Patients’ anti-PEG antibodies may not block effects of Elfabrio: Study

Approved ERT still found effective in lab studies of Fabry patients' blood

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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About a third of Fabry disease patients were found to have low levels of antibodies against a substance called polyethylene glycol, or PEG, that’s present in Elfabrio (pegunigalsidase-alfa), an enzyme replacement therapy approved in the U.S. earlier this year as a treatment for the genetic disorder.

However, these anti-PEG antibodies did not appear to block the therapy’s effectiveness in lab studies, the data show.

Gal A, or AGAL, is the enzyme that’s lacking in Fabry disease. Enzyme replacement therapy, or ERT, works to provide patients with a version of the enzyme that can increase Gal A activity in the blood. As expected, existing antibodies against Gal A did block enzyme activity in response to ERT.

“Since neutralizing antibodies may reduce the efficacy of ERT treatment in [Fabry] patients, patients on [Elfabrio] therapy should be tested for anti-PEG and anti-AGAL antibodies before and during treatment,” the researchers wrote.

The study, “Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease,” was published in Frontiers in Immunology. Chiesi, Elfabrio’s developer, funded the study but was not involved in its design or operation.

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FDA OKs PRX-102, now Elfabrio, to treat adults with Fabry disease

Elfabrio approved this year in both US and EU

The first available ERTs for Fabry, approved in the early 2000s in certain regions, have proven effective at boosting Gal A activity and easing disease symptoms. These include Takeda’s Replagal (agalsidase-alfa) — approved only outside the U.S. — and Sanofi’s Fabrazyme (agalsidase-beta), which is approved in the U.S. and the European Union.

However, for patients who do not make any of their own Gal A, there is a high risk that their immune system will develop antibodies against the lab-made version, impairing treatment efficacy.

Elfabrio was more recently approved in the U.S. and Europe. This ERT is linked to PEG, a large molecule that’s cleared from the body at a very slow rate. As such, it works to prolong the therapy’s presence in the bloodstream and also helps protect the therapeutic protein from unwanted immune attacks.

Research suggests that Elfabrio may be less likely to cause an immune response against Gal A than Replagal or Fabrazyme. Moreover, pre-existing antibodies in the bloodstream against Replagal or Fabrazyme are found to have a lower affinity for attacking Elfabrio.

One concern, however, is that most people are exposed to PEG routinely in daily life. It’s a common ingredient in cosmetics, soaps, over-the-counter laxatives, and certain vaccines, among other products. It is possible, then, that some people may have existing antibodies against PEG that could interfere with the effectiveness of any PEG-attached, or PEGylated, therapy.

In a recent study, scientists described the case of a healthy 41-year-old man in whom anti-PEG antibodies developed after receiving an mRNA-based COVID-19 vaccine containing PEG.

In lab studies, the antibodies recognized Elfabrio and had an inhibitory effect, causing the therapy to be cleared from the blood more quickly and the Gal A enzyme to have less activity.

This prompted the researchers to investigate the potential impact of pre-existing PEG antibodies on Elfabrio activity in the blood. Their study involved 102 Fabry patients.

At the time blood samples were drawn, 43 were receiving Fabrazyme or Replagal, while 17 were on Galafold (miglastat), an oral chaperone therapy. The remaining 42 patients were treatment-naïve. None had received Elfabrio.

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Anti-PEG antibodies did not seem to have inhibitory effect on Elfabrio

Among the participants, 15 had existing anti-Gal A antibodies and served as a control group. Of the other 87 people, 29 or nearly one-third showed evidence of anti-PEG antibodies. Antibody levels in these patients in response to ERT were lower than in the control group.

Altogether, these low levels of anti-PEG antibodies appeared not to have an inhibitory effect on Gal A enzyme activity in response to Elfabrio treatment. They also did not influence Elfabrio’s half-life, a measure reflecting how long a substance stays in the bloodstream.

It is conceivable that therapy efficacy may be better under next-generation [Elfabrio] therapy than under current ERTs.

On the other hand, pre-existing anti-Gal A antibodies did block Gal A activity in response to both Elfabrio and Fabrazyme relative to samples without these antibodies.

Still, this inhibition was stronger in response to Fabrazyme, ” which confirms our recent data, demonstrating that pre-existing anti-AGAL antibodies show less affinity towards [Elfabrio],” the researchers wrote.

Moreover, while these antibodies caused Elfabrio’s half-life to drop by about 60%, it still remained in the blood about fivefold longer than did Fabrazyme.

Among 14 Fabry patients known to have received an mRNA-based COVID-19 vaccine, there was no evidence of the development of anti-PEG antibodies an average of 7.5 months after vaccination.

Altogether, “it is conceivable that therapy efficacy may be better under next-generation [Elfabrio] therapy than under current ERTs in terms of reduced inhibitory effects of anti-AGAL and minor (marginal or insignificant) inhibitory effect of anti-PEG antibodies,” the researchers wrote.

As Elfabrio becomes available to patients, the effects of such treatment on antibody formation should be evaluated, “which will be the scope of a future study,” the researchers wrote.