Clinical Trials

Date: 2016-10-25

Type of information: Treatment of the first patient

phase: 3

Announcement: treatment of the first patient

Company: Protalix BioTherapeutics (Israel)

Product: PRX-102 (alpha-galactosidase-A)

Action mechanism:

• enzyme replacement therapy. PRX-102 is the Company's proprietary plant cell-expressed, chemically modified recombinant alpha-galactosidase-A enzyme in development as a long-term enzyme replacement therapy (ERT) for the treatment of Fabry disease.

Disease: Fabry disease

Therapeutic area: Rare diseases - Genetic diseases

Country: USA

Trial details:

• The BALANCE study is a 24-month multi-center, randomized, double blind, active control study of PRX-102 in Fabry disease patients with impaired renal function. Patients treated for at least 1 year with agalsidase beta and on a stable dose for at least 6 months will be screened and then randomized to continue treatment with either agalsidase beta at the same dose or to treatment with 1 mg/kg of PRX-102. The identity of the enzyme will be blinded to the patient and the investigator. Patients will receive intravenous infusions every two weeks. Patients will be randomized in a 2:1 ratio of PRX-102 to agalsidase beta. Randomization will be stratified by urinary protein to creatinine ratio by spot urine sample. (NCT02795676)

Latest news:

• • On October 25, 2016, Protalix BioTherapeutics announced that the first patient has been dosed in its global phase III clinical trial of PRX-102 for the treatment of Fabry disease. There are currently six of the leading Fabry centers activated and participating in the trial, with up to an additional 21 centers, currently in different initiation processes, that are expected to be opened before year end. The trial is designed to enroll 78 patients previously treated with Fabrazyme® (agalsidase beta) with a stable dose for at least six months. Enrolled patients will be randomized to continue treatment with 1 mg/kg of either Fabrazyme or PRX-102, at a 2:1 ratio of PRX-102 to Fabrazyme, respectively. Patients are to be treated via intravenous (IV) infusions every two weeks.
• The sites are recruiting adult symptomatic Fabry patients with plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 30% mean normal levels. All patients must have had treatment with a dose of 1 mg/kg agalsidase beta per infusion every two weeks for at least one year. In addition, to be included in the trial, patients need to have certain eGFR values and a meaningful decline in annualize eGFR slope.
• • On June 6, 2016, Protalix BioTherapeutics announced that based on guidance and feedback from the FDA, the company initiated its phase III clinical trial of PRX-102 for the treatment of Fabry disease. Guidance from the European Medicines Agency (EMA) has been incorporated into the development plan to support an EMA filing as well. The phase III efficacy and safety clinical trial, or, the BALANCE Study, is a 24-month multi-center, randomized, double-blind, active control study of PRX-102 in Fabry patients with impaired renal function. Seventy-eight patients previously treated with Fabrazyme® (agalsidase beta) for approximately one year, and with a stable dose for at least six months, will be enrolled and then randomized to continue treatment with 1 mg/kg with either Fabrazyme® or PRX-102, at a 2:1 ratio of PRX-102 to Fabrazyme®, respectively. Patients are to be treated via intravenous (IV) infusions every two weeks.
• The primary efficacy parameter is the comparison of the mean annualized change in estimated glomerular filtration rate (eGFR) between treatment groups. The secondary endpoints include Left Ventricular Mass Index (g/m2) by MRI, Plasma Lyso-Gb3, Plasma Gb3, Urine Lyso-Gb3, Exercise Tolerance (Stress Test), Short Form Brief Pain Inventory and Mainz Severity Score Index and Quality of Life. In addition, immunogenicity and safety parameters will be measured. At 12 months, Protalix intends to conduct an interim analysis to test for non-inferiority to support an anticipated regulatory filing with the EMA. Patients enrolled in the study will continue to be treated for a total of 24 months, at which point the data will be analyzed to test for superiority to support an FDA filing. To demonstrate superiority, during the SPA process, the FDA indicated that a 30% improvement in the rate of decline in eGFR relative to the active comparator arm is acceptable.
• Protalix also intends to initiate the BRIDGE Study, a single-arm, switch-over study from Replagal®, to provide supportive data for anticipated filings in the United States and the European Union. This trial is designed to enroll 22 Fabry patients, currently treated with Replagal (alpha-galactosidase), who are to be switched to 1 mg/kg of PRX-102 for 12 months. The primary endpoint of the BRIDGE Study is safety; additional exploratory efficacy parameters include Left Ventricular Mass Index (g/m2) by MRI, Plasma Lyso-Gb3, Plasma Gb3, Urine Lyso-Gb3, Exercise Tolerance (Stress Test), Short Form Brief Pain Inventory, Mainz Severity Score Index and Quality of Life.
• • On November 16, 2015,  Protalix BioTherapeutics announced that it recently held an End-of-Phase II meeting with the FDA to discuss the Company's proposed BLA plan for PRX-102 for the treatment of Fabry disease. Official FDA meeting minutes indicate the FDA's acceptance of the Company's path forward for a phase III clinical trial to support a full BLA approval. The phase III clinical trial will be a randomized, multi-center, placebo-controlled, safety and efficacy study in treatment-naïve Fabry patients evaluating the 1 mg/kg dose of PRX-102. The Company anticipates a small sample size of patients will be needed to achieve statistical significance with a study duration of approximately six months. The primary endpoint will be Gastrointestinal Symptoms, with key secondary endpoints including renal function.
• In the official FDA meeting minutes, the FDA noted that Protalix reported interim analysis results from its phase I/II clinical trial of PRX-102 that preliminarily show a favorable trend in the severity and frequency of abdominal pain and frequency of diarrhea after six months of treatment with PRX-102. According to the FDA, during a recent ERT (enzyme replacement therapy) shortage, patients who reduced or discontinued ERT dosing developed worsening of GI signs and symptoms within a few weeks to months.
• In addition to the phase III clinical trial, Protalix and the FDA also agreed to a phase III head-to-head superiority trial comparing PRX-102 versus Fabrazyme®, which the company plans to commence in early 2016. The primary endpoint for this head-to-head trial will be an improvement in eGFR. The trial will enroll patients who are currently treated with Fabrazyme®; such patients will be treated with 1mg/kg of PRX-102 for a two-year period. Interim results from this head-to-head trial will also provide supportive safety data for the BLA submission.

Is general: Yes