Elfabrio as effective as Fabrazyme for Fabry with kidney decline: Trial

Fewer infusion-related side effects seen with Elfabrio in BALANCE Phase 3 trial

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Elfabrio (pegunigalsidase alfa) is as safe and effective as Fabrazyme (agalsidase beta) and can prevent kidney decline in adults with Fabry disease over two years, according to final data from the BALANCE Phase 3 clinical trial.

Infusion-related side effects, in particular, occur significantly less often with Elfabrio than with Fabrazyme, data show.

“BALANCE demonstrated non-inferior renal efficacy and the potential for improved tolerability with [Elfabrio] compared with [Fabrazyme] in patients with [Fabry disease] and deteriorating renal function,” researchers wrote.

Full details of the trial were published in the Journal of Medical Genetics in the study “Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.”

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Elfabrio approved in US and EU this year

Earlier this year, Elfabrio was approved by the U.S. Food and Drug Administration and by the European Commission for adults with Fabry based, in part, on BALANCE trial data. The treatment was codeveloped by Protalix BioTherapeutics and Chiesi Global Rare Diseases.

People with Fabry disease carry mutations in the GLA gene, causing a deficiency in alpha-galactosidase A (Gal A), an enzyme that breaks down certain fatty molecules. Gal A deficiency results in the toxic buildup of Gb3 and lyso-Gb3 molecules in cells, causing damage to the heart, kidneys, and other organs.

As the first plant-based enzyme replacement therapy (ERT), Elfabrio delivers a functional version of the Gal A enzyme administered by infusion directly into a patient’s bloodstream. Using Protalix’s plant-based ProCellEx platform, the ERT has a longer half-life, or the time required for the blood level of a medication to reduce by half, potentially allowing for fewer doses.

The global BALANCE Phase 3 study (NCT02795676) compared the safety and effectiveness of Elfabrio against Sanofi Genzyme’s approved ERT Fabrazyme in 77 adults with Fabry and progressive kidney disease.

All participants were treated with Fabrazyme for at least one year before the BALANCE trial. Twenty-five participants were randomly assigned to continue with the treatment, and 52 received Elfabrio, both given at 1 mg/kg of body weight every two weeks for two years.

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Among the 77 participants given at least one dose of Elfabrio or Fabrazyme, the median estimated glomerular filtration rate (eGFR) at the study’s start (baseline) was similar between the two groups. Lower eGFR values indicate increasing kidney damage.

After two years, the median decline in eGFR was -2.51 (as measured in mL/min/1.73 meters squared/year) in the Elfabrio arm compared with -2.16 in the Fabrazyme arm, a non-inferior difference of -0.36. This difference among men was -1.43 and 1.64 in women.

At the beginning of the study, all participants who tested positive for antibodies against the respective enzyme replacement therapies were men. In this group, the median eGFR decline was -2.51 in the Elfabrio arm after two years compared with -2.16 in the Fabrazyme arm, a non-inferior difference of -0.36. The difference in those who tested negative for anti-ERT antibodies was -0.07.

Men had higher levels of lyso-Gb3 in their blood plasma, the liquid portion of blood without cells, throughout the study compared with women, a result the team noted as “expected.” At two years, the median change in lyso-Gb3 in men increased by 5.30 nanomolar (nM) with Elfabrio and decreased by 2.40 nM with Fabrazyme. In women, this change was minimal (0.10 vs. -0.30 nM).

Overall, the median lyso-Gb3 remained relatively stable in each arm with a less than 2 nM change from baseline to two years.

Lyso-Gb3 increases exceeding 20% and 10 nM from baseline were seen in individuals who tested positive for anti-ERT antibodies and a high urine protein-to-creatinine ratio, a sign of kidney dysfunction. All of these patients were men and were more frequently assigned to Elfabrio than Fabrazyme (18 vs. 8 patients). “Generally, the clinical significance of the magnitude of lyso-Gb3 changes in both groups should be interpreted with caution,” the researchers wrote.

The proportion of adverse events related to ERT was similar between Elfabrio and Fabrazyme (40% vs. 44%). No deaths were reported.

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Infusion-related reaction rate lower with Elfabrio

The infusion-related reaction rate was significantly lower with Elfabrio than with Fabrazyme (0.5 vs. 3.9 event/100 infusions), a finding similar in men and women. This reaction rate was also lower with Elfabrio than with Fabrazyme among antibody-positive and -negative patients.

Over two years, there was a notable drop in premedication use (based on a prior Fabrazyme regimen) in patients receiving Elfabrio (40.4% to 6.4%) and Fabrazyme (64.0% to 12.5%).

Fewer men tested positive for anti-ERT antibodies after two years of Elfabrio than at baseline (40% vs. 62%). While no women tested positive at baseline, one (5%) was positive after two years of Elfabrio. Similar results were seen in men taking Fabrazyme (38% vs. 44%).

Of the total Elfabrio infusions over two years, 46.0% were administered at home. The mean time to complete an infusion dropped from baseline in the Elfabrio group (3.1 to 1.6 hours) and Fabrazyme group (3.0 vs. 1.7 hours), with no significant difference between groups after two years.

“Based on rate of eGFR decline over 2 years, [Elfabrio] was non-inferior to [Fabrazyme],” the researchers concluded. “[Elfabrio] had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions.”