Antibodies to Fabry treatment tied to infusion reaction risk
Patients with ERT antibodies show higher disease-related biomarker levels
Written by |
People with Fabry disease who develop antidrug antibodies (ADAs) against enzyme replacement therapy (ERT) tend to show higher levels of disease-related biomarkers and experience more infusion-related reactions than those without these antibodies.
The review of 24 studies found the link between ADAs and kidney and heart outcomes was less consistent.
“This review underscores the importance of standardized ADA assessments and organ-specific outcomes to understand the full clinical impact of ADA formation and to guide more personalized treatment for patients with Fabry disease,” the researchers wrote.
The study, “Evaluating the relationship between antidrug antibodies and efficacy and safety outcomes in patients with Fabry disease receiving enzyme replacement therapy: a systematic literature review,” was published in the Orphanet Journal of Rare Diseases.
Fabry disease is caused by a lack of the enzyme alpha-galactosidase A (alpha-Gal A). Without enough enzyme, a fatty substance called globotriaosylceramide (Gb3), along with its metabolite lyso-Gb3, builds up in cells. Over time, this buildup can lead to kidney or heart damage, which can be symptoms of Fabry disease.
ADAs and ERT
The standard Fabry treatment is ERT, which supplies patients with the missing enzyme to help clear Gb3 and lyso-Gb3 from cells. But because ERT introduces a protein that the body may recognize as foreign, some patients develop antidrug antibodies (ADAs), which can reduce treatment effectiveness.
The researchers conducted their review because it’s not entirely clear how much effect ADAs actually have on ERT’s ability to control the disease or on safety. From a medical literature search, they identified 24 studies examining ADAs and their associations with disease biomarkers (Gb3, lyso-Gb3), kidney and heart outcomes, and safety measures.
The team found that 17 of 18 studies reported a statistically significant positive association between higher levels of Gb3 or lyso-Gb3 in patients with ADAs than in those without ADAs.
This was especially clear for elevated urine Gb3, where all six studies found higher levels in ADA-positive patients. In blood tests, one of three studies found a relationship between elevated blood Gb3 and ADAs. For blood lyso-Gb3, four of eight studies found significantly higher levels in patients with ADAs.
Kidney outcomes showed a less consistent pattern. Of nine studies that reported data on changes in kidney function, as measured by estimated glomerular filtration rate (eGFR), two showed a significantly faster decline in patients with ADAs and one showed a trend toward rapid eGFR decline with increasing ADA. Two showed no difference, and four reported data without a statistical analysis.
Heart-related findings were more limited, with four studies reporting on ADAs and heart outcomes. Two studies found a significant association between ADA positivity and worse heart measurements, including higher left ventricular mass, a measure related to heart muscle thickening. The other two found no significant association with cardiovascular outcomes.
Safety data suggested a stronger connection between ADAs and infusion-related reactions (IRRs). Symptoms can range from mild (flushing, itching, fever, and chills) to severe (difficulty breathing or low blood pressure).
Of the nine studies that examined this relationship, four found a statistically significant link between ADAs and IRRs, and two of these also found significant links to serious IRRs. Of seven studies comparing IRR rates by antibody status, five found higher rates in antibody-positive patients, while two found similar rates between groups.
In a pooled analysis, the proportion of ADA-positive patients affected by IRRs was more than double that in the ADA-negative population (38% vs 18%). Still, “IRRs still occurred in ADA-negative patients, suggesting that not all IRRs are necessarily related to the effects of ADAs,” the team noted.
Of the two studies that assessed hypersensitivity reactions, one found significantly more reactions in antibody-positive patients (42 patients vs five patients), while the other found no association. That same study found general adverse events, serious adverse events, and adverse drug reactions were all significantly more common in antibody-positive patients.
A statistical pooling of results (meta-analysis) was not possible due to differences in study designs, ADA testing methods, and varied reported outcomes, the researchers said. In addition, several studies didn’t distinguish between neutralizing antibodies, which block the enzyme’s activity, and non-neutralizing antibodies, which bind to the enzyme without blocking it.
Because of this, the scientists said, the reported associations do not demonstrate that ADAs directly cause worse outcomes, as factors such as more severe underlying disease could also explain some of the observed patterns.
“ADA positivity has been linked to IRR occurrence and increased levels of Fabry disease-related biomarkers, suggesting both the possibility of reduced ERT tolerability and diminished ERT activity in ADA-positive patients,” the team concluded.
Leave a comment
Fill in the required fields to post. Your email address will not be published.