RARE Daily

Protalix and Chiesi Report Positive Topline Results from Phase 3 Fabry Disease Study

April 4, 2022

Protalix BioTherapeutics and Chiesi Global Rare Diseases reported topline results from the BALANCE pivotal phase 3 clinical trial evaluating a 1 mg/kg dose of PRX-102, administered every two weeks, compared to agalsidase beta for the treatment of Fabry disease.

Photo: Dror Bashan, president and CEO of Protalix

PRX-102 successfully met the primary endpoint on kidney function in the active control, non-inferiority study vs. agalsidase beta (Fabrazyme), and demonstrated a favorable tolerability and immunogenicity profile. The partners are planning a BLA resubmission for the second half of 2022.

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.

Pegunigalsidase alfa (PRX–102) is a novel, PEGylated enzyme replacement therapy (ERT) under development for the treatment of Fabry disease.

“Based on results from our clinical program, we believe that PRX–102, as a PEGylated enzyme replacement therapy with potentially two different dosing regimens, may be a valuable new treatment option for individuals suffering from Fabry disease,” said Dror Bashan, president and CEO of Protalix.

The just completed pivotal phase 3 BALANCE clinical trial is a 24–month, randomized, double-blind, active control study of PRX–102 in adult Fabry patients with deteriorating renal function that was designed to evaluate the safety and efficacy of 1 mg/kg of PRX–102 administered every two weeks compared to agalsidase beta (Fabrazyme). The study enrolled 78 patients who were previously treated with agalsidase beta for at least one year with an estimated glomerular filtration rate (eGFR) slope at screening worse than –2 mL/min/1.73 m2/year. Patients were randomized on a 2:1 ratio for switching to PRX–102 or continuing agalsidase beta. A total of 77 patients were treated, 52 with PRX–102 and 25 with agalsidase beta.

“We believe that this multi-year study demonstrates the potential for switching from agalsidase beta to PRX–102 in the treatment of patients with Fabry disease. The study met our pre–defined criteria for non-inferiority of the primary endpoint of kidney function in a head–to–head active comparison on both the Intent–to–Treat (ITT) and Per Protocol (PP) analysis sets,” said Einat Brill Almon, senior vice president and chief development officer of Protalix. “These topline results show that PRX–102 was comparable to agalsidase beta in controlling eGFR decline, which is a key measure of Fabry disease progression, and continue to demonstrate a favorable tolerability profile for PRX–102. Combined with previous phase 3 results from our BRIGHT and BRIDGE studies, as well as the results from our phase 1/2 study and its long-term extension, we believe we have a compelling and consistent dataset from both treatment–naïve and ERT–experienced patients. Given these results, we plan, together with Chiesi, our commercialization partner, to work with regulatory agencies on the applicable submissions, hopefully bringing PRX–102 to approval as a new PEGylated enzyme replacement therapy for all adult Fabry patients.”

As first announced in October 2021, as part of a Type A End–of–Review meeting, the U.S. Food and Drug Administration, in principle, agreed that the proposed analysis of the BALANCE study demonstrating non-inferiority to agalsidase beta included in the data package for the PRX–102 biologics license application (BLA) resubmission has the potential to support the approval of PRX–102 for the treatment of Fabry disease. Given the changed regulatory landscape in the United States with the full approval of agalsidase beta in March 2021, the primary analysis of the BALANCE study was changed from superiority to non-inferiority, as demonstrating superiority is no longer required under FDA guidelines. The primary endpoint of the BALANCE study compared the eGFR annualized changes between the two treatment arms in the ITT analysis set (77 patients). The study met its pre-specified primary endpoint and demonstrated that PRX-102 was statistically non-inferior to agalsidase beta.

Treatment-related adverse events were reported for 21 (40.4 percent) patients in the PRX–102 arm compared to 11 (44 percent) in the agalsidase beta arm. The number of treatment-related events adjusted to 100 years of exposure is 42.85 events for the PRX-102 arm and 152.91 events for the agalsidase beta arm.

Usage of infusion pre-medication was tapered down during the study, if possible, for all patients. At baseline, 21 (40.4%) patients in the PRX–102 arm used infusion premedication compared to 16 (64.0%) in the agalsidase beta arm. At the end of the study, only three out of 47 (6.4%) patients in the PRX–102 arm used infusion premedication compared to three out of 24 (12.5%) in the agalsidase beta arm. Even with this reduction in use of premedication, there were fewer reported infusion-related reactions with PRX–102: 11 (21.2%) patients in the PRX–102 arm experienced a total of 13 events compared to six (24.0%) patients experiencing a total of 51 events in the agalsidase beta arm. The number of infusion-related reactions adjusted to 100 infusions is 0.5 for the PRX–102 arm and 3.9 for agalsidase beta arm.

Assessment of anti–PRX–102 antibodies or anti-agalsidase beta antibodies, respectively, in the study indicated that, for the PRX–102 arm, 18 (34.6 percent) patients were anti-drug antibody–positive at baseline, of which 17 (94.4 percent) had neutralizing antibody activity. For the agalsidase beta arm, eight (32 percent) patients were anti-drug antibody–positive at baseline, of which seven (87.5 percent) had neutralizing antibody activity. At the end of the two-year study, 11 (23.4 percent) patients receiving PRX–102 were anti-drug antibody–positive, of which seven (63.6 percent) had neutralizing antibody activity, while in the agalsidase beta arm six (26.1 percent) were anti-drug antibody–positive and all six (100 percent) had neutralizing antibody activity.

Out of the 78 randomized patients, six patients discontinued the study: out of the five (9.4 percent) from the PRX–102 arm, one patient withdrew consent prior to the first infusion, two discontinued due to personal reasons, and two due to adverse events (one due to an unrelated adverse event and one due to a treatment–related adverse event); one (4 percent) patient from the agalsidase beta arm discontinued for personal reasons. There were no deaths.

Of the patients that completed the trial, 69 have opted, with the advice of the treating physician, to continue receiving PRX–102 1 mg/kg every other week in a long-term open-label extension study.

“These data are especially encouraging following our recent announcement of the positive final results from our Phase III BRIGHT study of PRX-102 in Fabry disease and bring us one step closer towards potential approval of PRX-102 and launch in several countries as a much-needed treatment option for patients,” said Giacomo Chiesi, head of Chiesi Global Rare Diseases. “We believe the totality of the data observed suggests a favorable benefit-risk profile for the treatment of adult patients with a confirmed diagnosis of Fabry disease and the data will be included in our planned PRX–102 BLA resubmission to the FDA.”

Author: Rare Daily Staff

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