Protalix’s PRX-102 (pegunigalsidase alfa) for Fabry disease has three experts sceptical it can demonstrate efficacy superiority over Sanofi’s Fabrazyme (agalsidase beta) in the Phase III BALANCE trial. Still, if pegunigalsidase alfa demonstrates a clinically meaningful benefit through improved tolerability or more infrequent dosing in another Phase III study, the BRIGHT trial, the agency is unlikely to pull pegunigalsidase alfa from the market should BALANCE fail, some said. Instead, the FDA would likely ask for additional data, they explained.

A former FDA official said other compelling evidence of improved safety or convenience over standard-of-care (SOC) Fabrazyme could be enough for a full approval even without additional efficacy data. Pegunigalsidase alfa has a 27 April PDUFA date.

The 78-patient Phase III BALANCE trial, likely to read-out after the accelerated approval decision, could be too short and too small to demonstrate outright superiority along its endpoint of change in eGFR slope, the three experts agreed. One Fabry disease researcher said it could take up to 10 years to detect a statistically significant change between the two enzyme replacement therapies (ERTs) in this particularly heterogeneous disease population. Another three experts declined to comment on success prospects.

Though some experts said they are encouraged by positive efficacy results from the open-label BRIDGE trial, which saw patients taking Takeda’s ERT Replagal (agalsidase alfa) switch to pegunigalsidase alfa, it falls short of convincing. In particular, Replagal is not available in the US and is given at a lower dose than pegunigalsidase alfa, limiting the extrapolation potential to BALANCE, which compares equal doses of pegunigalsidase alfa and Fabrazyme, one BALANCE investigator said.

Pegunigalsidase alfa’s MOA, and in particular its longer half-life, suggest it can be more tolerable and last longer than Fabrazyme, leading to more infrequent dosing and fewer infusion-related adverse events (AEs), some experts said. The open-label BRIGHT trial, set to read-out 1Q21, is measuring safety in patients who switch from Fabrazyme every two weeks to pegunigalsidase alfa every four weeks, according to

Analyst reports predict accelerated approval and give pegunigalsidase alfa a strong chance of outperforming Fabrazyme in the market. Clinicians this publication spoke to see the potential for better immunogenicity and dosing schedule as key drivers of uptake regardless of whether outright superiority in efficacy is shown.

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A GlobalData consensus predicts peak sales of $39m by 2026. Protalix has a market cap of $153.9m. At press time, a Protalix spokesperson had not responded to a request for comment.

Outright renal superiority has shaky expectations

The BALANCE trial’s primary endpoint of eGFR slope is a well-established FDA benchmark for efficacy in Fabry disease, said BALANCE investigator Dr Khan Nedd, chief medical officer, Infusion Associates, Grand Rapids, Michigan. But the heterogeneity of Fabry disease patients and the multitude of confounding factors that influence eGFR decline weaken the prospects of detecting meaningful change along this scale, explained Dr James Shayman, professor, Department of Pharmacology, University of Michigan Medical School, Ann Arbor.

It is difficult to gather accurate eGFR measurements for patients with stage 3 or better levels of renal function, corresponding to an eGFR of more than 60 mL/min/1.73m², Shayman explained. BALANCE allows for patients with screening eGFR between 40 and 120 mL/min/1.73m. In addition, most people begin to naturally lose an average of 1% of their GFR per year once they are 35 years old, he added. BALANCE patients are between ages 18 to 60 years old, according to

Because pegunigalsidase alfa and Fabrazyme are similar enzyme molecules, it could take up to 10 years to demonstrate a significant difference in their efficacy, said Dr Robert Hopkin, associate professor, Clinical Paediatrics, Cincinnati Children’s Hospital Medical Centre, Ohio. Additionally, small trial sizes—particularly in cases with less than 100 patients—add to the difficulty in powering a study to detect statistically significant changes in eGFR slope, Hayman added. The 78-patient BALANCE trial is measuring patients’ eGFR slope every month for a period of two years, according to

Still, a negative eGFR slope is important for regulators and clinicians even when the patient has a normal baseline reading because the former correlates with long-term complications, added Dr Eric Wallace, BALANCE investigator and nephrologist, University of Alabama Hospital, Birmingham.

Potential safety, convenience benefits bolster full approval chances, but caveats remain

If BALANCE does not meet its primary endpoint, the FDA would likely require either additional analysis of existing data or an additional study to grant full approval, said Hopkin and the first regulatory consultant. Some positive efficacy signals in BALANCE, combined with BRIGHT data supporting an improved tolerability profile, would likely cause the FDA to continue allowing the marketing of pegunigalsidase alfa while Protalix gathers more confirmatory data in the event it does not hit its target in BALANCE, the first consultant added.

Additionally, the second regulatory consultant explained that the FDA’s definition of superiority is not limited to efficacy, as a clinically significant improvement in safety or another patient benefit, including an improved dosing schedule, would also qualify. As a result, if the FDA grants accelerated approval based on BRIDGE and BRIGHT data, this would indicate the agency already believes that pegunigalsidase alfa offers a clinical benefit outside of outright superiority in efficacy over existing ERTs, she added. This, in turn, diminishes the importance of BALANCE’s eGFR slope readout in the FDA’s full approval decision, she explained.

Pegunigalsidase alfa has been shown to have a longer half-life than other ERTs, including Fabrazyme, causing measurable serum levels to last longer in the serum, Wallace explained. The hypothesis is that a longer half-life will correspond to improved patient outcomes, but this must be confirmed by the results of the BALANCE study, he added.

Published results from the BRIDGE trial are supportive evidence of pegunigalsidase alfa’s efficacy, Nedd and Wallace agreed. In BRIDGE, the annualised eGFR slope of patients improved from -5.90 mL/min/1.73m2/year on Replagal to -1.19 mL/min/1.73m2/year on pegunigalsidase alfa, according to a 30 December 2020 company press release. However, Replagal is dosed at a lower dose than pegunigalsidase alfa in BRIDGE which is important in this crossover study as a dose effect may be contributing to the positive results seen, Wallace explained. Though Wallace declined to comment on how BRIDGE data could influence regulatory decisions, he said BALANCE results were necessary to confirm the positive effect in BRIDGE given that pegunigalsidase alfa and Fabrazyme are dosed equally in the ongoing study.

While Fabrazyme is a largely unmodified version of human alpha-galactosidase A, pegunigalsidase alfa pegylates the enzyme, thereby hiding some of the protein epitopes to which the body reacts and develops antibodies, Hopkin explained. As a result, pegunigalsidase alfa could lead to less infusion response from patients, fewer infusion reactions, and more drug delivered to the cells that need it, he added. In a preclinical study, approximately 84% of pegunigalsidase alfa’s enzyme activity was preserved after 10 days in lysosomal-like conditions compared to approximately 1% in each commercially available ERT (p=0.01) (Kizhner T., et al. (2015) Molecular Genetics and Metabolism 114: 259–267).

The ongoing, 30-patient BRIGHT study (n=30) doses patients previously on Fabrazyme with 2mg/kg infusions of pegunigalsidase alfa every four weeks and is measuring treatment-emergent AEs after one year as its primary endpoint, according to Both BALANCE and BRIDGE dose 1mg/kg every two weeks, consistent with the recommended dosing of Fabrazyme. In BRIDGE, most AEs were mild or moderate—the most common treatment-emergent AEs being nasopharyngitis, headache and diarrhoea—and 2 of the 22 patients withdrew due to hypersensitivity reaction that was resolved.

Immunogenicity benefits could drive approval, strong uptake 

Successful demonstration of superiority over Fabrazyme in BALANCE would all but guarantee widespread first-line use and supplantation of Fabrazyme as the primary Fabry disease therapy, Hopkin said. Without it, immunogenicity and patient-centric quality-of-life measures will be key drivers of uptake, he added.

Even if eGFR improvements are not particularly differentiated among pegunigalsidase alfa and Fabrazyme, a majority of patients would likely switch to pegunigalsidase alfa if a more infrequent dosing schedule is approved, Nedd added. Given that Fabry disease runs in families, patients tend to be more knowledgeable of treatment developments than many other patient groups, making it easier for new drugs to gain market traction, he explained.

Additionally, though the average age of diagnosis for Fabry disease is mid-30s, there is a growing trend toward earlier diagnoses, broadening the potential market for pegunigalsidase alfa, Hopkin said. The BALANCE trial is enrolling patients 18 and older. There is now genetic testing for Fabry disease at birth, and symptoms can appear as early as 5–7 years for men or 8–10 years for women, he added. Fabry patients typically begin taking ERTs as soon as symptoms appear, he said.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.