Protalix and Chiesi Report Final Results of Phase 3 Trial of Experimental Fabry Disease Treatment

Protalix BioTherapeutics and Chiesi Global Rare Diseases reported final results from the BRIGHT phase 3 clinical trial evaluating pegunigalsidase alfa for the potential treatment of Fabry disease, which achieved the key objectives for safety, efficacy, and pharmacokinetics.

Photo: Giacomo Chiesi, head of Chiesi Global Rare Diseases

The results indicate that treatment with 2 mg/kg of pegunigalsidase alfa (PRX‑102) administered by intravenous infusion every four weeks was well tolerated, and Fabry disease assessed by estimated glomerular filtration rate (eGFR) slope and plasma lyso-Gb3 concentration was stable.

Protalix says the final data is an important milestone in the progress of the PRX-102 program.

“The availability of this data for review by the U.S. Food and Drug Administration, the European Medicines Agency and other regulators is another step forward towards the anticipated approval of PRX-102 as a potential good alternative for adult Fabry patients in both the regular 1 mg\kg every two weeks as well as the 2 mg\kg every four weeks regimen,” said Dror Bashan, president and CEO of Protalix.

Fabry disease is an X-linked inherited disease that results from deficient activity of the lysosomal α‑Galactosidase‑A enzyme resulting in progressive accumulation of abnormal deposits of a fatty substance called globotriaosylceramide (Gb3) in blood vessel walls throughout a person’s body. Fabry disease occurs in one person per 40,000 to 60,000. Fabry patients inherit a deficiency of the α‑Galactosidase‑A enzyme, which is normally responsible for the breakdown of Gb3. The abnormal storage of Gb3 increases with time resulting in the accumulation of Gb3, primarily in the blood and in the blood vessel walls. The ultimate consequences of Gb3 deposition range from episodes of pain and impaired peripheral sensation to end-organ failure—particularly of the kidneys, but also of the heart and the cerebrovascular system.

PRX-102 is a plant cell-expressed recombinant, PEGylated, cross-linked α‑galactosidase‑A product candidate. The BRIGHT phase 3 clinical trial was a multicenter, multinational open-label, switch-over study designed to evaluate the safety, efficacy, and pharmacokinetics of treatment with 2 mg/kg of PRX-102 administered every four weeks for 52 weeks (a total of 14 infusions). The study enrolled 30 adult patients with Fabry disease (24 males and 6 females) with mean age of 40.5 years, ranging from 19 to 58 years, who previously received an approved enzyme replacement therapy (ERT) for at least three years on a stable dose administered every two weeks (agalsidase alfa – Replagal or agalsidase beta—Fabrazyme). The most common Fabry disease symptoms at baseline were acroparesthesia, heat intolerance, angiokeratomas, and hypohydrosis.

All patients who participated in the study received at least one dose of PRX-102, and 29 patients completed the study. Of these 29 patients, 28 received the intended regimen of 2 mg/kg of PRX-102 every four weeks throughout the entire study, while one patient was switched to 1 mg/kg of PRX-102 every two weeks per protocol at the 11th infusion. One patient withdrew from the study after the first infusion due to a traffic accident.

First infusions of PRX-102 were administered under controlled conditions at the investigational site. Based on pre-specified criteria in the study protocol, patients were able to receive their PRX-102 infusions at a home care setup once the Investigator and Sponsor Medical Monitor agreed that it was safe to do so.

Overall, 33 of 182 total treatment-emergent adverse events (TEAEs) reported in nine (30 percent) patients were considered treatment-related; all were mild or moderate in severity and the majority were resolved at the end of the study. There were no serious or severe treatment-related TEAEs and no TEAEs led to death or study withdrawal. Of the treatment-related TEAEs, 27 were infusion-related reactions (IRRs) and the remainder were single events of diarrhea, erythema, fatigue, influenza-like illness, increased urine protein/creatinine ratio, and urine positive for white blood cells. The 27 IRRs were reported in five (16.7 percent) patients, all male. All IRRs occurred during the infusion or within two hours post-infusion; no events were recorded between two and 24 hours post-infusion. None of the patients without anti-drug antibodies (ADAs) at screening developed treatment-induced ADAs following the switch to PRX-102 treatment.

Study outcome measures show that plasma lyso‑Gb3 concentrations remained stable during the study with a mean change of 3.01 nM (0.94) from baseline (19.36 nM ±3.35) to Week 52 (22.23 ±3.60 nM). Mean absolute eGFR values were stable during the 52‑week treatment period, with a mean change from baseline of ‑1.27 mL/min/1.73 m2(1.39). Mean eGFR slope, at the end of the study, for the overall population, was ‑2.92 (1.05) mL/min/1.73m2/year indicating stability.

“Based on these data and additional clinical studies, we believe PRX-102 may be an important new treatment option for patients who are currently receiving ERT infusions every two weeks, and we look forward to advancing our work around the world to obtain regulatory approvals as quickly as possible and provide access to the Fabry disease community,” said Giacomo Chiesi, head of Chiesi Global Rare Diseases.

Additional long-term data is being collected as part of an extension study. The companies intend to present final data from the BRIGHT phase 3 clinical trial at one or more medical conferences.