In Fabry disease (FD), GLA mutations cause an enzyme deficiency, glycosphingolipid accumulation, and potentially lethal kidney, heart and central nervous system involvement . Globotriaosylceramide (Gb3) is the best-characterized accumulated glycosphingolipid, but the relative increase in plasma globotriaosylsphingosine (lyso-Gb3) is larger (up to >100-fold higher than controls). Circulating lyso-Gb3 directly injures podocytes, eliciting a stress response similar to the high-glucose stress response [2–4]. Fabry nephropathy starts in childhood. In children, podocyte glycolipid deposits are larger than in endothelial cells, correlate with proteinuria and associate with podocyte injury (foot process effacement), which precedes proteinuria . Pathological albuminuria is usually the first evidence of Fabry nephropathy, progressing to overt proteinuria that may reach the nephrotic range . Glomerular filtration rate (GFR) decreases, leading to renal replacement therapy (RRT) at age ∼40 years in classical FD [6, 7]. The magnitude of proteinuria is a key determinant of nephropathy progression in treated and non-treated patients, placing podocytes at the centre of Fabry nephropathy [8, 9]. ENZYME REPLACEMENT THERAPY DOSE Enzyme replacement therapy (ERT), consisting of the intravenous biweekly administration of recombinant human alfa-galactosidase A (agalsidase), has been available in Europe since 2001 . Surprisingly, the approved dose of agalsidase-beta (1.0 mg/kg/biweekly) is 5-fold higher than for agalsidase-alfa (0.2 mg/kg/biweekly) and agalsidase-alfa was not approved by the Federal Drug administration (FDA), not being available in USA. Agalsidase has been used in thousands of patients. For practising physicians, the choice between two enzyme preparations is welcomed, but the large dose difference is puzzling. The availability of two agalsidase preparations allowed treatment during a global agalsidase-beta shortage [11–15]. In this issue, Krämer et al. present the longest follow-up (3 years) of the largest study (n > 100) switching or not from agalsidase-beta 1.0 mg/kg/biweekly to agalsidase-alfa 0.2 mg/kg/biweekly . It compares patients on agalsidase-beta 1.0 mg/kg/biweekly throughout with those switched to alfa 0.2 mg/kg/biweekly (switch group), and with those reswitched to beta 1.0 mg/kg/biweekly after at least 1 year on alfa 0.2 mg/kg/biweekly. Estimated GFR (eGFR) from serum creatinine remained stable on beta 1.0 mg/kg/biweekly, while it decreased in the switch group (−7.2/−8.1 mL/min/1.73 m2/year) (Figure 1). In patients reswitched to beta 1.0 mg/kg/biweekly, mean eGFR decreased 5.7 mL/min/1.73 m2/year on lower dose and 1.8 mL/min/1.73 m2/year the next year on beta 1.0 mg/kg/biweekly. Three equations to estimate GFR yielded similar results. We focused on the serum creatinine-based equation since it allows comparison with other Fabry studies. The difference in chronic kidney disease (CKD) progression cannot be attributed to less severe baseline disease in patients remaining on beta, since overall disease severity [Mainz Severity Score Index (MSSI) score] was highest in this group and the difference from the reswitch group was statistically significant. Lumping together men and women may be an issue, since mean CKD progression is slower in Fabry women than in men [8, 9]. However, the proportion of women on agalsidase-beta was significantly lower (22%) than in the switch and reswitch arms (50 and 43%, respectively), increasing the significance of the results, which show faster progression in the switch arms despite including more women. Differences in eGFR slope were not adjusted for disease severity. However, patients on agalsidase-beta throughout had features of higher disease severity, in addition to the predominance of males and higher MSSI scores. Thus, they had lower residual alfa-galactosidase A enzyme activity and more pain attacks, while there were no differences in angiotensin blockers or age. FIGURE 1 View largeDownload slide Annual change of eGFR from serum creatinine. Data from Krämer et al. ; the TKT010 randomized controlled trial (RCT) and the Fabry Outcome Survey (FOS) registry . For Krämer et al. follow-up-1 (FU-1) and follow-up-2 (FU-2) are displayed side-to-side for the regular dose (agalsidase-beta 1.0 mg/kg/biweekly throughout, which, as the other arms, is separated into two columns for FU-1 and FU-2, respectively: 5.0 ± 14.2 and −3.2 ± 11.2 mL/min/1.73 m2/year, respectively), switch (at least 1 year on agalsidase-alfa 0.2 mg/kg/biweekly followed by 1 year on agalsidase-alfa 0.2 mg/kg/biweekly; −7.2 ± 9.3 and −8.1 ± 12.1 mL/min/1.73 m2/year, respectively) and reswitch groups (at least 1 year on agalsidase-alfa 0.2 mg/kg/biweekly followed by 1 year on agalsidase-beta 1.0 mg/kg/biweekly; −5.6 ± 7.7 and −1.8 ± 5.2 mL/min/1.73 m2/year, respectively).). The ‘switch’ label of individual columns indicates that patients had been at least 12 months on agalsidase-alfa 0.2 mg/kg/biweekly. TKT010 compared agalsidase-alfa 0.2 mg/kg/biweekly versus placebo for 6 months with a primary outcome of eGFR. Data have been annualized. The FOS registry analysed patients that had available serum creatinine values at baseline and after 5 years of therapy with agalsidase-alfa 0.2 mg/kg/biweekly. The hidden biases potentially associated with this approach are discussed in the text. eGFR from serum creatinine is presented since it allows to present data obtained using the same equation for all studies. FIGURE 1 View largeDownload slide Annual change of eGFR from serum creatinine. Data from Krämer et al. ; the TKT010 randomized controlled trial (RCT) and the Fabry Outcome Survey (FOS) registry . For Krämer et al. follow-up-1 (FU-1) and follow-up-2 (FU-2) are displayed side-to-side for the regular dose (agalsidase-beta 1.0 mg/kg/biweekly throughout, which, as the other arms, is separated into two columns for FU-1 and FU-2, respectively: 5.0 ± 14.2 and −3.2 ± 11.2 mL/min/1.73 m2/year, respectively), switch (at least 1 year on agalsidase-alfa 0.2 mg/kg/biweekly followed by 1 year on agalsidase-alfa 0.2 mg/kg/biweekly; −7.2 ± 9.3 and −8.1 ± 12.1 mL/min/1.73 m2/year, respectively) and reswitch groups (at least 1 year on agalsidase-alfa 0.2 mg/kg/biweekly followed by 1 year on agalsidase-beta 1.0 mg/kg/biweekly; −5.6 ± 7.7 and −1.8 ± 5.2 mL/min/1.73 m2/year, respectively).). The ‘switch’ label of individual columns indicates that patients had been at least 12 months on agalsidase-alfa 0.2 mg/kg/biweekly. TKT010 compared agalsidase-alfa 0.2 mg/kg/biweekly versus placebo for 6 months with a primary outcome of eGFR. Data have been annualized. The FOS registry analysed patients that had available serum creatinine values at baseline and after 5 years of therapy with agalsidase-alfa 0.2 mg/kg/biweekly. The hidden biases potentially associated with this approach are discussed in the text. eGFR from serum creatinine is presented since it allows to present data obtained using the same equation for all studies. Circulating lyso-Gb3 decreased upon switching from alfa 0.2 mg/kg/biweekly to beta 1.0 mg/kg/biweekly, supporting a dose–response relationship between agalsidase and glycosphingolipid clearance. The authors conclude that switching to agalsidase-alfa was associated with a continuous decline in eGFR, and reswitching to agalsidase-beta attenuated the decline. They are rightfully conservative when assessing the results and indicate that these data cannot answer the question of which is the better compound and/or the optimal ERT dose. However, these results should be viewed in the context of a trickle of data suggesting an impact of agalsidase dose on outcomes. WHERE DO DOSES COME FROM? The cell origin of human agalsidase-alfa and -beta (human fibrosarcoma versus hamster ovary cells) has been argued to underlie potential differences in pharmacokinetics/pharmacodynamics that would explain the different doses . However, doses do not originate from theoretical considerations regarding the production process, but from early dose-finding clinical trials. In this regard, after a dose-finding safety Phase I clinical trial tested five different single doses (0.007–0.1 mg/kg) of agalsidase-alfa, the dose chosen for the pivotal trial (0.2 mg/kg/biweekly) was twice the highest dose tested in the dose-finding trial  (Figure 2a). In contrast, 1.0 mg/kg/biweekly agalsidase-beta was one of three different doses administered biweekly for 10 weeks in a dose-finding trial [18, 21] (Figure 2a). The higher approved dose of agalsidase-beta was associated with a 9-fold higher area under the curve of intracellular alfa-galactosidase A activity over 2 weeks in Fabry patients than 0.2 mg/kg/biweekly agalsidase-alfa (Figure 2c) . Thus, the approved doses of both agalsidase preparations are not equivalent in terms of intracellular alfa-galactosidase A activity in vivo. FIGURE 2 View largeDownload slide Agalsidase dose-response. (a) Phase 1 dose-response studies, approved dose and post-approval dose studies for agalsidase-alfa and beta. For agalsidase-alfa, a single-dose ranging from 0.007 to 0.1 was tested before settling on 0.2 mg/kg every other week (EOW) in the pivotal trial, which is the approved dose. Later studies tested doses up to 0.4 mg/kg, without proof of a dose-response. For agalsidase-beta, three doses were tested for five consecutive infusions EOW. Later studies tested doses of 0.5 mg/kg EOW in children, demonstrating clearance of kidney capillaries but variable and unpredictable podocyte responses . (b) Classical dose-response curves (https://en.wikipedia.org/wiki/Dose%E2%80%93response_relationship#/media/File: DoseResponse000.svg), display a sigmoid morphology. Thus, for very low doses, no dose-response can be demonstrated, as is the case for very high doses. (c) Approved dose of agalsidase-alfa and -beta and intracellular agalsidase A activity area under the curve (AUC) over 2 weeks in peripheral blood leucocytes following administration of a single approved dose . FIGURE 2 View largeDownload slide Agalsidase dose-response. (a) Phase 1 dose-response studies, approved dose and post-approval dose studies for agalsidase-alfa and beta. For agalsidase-alfa, a single-dose ranging from 0.007 to 0.1 was tested before settling on 0.2 mg/kg every other week (EOW) in the pivotal trial, which is the approved dose. Later studies tested doses up to 0.4 mg/kg, without proof of a dose-response. For agalsidase-beta, three doses were tested for five consecutive infusions EOW. Later studies tested doses of 0.5 mg/kg EOW in children, demonstrating clearance of kidney capillaries but variable and unpredictable podocyte responses . (b) Classical dose-response curves (https://en.wikipedia.org/wiki/Dose%E2%80%93response_relationship#/media/File: DoseResponse000.svg), display a sigmoid morphology. Thus, for very low doses, no dose-response can be demonstrated, as is the case for very high doses. (c) Approved dose of agalsidase-alfa and -beta and intracellular agalsidase A activity area under the curve (AUC) over 2 weeks in peripheral blood leucocytes following administration of a single approved dose . WHY OUTCOMES FROM RANDOMIZED CONTROLLED TRIALS DIFFER FROM SOME OBSERVATIONAL STUDIES? A striking claim of the pivotal agalsidase-alfa trial was that ERT preserved renal function significantly better than placebo for 6 months . However, differences depended on a single outlier placebo patient that lost a striking 70 mL/min/1.73 m2 GFR within 6 months, requiring RRT. A subsequent placebo-controlled trial, one of the largest to date in FD, compared agalsidase-alfa 0.2 mg/kg/biweekly to placebo, with a primary endpoint of eGFR. The results of this unpublished trial are available at the FDA website (www.fda.gov/ohrms/dockets/ac/03/briefing/3917B2_01_TKT%20Replagal%20Background%20.pdf). Fabry patients on agalsidase-alfa lost 4.7 mL/min/1.73 m2 eGFR in 6 months, versus 3.5 mL/min/1.73 m2 for placebo patients (Figure 1). These results are in line with the publication by Krämer et al. , but in striking contrast to more optimistic data from the Fabry Outcome Survey (FOS) registry . Disease heterogeneity may have played a role in these differences . GLA mutations associated with residual enzyme activity may cause late-onset FD variants. Some of the most common in Europe, such as N215S, display mild, frequently non-progressive kidney involvement. Over-representation of these patients may yield an over-optimistic assessment of the impact of ERT on renal function. Additionally, being an X-linked disease, the few females that do progress to RRT may be diluted in a wider pool of females with milder, non-progressive renal disease . Thus, mean renal disease progression in large groups of females, even in those with higher albuminuria, is very similar to age-associated loss of GFR . An additional issue may fatally flaw some observational studies. The following methods statement from a widely cited Registry study clearly illustrates the problem: ‘This analysis included adult patients (>18 years of age at baseline) with data on creatinine concentrations available in FOS at baseline and after ≥5 years of treatment with agalsidase-alfa, consisting of 40-minute infusions at a dosage of 0.2 mg/kg every 2 weeks.’ . This type of design, which at first read appears reasonable, is associated with a hidden selection bias excluding patients with more severe disease that either died or started RRT before the 5-year mark or were switched to agalsidase-beta 1.0 mg/kg/biweekly or to a higher agalsidase-alfa dose because of a suboptimal response to the lower dose. There are examples of all of these occurrences [23, 24]. Schiffmann, the first author of the pivotal agalsidase-alfa trial , enroled 12/41 (30%) patients from different agalsidase-alfa trials in a study switching from 0.2 mg/kg/biweekly agalsidase-alfa to weekly dosing, using as inclusion criterion having experienced a loss of eGFR ≥5 mL/min/year after 2–4 years on agalsidase-alfa at the approved dose . That is, in his experience, a third of patients on 0.2 mg/kg/biweekly agalsidase-alfa met criteria to consider their nephropathy rapidly progressive before the 5-year mark, and the monthly dose was doubled. These patients would be excluded from FOS registry analyses exploring the benefit of 0.2 mg/kg/biweekly agalsidase-alfa. IS THERE A DOSE-RESPONSE FOR AGALSIDASE? The results by Krämer et al. are compatible with a dose-response for agalsidase . This is not unexpected, given that drugs usually have a dose-response. Post-approval clinical trials have explored different dosing regimens for agalsidase-alfa and agalsidase-beta. For agalsidase-alfa, no dose-response on the readout serum Gb3 or other readouts was observed for doses from 0.1 to 0.4 mg/kg/weekly, including the approved dose (0.2 mg/kg/biweekly) [25, 26]. Although the design of these studies has been criticized , the absence of a clear dose-response curve raises the spectrum of having compared doses in the lower non-linear end of the dose-response curve (Figure 2b). In the pivotal trial, agalsidase-alfa 0.2 mg/kg/biweekly significantly decreased kidney capillary endothelial deposits by 60% (by −1.2 ± 0.26 from a baseline score of 2.0 ± 0.23) and serum Gb3 by 54% (from 12.14 to 5.58 nmol/mL) in 24 weeks, demonstrating efficacy . However, in the pivotal trial, agalsidase-beta 1.0 mg/kg/biweekly significantly decreased kidney capillary endothelial deposits by 84% (by −1.6 ± 1.2 from a baseline score of 1.9 ± 0.8) and serum Gb3 by >90% [from 13–14 ng/µL to undetectable (<1.2 ng/µL)] in 20 weeks . This difference in the magnitude of decrease of glycolipid burden between pivotal trials is also compatible with an agalsidase dose-response. In the Fabrazyme: Intervening Early at Low Dose (FIELD) clinical trial, a lower agalsidase-beta dose (0.5 mg/kg/biweekly or 1 mg/kg/month) for 5 years demonstrated total clearance of kidney capillary endothelium, but variable and unpredictable podocyte responses in children . This suggests different, dose-dependent clearance rates for different cell types and an impact of dose especially in difficult-to-clear cells, such as podocytes. ENDOTHELIAL CELLS VERSUS PODOCYTES What may be the biological basis underlying the different outcomes observed by Krämer et al.? Results from the FIELD trial provide some clues, by clearly demonstrating that podocytes are more difficult to clear than endothelial cells . Indeed, FIELD suggests that a lower agalsidase-beta dose may efficiently clear capillary endothelial cells, but this may be dissociated from podocyte clearance. This is not totally unexpected, given the large amounts of glycolipids accumulated in podocytes, which are very long-lived cells localized outside the capillaries, which may impair enzyme access. A multicentric observational study supports this view. Among 20 relatively young patients (median age 21 years) treated with either agalsidase-alfa 0.2 mg/kg/biweekly or different combinations of agalsidase-alfa or -beta at mean doses above 0.2 mg/kg/biweekly, cumulative agalsidase dose correlated with reduction in podocyte glycolipid inclusions (r = 0.69; P = 0.001) and in males, with reduction in plasma lyso-Gb3 levels (r = 0.71; P = 0.01) . Only three patients achieved complete or almost complete podocyte clearance: these were 3/4 patients having received the highest cumulative dose. Additionally, 9/10 patients receiving the higher dose completely cleared kidney arterial/arteriolar endothelial cells, while clearance was only achieved in 2/8 patients on long-term agalsidase-alfa 0.2 mg/kg/biweekly. Thus, the higher glycolipid clearance in both arterial/arteriolar endothelium and podocytes achieved by agalsidase-beta 1.0 mg/kg/biweekly may underlie the better kidney outcomes observed for this dose by Krämer et al. ARE THERE HEAD-TO-HEAD COMPARISONS OF AGALSIDASE-ALFA AND -BETA? One completed and one ongoing trial compared head-to-head agalsidase-alfa versus agalsidase-beta [29, 30]. The completed trial tested the 0.2 mg/kg/biweekly dose, which is not approved for agalsidase-beta . Treatment failure occurred frequently and seemed related to age and severe pre-treatment disease . An ongoing 10-year trial reported interim 5-year results when <20% of the estimated sample size had been recruited . Severe clinical events, the primary outcome measure, had occurred in 19.4% of patients receiving agalsidase-alfa 0.2 mg/kg/biweekly and in 13.3% of patients receiving agalsidase-beta 1 mg/kg/biweekly. A more recent, 8-year report, with recruitment still lagging several-fold below expectations, reported two-fold more clinical events per patient on agalsidase-alfa (45 events in 69 patients, 0.65 events per patient) than on agalsidase-beta (15 events in 46 patients, 0.33 events per patient), despite a significantly higher disease severity at baseline in patients randomized to beta . As expected by the low recruitment, which yielded the study underpowered, differences in severe events were not statistically significant. Again, a clear discrepancy is observed between clinical trial and registry outcomes, since FOS data suggested an estimated median survival for agalsidase-alfa-treated male Fabry patients of 77.5 years , which is higher than the life expectancy for general population males in the USA (76.1 years) and in the range of general population European Union (EU)-28 data (77.9 years). Regarding severe clinical events, Krämer et al. did not observe differences in RRT need or transitory ischemic attack/stroke, but patients switched to agalsidase-alfa had a higher risk of pacemaker/implantable cardioverter defibrillator implantation and the two deaths occurred in agalsidase-alfa arms . WHAT ABOUT NEUTRALIZING ANTIBODIES? It has been claimed that recombinant proteins obtained from hamster cells (which include recombinant erythropoietin) display xenoantigens that may promote an immune response that decreases their efficacy, thus justifying the higher agalsidase-beta dose . However, this interesting hypothesis is not supported by clinical data . It is more likely that complete absence of immunogenic material as a consequence of a severe mutation predisposes to development of antibodies when exposed to the missing protein. This phenomenon is well known for Alport syndrome patients receiving a kidney graft. In this regard, anti-agalsidase antibodies have not been reported in Fabry women and, when assessed with the same method, they were more frequent in males with severe mutations than in those with milder mutations, without differences between agalsidase formulations . The presence of agalsidase inhibitory activity in serum was associated with higher lyso-Gb3 levels and worse disease severity scores . In a different study, antibody development associated to an increase in lyso-Gb3 levels, which was more marked in patients receiving agalsidase-alfa 0.2 mg/kg/biweekly than in those on agalsidase-beta 1.0 mg/kg/biweekly. Switching antibody-positive males from agalsidase-alfa 0.2 mg/kg/biweekly to agalsidase-beta 1.0 mg/kg/biweekly lowered lyso-Gb3 . In another study, patients with high antibody titres benefited the most in terms of lyso-Gb3 lowering from switching from agalsidase-alfa 0.2 mg/kg/biweekly to agalsidase-beta 1.0 mg/kg/biweekly . These data point to a beneficial effect of higher dosed agalsidase-beta in patients with anti-agalsidase antibodies. In a smaller study, Immunoglobulin G antibodies were detected in 8/9 (89%) males with a nonsense mutation and in 6/15 (40%) males with a missense mutation (Fisher’s exact test P = 0.033), and in 4/10 (40%) males on agalsidase-alfa 0.2 mg/kg/biweekly and 8/10 (80%) males on agalsidase-beta 1.0 mg/kg/biweekly (Fisher’s exact test P = 0.169), but the interaction between genotype and dose was not explored . Antibodies are cross-reactive to both agalsidase formulations, indicating that they recognize a common epitope, further supporting an immune response to a previously missing alfa-galactosidase A antigen, not to a specific enzyme formulation [34, 38]. CONCLUSIONS In conclusion, the observational data by Krämer et al. fit within a growing body of evidence from clinical trials and observational studies suggesting the existence of a dose-response relationship for agalsidase in Fabry nephropathy, independently of the agalsidase formulation . Although large by FD standards, the sample size is small and follow-up is short in absolute terms. Additionally, despite the 5-fold difference in dose between formulations, an ongoing head-to-head clinical trial has so far only observed a numerically 50% lower incidence of severe clinical events with agalsidase-beta, which is not in any way commensurate with the difference in dose. The difference in events is not yet statistically significant, and we should wait for the trial completion. Bearing this in mind, dosing decisions should be individualized according to patient characteristics and preferences. FUNDING A.O. and M.D.S.-N. are supported by FIS PI16/02057, PI15/00298, CP14/00133, FEDER funds ISCIII-RETIC REDinREN RD16/0009, Sociedad Española de Nefrología and Miguel Servet MS14/00133. CONFLICT OF INTEREST STATEMENT A.O. is consultant for Genzyme, a Sanofi company, and has received speaker fees from Shire and Amicus. M.D.S.-N. has received speaker fees from Genzyme, a Sanofi company. (See related article by Krämer et al. Fabry disease under enzyme replacement therapy—new insights in efficacy of different dosages. Nephrol Dial Transplant 2018; 33: 1362--1372) REFERENCES 1 Germain DP. Fabry disease . Orphanet J Rare Dis 2010 ; 5 : 30 Google Scholar CrossRef Search ADS PubMed 2 Trimarchi H , Canzonieri R , Schiel A et al. 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Nephrology Dialysis Transplantation – Oxford University Press
Published: Aug 1, 2018
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