Fabry disease patients may naturally have higher levels of neutralizing antibodies against Fabrazyme (agalsidase beta) than against Protalix BioTherapeutics‘ investigational PRX-102 (pegunigalsidase alfa), BALANCE Phase 3 trial data suggest.
As antibodies can limit the effectiveness of enzyme replacement therapies, developing less of them suggests that patients will potentially have higher levels of the active enzyme — and derive more benefits — when treated with PRX-102 compared with Fabrazyme.
These findings were reported at the 2020 Annual WORLD Symposium held in Florida, in the poster presentation, “Pegunigalsidase alfa, a novel PEGylated ERT, evaluated in Fabry patients with progressing kidney disease, RCT study design.”
The enzyme is responsible for breaking down a fatty molecule called globotriaosylceramide (Gb3), which builds up in patients, causing problems in different organs and tissues, including the heart, brain, and kidney.
PXR-102 delivers a fully functional copy of alpha-galactosidase A to patients. But the enzyme is chemically modified in a way that makes it more stable than current ERT therapies, potentially allowing for more time between treatment infusions.
Two ongoing Phase 3 trials are investigating if the experimental therapy is better at slowing declines in kidney health than the two commercially available ERTs for Fabry, Fabrazyme (by Sanofi Genzyme) and Replagal (agalsidase alpha; by Shire).
BRIDGE (NCT03018730) is a single-arm study in 22 Fabry patients, all previously using Replagal for at least two years before switching to PXR-102, administered via intravenous (into-the-vein) infusion every two weeks for one year.
Results from the first 16 patients completing 12 months of treatment showed that PXR-102 meaningfully reduced the rate of kidney decline — assessed as the annual change in the estimated Glomerular Filtration Rate (eGFR).
While on Replagal, these patients had been experiencing a 5.1 mL/min/1.73m² reduction in their average eGFR per year. Over one year of PXR-102’s use, the drop in eGFR scores fell to 0.23 mL/min/1.73m².
Patients who experience yearly reductions of 3 mL/min/1.73m² (square meters) or less are considered to have stable disease.
PXR-102 was seen to be safe and well-tolerated, and also induced a decline in blood levels of Lyso-Gb3 — a biomarker of disease severity — particularly in men.
BALANCE (NCT02795676), also a Phase 3 trial, is assessing PXR-102 in patients with progressive kidney disease — those with kidney function ranging from normal to severely affected, but worsening across this group. All were taking Fabrazyme for at least one year before entering the study.
Unlike in BRIGDE, people in BALANCE were randomly assigned to either continue on Fabrazyme or to switch to PXR-102. Both treatment are being given via intravenous infusion every two weeks for two years.
Researchers in the poster described the baseline (study start) characteristics of the 75 patients enrolled in this trial across 29 sites in Europe and the U.S.
In total, 46 men and 29 women were enrolled with an average age of 45. About half had a mild loss of kidney function and 27% had moderate to severe loss of renal function. Men had more advanced kidney disease than did women.
Most were experiencing a rapid decline in kidney function, with an average reduction in eGFR scores of 8.1 mL/min/1.73m² per year, regardless of how severe their kidney impairment. Those with poorer kidney function were progressing somewhat faster than the others.
Researchers also measured neutralizing (anti-drug) antibodies in these patients, which can limit the effectiveness of enzyme replacement therapies. They found that 7.7% of women and 41% of men had such antibodies, but levels of antibodies against the active ingredient of Fabrazyme were much higher than those targeting PXR-102.
This suggested that patients on Fabrazyme were only left with 23% of the treatment’s enzymatic activity, while those on PXR-102 had about 40% of enzymatic activity.
In addition to measuring the decline in kidney function, researchers will assess changes in heart function, levels of disease biomarkers, pain and use of pain medication, as well as quality of life as secondary measures.
BRIDGE is expected to conclude in July, and BALANCE to finish with data collection in October 2021.
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