension (OLE) trials, a multi-level network meta-regression was conducted, adjusting for various baseline covariates, including previous ERT duration, to obtain relative effect estimates on 6-minute walk distance (6MWD, meters [m]) and forced vital capacity (FVC, % predicted [pp]). Analyses of two networks were conducted: Network A, including only RCTs, and network B, additionally including single-arm OLE and phase I/II studies. Results: Network B (full evidence analysis) showed that cipa+mig was associated with a relative increase in 6MWD (mean difference 28.93 m, 95% credible interval [8.26-50.11 m]; Bayesian probability 99.7%) and FVC (2.88 pp [1.07-4.71 pp]; >99.9%) compared with aval. The comparison between cipa+mig and aval became more favorable for cipa+mig with increasing previous ERT duration for both end points. Analysis of network A showed that cipa+mig was associated with a relative decrease in 6MWD (-10.02 m [-23.62 to 4.00 m]; 91.8%) and FVC (-1.45 pp [-3.01 to 0.07 pp]; 96.8%) compared with aval. Conclusion: Cipa+mig showed a favorable effect versus aval when all available evidence was used in the analysis.

Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement.

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration.

Fabry disease Enzyme Enhancement on migalastat Study: FEES.

BACKGROUND: There is limited information on the α-galactosidase A (α-Gal-A) in vivo response in Fabry patients receiving migalastat. In this single centre study, we evaluated changes from baseline in α-Gal A activity, lyso-Gb3 and other assessments in patients on migalastat. RESULTS: 79 patients were recruited (48 M:31F; median duration receiving migalastat 3.8 years [range = 0.4-14.9 years]). N215S was the commonest genotype in males (67 %) and females (29 %). Leukocyte α-Gal-A showed a positive change from baseline in males (n = 4; median = 20.05); females (n = 8; median = 26). Of these, 3 males and 1 female had N215S (median = 16.7), while 7 females and 1 male had other genotypes (median = 26). No significant changes observed in plasma α-Gal-A. Cross-sectional analysis of post-baseline data confirmed leukocyte α-Gal-A enhancement in males (n = 47; median = 20); females (n = 30; median = 72); N215S (n = 41; median = 29) and other genotypes (n = 36; median = 36.5). Plasma and dried blood spot (DBS) lyso-Gb3 correlated at baseline and post-baseline (r = 0.77 and r = 0.96; p=<0.0001). CONCLUSIONS: In the 12 patients with paired data, there was a median enzyme enhancement of 17.4 (relative change = 2.54) and 33 (relative change = 0.87) in males and in females, respectively. The cross-sectional post-baseline data in 47 patients corroborated leukocyte α-Gal-A enhancement on migalastat. Plasma and DBS lyso-Gb3 correlated well supporting DBS utility for disease monitoring.

A Systematic Review on Safety and Efficacy of Migalastat for the treatment of Fabry's Disease.

INTRODUCTION: Fabry's disease (FD) is a genetic lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) lost/reduced activity. We aim to systematically assess the safety and efficacy of Migalastat, an oral pharmacological chaperone, that has been approved for the treatment of FD in patients with amenable mutations. METHODS: We conducted literature search following the PRISMA guidelines in major databases up to 4 February 2024, for studies that assessed the clinical outcomes of migalastat in patients with FD. The New Castle Ottawa Scale was used to evaluate the quality of the included studies. RESULTS: A total of 2141 records were identified through database searches and register searches, amongst which 26 records were screened, and 12 of these were excluded. The remaining 14 reports were sought for retrieval. The 12 retrieved articles were assessed for eligibility and their quality was assessed after their inclusion. Amongst the included studies, 5 were of high quality, 6 were of medium quality, and 1 was of low quality. CONCLUSION: Migalastat showed varied effects on enzyme activity and substrate levels, with gender-specific differences noted in GL-3 substrate activity and eGFR. Overall, it improved cardiac and renal outcomes similarly to enzyme replacement therapy, with a comparable safety profile.

Response to Comments on "Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice".

We thank Dr. Weimer and her colleagues for their comments related to our recent work (Anding et al., 2023) and are grateful for the opportunity to further discuss the importance of efficient lysosomal targeting of enzyme-replacement therapies (ERT) for the treatment of Pompe disease. Patients with Pompe disease have mutations in the gene that encodes for acid α glucosidase (GAA), a lysosomal enzyme necessary for the breakdown of glycogen. The first-generation ERT, alglucosidase alfa, provides a lifesaving therapy for the severe form of the disease (infantile onset Pompe disease) and improves or stabilizes respiratory and motor function in patients with less severe disease (late onset Pompe disease). Despite these gains, significant unmet need remains, particularly in patients who display respiratory and motor decline following years of treatment. Poor tissue uptake and lysosomal targeting via inefficient binding of the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) in skeletal muscle contributed to this suboptimal treatment response, prompting the development of new ERTs with increased levels of M6P.

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Baseline Characteristics of Fabry Disease "Amenable" Migalastat Patients in Argentinian Cohort.

Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.

A case report of Tangier disease presents with acute sensorimotor polyneuropathy and its treatment approach.

Polyneuropathy is a frequently encountered clinical presentation where peripheral nerves are affected due to the same cause and physiopathological processes. We report a case of acute sensorimotor polyneuropathy in a patient with Tangier disease (TD) who was treated with miglustat which is a glycosphingolipid synthesis inhibitor. TD is a very rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes the cholesterol efflux regulatory protein. It leads to accumulation of cholesterol esters within various tissues and affects lipid metabolism by deficiency of high-density lipoprotein (HDL) in the blood. Due to the accumulation of cholesterol esters in Schwann cells, it could provoke polyneuropathy in TD. Our case presented to our clinic with quadriparesis and after treated with miglustat therapy his weakness regressed.

A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

Fabry disease biomarkers in patients switched from enzyme-replacement therapy to migalastat oral chaperone therapy.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or ß to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p ≥ 0.05) over a minimum of 12 months compared with baseline following the treatment switch. Conclusion: In this cohort of patients with Fabry disease with amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.

Effects of miglustat therapy on neurological disorder and survival in early-infantile Niemann-Pick disease type C: a national French retrospective study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients. METHODS: Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded. RESULTS: Ten patients were included in the treated group (year of birth: 2006-2012), and 16 patients in the untreated group [born 1987-2005 (n = 15), 2012 (n = 1)]. The median age at neurological onset was 9 months (5-18) in the treated group, and 12 months (3-18) in the untreated group (p = 0.22). Miglustat therapy was started at a median age of 24.5 months (9-29) and median duration was 30 months (11-56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p = 0.11). CONCLUSIONS: Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C.

Cipaglucosidase Alfa: First Approval.

Cipaglucosidase alfa (Pombiliti™) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer miglustat as a two-component therapy for Pompe disease. Pompe disease is a rare, inherited lysosomal disease caused by a deficiency of the enzyme GAA, which leads to accumulation of glycogen in various tissues. On 27 March 2023, cipaglucosidase alfa was approved in the EU as a long-term enzyme replacement therapy (ERT) used in combination with miglustat for the treatment of adults with late-onset Pompe disease. This article summarizes the milestones in the development of cipaglucosidase alfa leading to this first approval.

Current advancements in therapy for Niemann-Pick disease: progress and pitfalls.

INTRODUCTION: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder. To combat the progressive neurodegeneration in NPC, disease-modifying treatment needs to be introduced early in the course of the disease. The only approved, disease-modifying treatment is a substrate-reduction treatment, miglustat. Given miglustat's limited efficacy, new compounds are under development, including gene therapy; however, many are still far from clinical use. Moreover, the phenotypic heterogeneity and variable course of the disease can impede the development and approval of new agents. AREAS COVERED: Here, we offer an expert review of these therapeutic candidates, with a broad scope not only on the main pharmacotherapies, but also on experimental approaches, gene therapies, and symptomatic strategies. The National Institute of Health (NIH) database PubMed has been searched for the combination of the words 'Niemann-Pick type C'+ 'treatment' or 'therapy' or 'trial.' The website clinicaltrials.gov has also been consulted. EXPERT OPINION: We conclude a combination of treatment strategies should be sought, with a holistic approach, to improve the quality of life of affected individuals and their families.

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease.

Fabry disease is a lysosomal storage disease caused by mutations in the GLA gene that encodes alpha-galactosidase (AGAL). The disease causes abnormal globotriaosylceramide (Gb3) storage in the lysosomes. Variants responsible for the genotypic spectrum of Fabry disease include mutations that abolish enzymatic activity and those that cause protein instability. The latter can be successfully treated with small molecules that either bind and stabilize AGAL or indirectly improve its cellular activity. This paper describes the first attempt to reposition curcumin, a nutraceutical, to treat Fabry disease. We tested the efficacy of curcumin in a cell model and found an improvement in AGAL activity for 80% of the tested mutant genotypes (four out of five tested). The fold-increase was dependent on the mutant and ranged from 1.4 to 2.2. We produced evidence that supports a co-chaperone role for curcumin when administered with AGAL pharmacological chaperones (1-deoxygalactonojirimycin and galactose). The combined treatment with curcumin and either pharmacological chaperone was beneficial for four out of five tested mutants and showed fold-increases ranging from 1.1 to 2.3 for DGJ and from 1.1 to 2.8 for galactose. Finally, we tested a long-term treatment on one mutant (L300F) and detected an improvement in Gb3 clearance and lysosomal markers (LAMP-1 and GAA). Altogether, our findings confirmed the necessity of personalized therapies for Fabry patients and paved the way to further studies and trials of treatments for Fabry disease.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Pharmacometric model of agalsidase-migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule.

Recently, a new mechanism of drug-drug interaction (DDI) was reported between agalsidase, a therapeutic protein, and migalastat, a small molecule, both of which are treatment options of Fabry disease. Migalastat is a pharmacological chaperone that stabilizes the native form of both endogenous and exogenous agalsidase. In Fabry patients co-administrated with agalsidase and migalastat, the increase in active agalsidase exposure is considered a pharmacokinetic effect of agalsidase infusion but a pharmacodynamic effect of migalastat administration, which makes this new DDI mechanism even more interesting. To quantitatively characterize the interaction between agalsidase and migalastat in human, a pharmacometric DDI model was developed using literature reported concentration-time data. The final model includes three components: a 1-compartment linear model component for migalastat; a 2-compartment linear model component for agalsidase; and a DDI component where the agalsidase-migalastat complex is formed via second order association constant kon, dissociated with first order dissociation constant koff, and distributed/eliminated with same rates as agalsidase alone, albeit the complex (i.e., bound agalsidase) has higher enzyme activity compared to free agalsidase. The final model adequately captured several key features of the unique interaction between agalsidase and migalastat, and successfully characterized the kinetics of migalastat as well as the kinetics and activities of agalsidase when both drugs were used alone or in combination following different doses. Most parameters were reasonably estimated with good precision. Because the model includes mechanistic basis of therapeutic protein and small molecule pharmacological chaperone interaction, it can potentially serve as a foundational work for DDIs with similar mechanism.

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes.

BACKGROUND: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear. METHODS: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated. RESULTS: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations. CONCLUSIONS: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs.

A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.