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BackgroundPegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than −2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year.MethodsPatients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms.ResultsSeventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18–60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was −7.3 (−30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was −0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths.ConclusionsBased on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions.Trial registration number NCT02795676.

Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.

Migalastat stabilizes mutant α-galactosidase in Fabry's disease, reducing globotriaosylceramide deposition. In this study, the percentage of patients with a decrease of 50% or more in kidney interstitial capillary deposition at 6 months was similar in the migalastat and placebo groups. Fabry’s disease is a rare, progressive, and devastating X-linked disorder caused by the functional deficiency of lysosomal α-galactosidase. 1 The resultant accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), can lead to multisystem disease and early death. 2 Binding of the pharmacologic chaperone migalastat to the active site of α-galactosidase stabilizes certain mutant enzymes, thus facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates. 3 – 7 In patients with mutant enzymes that are identified with the validated assay, orally administered migalastat may be an alternative treatment option for addressing certain unmet medical needs associated with enzyme-replacement therapy — for . . .

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34 + -selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb 3 ) and globotriaosylsphingosine (lyso-Gb 3 ) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy. Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.

BackgroundFabry 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.MethodsThis 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.ResultsDuring 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.ConclusionsThe 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.

The difference in median eGFR slope for the intent-to-treat population between arms was −0.36 mL/min/1.73 m2/year (95% CI −2.44, 1.73). Since the lower limit of the CI was above the prespecified non-inferiority margin, the non-inferiority was achieved.2 Since the PEGylation of pegunigalsidase alfa leads to a sustained half life and seems to reduce the affinity of already pre-existing ADAs towards agalsidase alfa and agalsidase beta,3 4 an additional focus of the study was the analysis of the safety (frequency of infusion-associated reactions) and the immunogenicity of pegunigalsidase alfa compared to agalsidase beta. [...]the presentation of immunogenicity must be evaluated in light of the methodological limitations, which have also been addressed in parts previously in another context.5 Due to the prolonged half life of pegunigalsidase alfa (~80 hours), it is conceivable that antibody titres measured by ELISAs, which target free antibodies (as stated within both manuscripts1 2), might not be appropriate (figure 1A). In case of low or medium antibody titres, this might result in false negative results. Since this effect is likely to be stronger the closer the time of blood collection is to the last infusion, it would be most useful to measure antibody titres immediately before the next infusion. [...]it is conceivable that depending on the applied method, the most prominent Ig classes including IgA, IgG and IgM9 10 might have been overseen. [...]we conclude that due to the lack of methodological information and resulting data, the presented results concerning the immunogenicity of pegunigalsidase alfa should be interpreted with caution.

It is estimated that ~2 billion people worldwide cannot afford even basic medicines. B ioreactor-produced r ecombinant p rotein t herapies (BRPTs), among the world’s most-expensive medicines, have revolutionized treatment of a wide-spectrum of human-diseases, particularly the ~ 7,000 incurable, rare human single-protein, monogenic-deficiency diseases. Currently, BRPT are limited by toxicity, immunogenicity, short protein T 1 / 2 s and high-cost, creating a worldwide access-gap between those who can afford BRPTs versus those who cannot. Fabry disease (FD) is a monogenic deficiency disease caused by pathogenic-variants of the galactosidase-a (GLA) gene. FD damages heart, kidneys, CNS, gastrointestinal tract, and eyes. State-of-the-art anti-FD therapy, hGLA enzyme-replacement-therapy (ERT), requires bi-weekly IV infusions lifelong, costing ~ $200,000 per-patient per-year. High-lifetime costs can cause significant numbers of FD patients to permanently discontinue hGLA-ERT, thereby accelerating FD progression, which can lead to premature-death. Subcutaneously administered plasmid DNA alone has not been previously reported to transfect subcutaneous fat. Here we show one S ubcutaneous A dministration of H EDGES D NA vectors A lone ( SAHDA ) encoding the wildtype hGLA protein safely produces durable hGLA serum protein levels in the 1–10 ng/mL normal human hGLA range in immunocompetent mice. Unexpectedly, one administration of a highly-optimized SAHDA version encoding hGLA produced durable, ~ 100-fold higher hGLA serum protein levels than the 10 ng/mL high-normal human level. Importantly, components of the SADHA platform can be simply-modified to control the level and duration of hGLA serum protein-levels produced over a broad temporal-range in mice. Furthermore, one SAHDA-based administration of a HEDGES DNA-vector encoding a highly-neutralizing anti-SARS-CoV-2 monoclonal antibody (mAb) safely produces long-term protective serum mAb levels in immunocompetent-mice. SAHDA offers multiple advantages over BRPT, including not requiring an intact cold-chain and being readily freeze-dried. This combination enables SAHDA’s rapid deployment, then prolonged storage at ambient temperatures, even in equatorial-areas worldwide. SAHDA can readily be self-administered worldwide. It also obviates severe intravenous-infusion reactions. Taken-together, SAHDA may more effectively-, safely-, durably-, and cost-effectively-treat a spectrum of now poorly-treatable diseases worldwide.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α -galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α -galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α -galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α -galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α -galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. Specimens from dried blood spots of 34 736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid β-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. All 34 736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17 368). The positive predictive values were 32% (95% CI 16–52), 80% (28–99), and 50% (7–93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood. Austrian Ministry of Health, Family, and Women.

A 44-year-old man presented with a 5-year history of heat intolerance and burning pain in his hands and feet. He had periumbilical angiokeratomas and nonnephrotic proteinuria. A kidney biopsy was performed.