ERT Dose Should be Tailored to Patient for Optimal Effectiveness, Study Shows

Adjusting the dose of enzyme replacement therapy (ERT) for each patient may be essential to achieve complete neutralization of antibodies against the treatment, and reach better results to halt the progression of Fabry disease, according to a recent study.

The study, “Dose-Dependent Effect of Enzyme Replacement Therapy on Neutralizing Antidrug Antibody Titers and Clinical Outcome in Patients with Fabry Disease,” was published in the Journal of the American Society of Nephrology.

Fabry disease is caused by absent or markedly reduced α-galactosidase A (GLA) enzymatic activity, which leads to the damaging accumulation of two fat molecules — Gb3 and lysoGb3 — in tissues such as the heart, kidneys, nervous system, eyes, and skin.

ERT replaces the faulty GLA enzyme and restores its normal function. Currently, two versions of the enzyme are commercially available — agalsidase alpha (or Replagal, developed by Shire) and agalsidase beta (or Fabrazyme, developed by Sanofi Genzyme) — but only Fabrazyme is approved by the U.S. Food and Drug Administration.

However, patients’ immune systems often “attack” these versions of the enzyme by producing antibodies against them — called antidrug antibodies (ADA) — which limits the effectiveness of the therapy and leads to a progressive loss of kidney function.

Previous studies have shown that 70% of male patients with Fabry disease produce ADAs, potentially compromising ERT action.

Preliminary data have shown that agalsidase ERT can saturate ADA-binding sites during treatment, meaning that all antibodies become bound to the agalsidase, leaving more free enzyme to effectively perform its action. Better responses to treatment (i.e., decreasing lyso-Gb3 levels) were also observed where ADA-binding sites were saturated. These responses were shown to be dependent on the applied ERT dose.

This suggests that patients may be classified as ADA-saturated (with agalsidase excess) and ADA-non-saturated (antibody excess/agalsidase deficit).

Researchers in Germany, Austria, and Switzerland have now assessed the levels of ADAs in male Fabry disease patients and evaluated whether ADA-saturated patients showed better treatment responses than ADA-non-saturated patients. They also investigated ERT’s ability to neutralize these antibodies, and whether dose adjustment of ERT could induce ADA saturation.

The long-term data of 26 male patients who had been treated with ERT for at least six months and who were positive for the presence of ADAs were retrospectively analyzed.

Patients’ mean age at recruitment was 40 years, and they had received ERT for a median of 94 months.

Eleven patients had been treated with Replagal, 15 with Fabrazyme, and three had switched from Replagal to Fabrazyme between treatment initiation and follow-up.

The results showed that while all patients showed comparable disease burden before ERT, ADA-non-saturated patients (12 individuals) had a steeper decrease in kidney function, a significant increase in heart wall thickness, and a weaker decline in lyso-Gb3 levels — a biomarker of the disease — than ADA-saturated patients (14 individuals).

The data indicate that in patients with ADAs, “a saturated status during infusion [ERT administration] might be beneficial in terms of clinical outcome and less severe disease progression of affected patients,” the researchers said.

Thus, ERT’s effectiveness in these patients appears to depend on the levels of ADAs and ADA saturation during treatment.

The team also found that Replagal and Fabrazyme had similar capacity to neutralize ADAs.

In patients with no ADA saturation, dose escalation — either within the same ERT or involving a switch to the other ERT — resulted in ADA saturation and reduced levels of lyso-Gb3, suggesting that Fabry disease patients may benefit from a more personalized treatment to achieve optimal results.

However, researchers noted that switching from Replagal to Fabrazyme in some patients led to an increase in the total levels of ADAs, at least in the short term, which should be further explored.

The team suggested that all male patients with Fabry disease who are receiving ERT should be tested regularly for ADA levels, as well as ADA saturation during treatment.

If the current ERT dose does not completely neutralize the patient’s ADAs, the patient may benefit from an approved dose escalation or a switch to alternative therapy options.

They also noted that additional studies are required to confirm this association between ADA saturation status and clinical response, and to evaluate whether lyso-Gb3 levels can be used as a marker of the presence of ADAs.