Image1_Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease.JPEG

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was −0.36 mL/min/1.73 m2/year [−2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of −3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.</p

Correlation and agreement between 2D-ECHO-based and CARTO-derived LAV.

<p>Upper row: Pearson’s correlation. Middle row: scatterplots for absolute differences between 2D-ECHO-based and CARTO-derived LAV versus CARTO-derived LAV. Lower row: scatterplots for relative differences between 2D-ECHO-based and CARTO-derived LAV versus CARTO-derived LAV. Red line—identity line; black line—regression line; blue line—bias; green line—limits of agreement (±1.96 standard deviation). Abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.g001" target="_blank">Fig 1</a>.</p

Receiver operating characteristics (ROC) for the prediction of CARTO-derived LAV > 130 ml.

<p>ROC curves are plotted for LAD³ (in blue), LAV_Ellipsoid (in red) and (3) LAV_Planimetry (in green). Panel A: ROC for raw 2D-ECHO-based LAV. Panel B: ROC for multivariately adjusted 2D-ECHO-based LAV (the adjustment was the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.g004" target="_blank">Fig 4</a>). Points corresponding to 2D-ECHO-based LAV > 130 ml are indicated by arrows. AUC—area under the curve; other abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.g001" target="_blank">Fig 1</a>.</p

Absolute and relative agreement between 2D-ECHO-based and CARTO-derived LAV in categories by LA size.

<p>Absolute and relative differences are shown in upper and lower row of graphs, respectively. Data are dichotomized by median of LAV_CARTO (130 ml). The points and whiskers represent mean and ±1.96 standard deviation. Abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.g001" target="_blank">Fig 1</a>.</p

Distribution of left atrial atrial size indices.

<p>Abbreviations: IQR—interquartile range; LAD³ –cubed left atrial diameter in parasternal long-axis view; LAV_Ellipsoid−left atrial volume (LAV) assessed by the prolate-ellipsoid method; LAV_Planimetry−LAV assessed by the planimetric method; LAV_CARTO−CARTO-derived LAV.</p

Correlation of raw and adjusted 2D-ECHO-based LAV with CARTO-derived LAV.

<p>Upper row: raw values. Middle row: simple linear adjustment. Lower row: multivariate adjustment for clinical covariates. Regression coefficients from Tables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.t002" target="_blank">2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.t003" target="_blank">3</a> were used for the simple and multivariate adjustment, respectively. Specifically, adjusted LAV was calculated as:</p> <p>68 + 0.62 LAD³;</p> <p>42 + 1.32 LAV_Ellipsoid;</p> <p>66 + 0.81 LAV_Planimetry;</p> <p>67 + 0.42 LAD³ + 15 (if male) + 0.44 Age + 34 (if persistent AF) + 14 (if SHD);</p> <p>49 + 0.98 LAV_Ellipsoid + 12 (if male) + 0.34 Age + 32 (if persistent AF) + 10 (if SHD);</p> <p>64 + 0.60 LAV_Planimetry + 18 (if male) + 0.38 Age + 40 (if persistent AF) + 14 (if SHD).</p> <p>Red line–identity line; black line–regression line. Adj = adjusted. Other abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152553#pone.0152553.g001" target="_blank">Fig 1</a>.</p

Stepwise forward multivariate regression analysis of determinants of LAV_CARTO.

<p>Stepwise forward multivariate regression analysis of determinants of LAV_CARTO.</p

Baseline characteristics.

<p>Baseline characteristics.</p

Univariate regression between individual 2D-ECHO-based LAV indices and LAV_CARTO (dependent variable).

<p>Univariate regression between individual 2D-ECHO-based LAV indices and LAV_CARTO (dependent variable).</p

Thirty-day mortality according to the BMI category and type of heart failure.

<p>Thirty-day mortality according to the BMI category and type of heart failure.</p