BALANCE Interim Results
On June 2, 2021, Protalix (NYSE:PLX) and development partner, Chiesi Global Rare Diseases, provided an update regarding clinical development of Protalix’ candidate pegunigalsidase alfa (PRX-102) and hosted a conference call and webcast the same morning to discuss results. Featured on the call was Dr. Ulrich Granzer, a consultant to Protalix with specialization in drug development and regulatory affairs.
Protalix’ interim analysis stated that the confidence interval for the intent to treat population fell below the non-inferiority threshold while the per protocol group population confidence interval was above the threshold. No numbers were provided for the mean or range of the confidence interval as the data remains blinded.
PRX-102 is currently being evaluated in the Phase III BALANCE trial for Fabry Disease and is Protalix’ pegylated enzyme that offers enhanced longevity in the body. The pegylation provides for an extended therapeutic effect which may allow for less frequent dosing compared with current standard of care thereby reducing patient burden. The BALANCE study is a 24-month, randomized, double-blind, active control study designed to evaluate safety and efficacy of 1 mg/kg PRX-102 dosed every two weeks versus agalsidase beta (Fabrazyme). The study enrolled 78 patients who were randomized in a 2:1 ratio.
The primary endpoint evaluated in the interim analysis was comparison of mean annualized change of estimated glomerular filtration rate (eGFR) after completion of 12 months of treatment between the two arms (PRX-102 and Fabrazyme). Efficacy analysis was conducted on both Intention to Treat (ITT) and Per Protocol (PP) patient subgroups. ITT patients consisted of 77 randomized patients who received at least one dose while PP patients were those who completed at least 12 months of treatment with no major protocol violations (74 patients).
Interim results, based on analysis of the ITT population, did not achieve non-inferiority, as the lower bound of the confidence interval was below the pre-specified threshold. The confidence interval for the PP populations, however, was above the non-inferiority margin. Two patients discontinued the study due to treatment emergent adverse events (TEAE). One of the two discontinued due to related adverse events. No deaths were registered. Overall, the safety data was favorable and appears consistent with previous clinical work on PRX-102. Final data for the trial is anticipated to be unblinded in 2Q:22.
Regarding the FDA application, Protalix plans to submit a Type A meeting request with the FDA to determine the requirements needed to address the discrepancies in the complete response letter (CRL). The company is now developing the briefing book and preparing the analysis to present at the Type A meeting anticipated to take place in 3Q:21. Refer to our previous report for a discussion of milestones required for resubmission.
On the European front, Protalix and Chiesi intend to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) before the end of the year. While the EMA is considering the application, BALANCE study data will be available for the agency’s review. Dr. Granzer clarified that the EMA assesses not only results for the primary endpoint but also the totality of the data and evidence presented in the application, which will include all studies conducted by Protalix and all components of these studies. He suggested that the EMA will take a holistic view of PRX-102, including safety, efficacy and secondary endpoints and expects the EMA to also consider results from the BRIGHT and BRIDGE studies.
While we would have hoped to see the confidence intervals for both the ITT and PP populations exceed the non-inferiority threshold, it is a positive that the PP group did exceed this cutoff. Very limited data was provided for the study which prevents investors from making thorough assessments of the information provided. In small studies such as this, it is difficult to generate data consistent enough to show superiority even when the outcome is better due to variance in patient results. The trial will have another chance at other monthly intervals to generate updated results. We will eagerly be following updates related to the Type A meeting and the anticipated visit by the FDA to Protalix’ facilities to satisfy the one apparent deficiency: an onsite inspection.
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