Amicus Therapeutics (FOLD), Glaxo (GSK) Report Study 011 Did Not Achieve Primary Endpoint
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Amicus Therapeutics (Nasdaq: FOLD) and GlaxoSmithKline plc (NYSE: GSK) announced the 6-month primary treatment period results from the first Phase 3 global registration study (Study 011) of investigational oral migalastat HCl monotherapy in males and females with Fabry disease who had genetic mutations identified as amenable to migalastat HCl in a cell-based assay. Study 011 randomized a total of 67 patients to receive oral migalastat HCl 150 mg or placebo on an every-other-day (QOD) dosing schedule during a 6-month, double-blind primary treatment period.
Reduction of GL-3 Substrate in Kidney Interstitial Capillaries:
Globotriaosylceramide (GL-3) is the lipid substrate that accumulates in tissues of patients with Fabry disease, most notably in the kidney. GL-3 clearance from the kidney interstitial capillaries has been used as a marker of treatment effect in Fabry disease. The pre-designated primary endpoint of Study 011 was a responder analysis evaluating the number of patients who demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 after 6 months of treatment with migalastat HCl compared to placebo. During a 6-month open label follow-up period all patients received migalastat HCl. The FDA has also indicated that it will consider the 12-month efficacy and safety data from Study 011. The paired kidney biopsies from baseline and month 6 were assessed by histological scoring using the published, quantitative Barisoni Lipid Inclusion Scoring System with Virtual Microscopy (BLISS-VM).1 This methodology will also be utilized for the evaluation of the kidney biopsies at month 12. Amicus and GSK remain blinded to the 12-month data.
In Study 011 patients with evaluable baseline biopsies, 13/32 (41%) in the migalastat HCl treatment group demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 after 6 months of study treatment versus 9/32 (28%) in the placebo group. This difference did not achieve statistical significance (p=0.3) according to the pre-specified primary endpoint analysis.
In addition to the binary responder analysis reported above, a pre-specified secondary analysis assessing the absolute percent change in kidney interstitial capillary GL-3 from baseline to month 6 was performed. Taken alone this analysis showed a median reduction of 41% in the migalastat HCl group versus a median reduction of 6% in the placebo group (p=0.093).
To date, no drug-related serious adverse events have been observed. The most common treatment emergent adverse events occurring in 10% or more of subjects were (migalastat; placebo, respectively): headache (35%; 21%); fatigue (12%; 12%); nausea (12%; 9%); nasopharyngitis, or inflammation of the nose and throat (15%; 6%); and parasthesia, or tingling sensation of the skin (9%; 12%). The 4 dropouts in this portion of the study were deemed by the investigators to be unrelated to study medication.
The 6-month secondary endpoints in Study 011 continue to be analyzed and will be presented at the Lysosomal Disease Network WORLD Symposium (LDN WORLD), to be held February 12-15, 2013, in Orlando, Florida. Secondary endpoints include urine GL-3 and renal function (iohexol GFR, eGFR and 24-hour urine protein).
John F. Crowley, Chairman and Chief Executive Officer of Amicus, stated "Consistent with our Phase 2 experience, the 6-month results from Study 011 demonstrate notable trends in kidney interstitial capillary GL-3 reduction in favor of migalastat HCl monotherapy compared to placebo. We look forward to announcing additional 6-month results at the WORLD Symposium in February, including a presentation of important secondary and tertiary endpoints in this study. We also anticipate 12-month results from this study in the first half of 2013. Once we have the 12-month data, we intend to meet with FDA to discuss a U.S. approval pathway. We continue to believe that migalastat HCl may become an important treatment option as an oral monotherapy drug for both men and women with Fabry disease who have amenable mutations."
Marc Dunoyer, Global Head of GSK Rare Diseases added, "GSK and Amicus are committed to advancing migalastat HCl as a monotherapy in Fabry patients with amenable mutations. While these 6-month data are encouraging, there is additional work to be done. We continue to analyze the 6-month results and look forward to receiving the 12-month results from this study. In addition the results of Study 012, our second Phase 3 Fabry monotherapy study, will add to the totality of our data and give us a more complete picture of the clinical effect of migalastat HCl. This study, an 18-month comparison of migalastat to ERT, with iohexol GFR as the primary endpoint, is fully recruited and due to report in 2014."
The 6-month primary treatment period in Study 011 was completed in June 2012 in 63 out of 67 randomized patients. All 63 of these patients entered the 6-month open-label follow-up period in Study 011, to continue to receive migalastat HCl or to switch from placebo to migalastat HCl. In December 2012, a total of 59 patients completed this treatment period and received an additional kidney biopsy at month 12. In addition, 57 out of 59 patients who completed Study 011 continue to receive migalastat HCl in both ongoing open-label extension studies. The results from the 6-12 month period of study 011 are expected in the first half of 2013 and will include 12-month data in the migalastat HCl group and 6-month data in the placebo crossover group.
A second Phase 3 global registration study (Study 012) is also underway to compare open-label migalastat HCl to enzyme replacement therapy (ERT) to primarily support global registration. Study 012 (The ATTRACT, or FAB-AT1001-012 Study) is a randomized, open-label 18-month Phase 3 study investigating the safety and efficacy of oral migalastat HCl 150 mg QOD compared to standard-of-care infused therapy using ERTs (Fabrazyme® and Replagal®). This study achieved final enrollment of 60 total patients in December 2012.
Study 011 Design
Study 011 - also referred to as FACETS - is one of two ongoing Phase 3 studies of migalastat HCl monotherapy being conducted by Amicus and GlaxoSmithKline (GSK). This study was designed based on feedback from the U.S. Food and Drug Administration (FDA), and is primarily intended to support U.S. registration. Study 011 randomized 67 patients (24 males and 43 females) diagnosed with Fabry disease who had genetic mutations amenable to chaperone monotherapy in a cell-based assay. For the 6-month, double-blind primary treatment period patients were randomized to migalastat HCl 150 mg or placebo on an every-other-day (QOD) oral dosing schedule. During a 6-month open-label follow up period, patients continued treatment with migalastat HCl or switched from placebo to migalastat HCl.
The primary analysis compared the number of responders in the migalastat HCl versus placebo groups, based on a 50% or greater reduction in interstitial capillary globotriaosylceramide (GL-3) during the 6-month, double-blind treatment period. GL-3 – also referred to as peritubular capillary (PTC) inclusions – is measured in kidney biopsies. Pathologists blinded to biopsy sequence used the published, quantitative Barisoni Lipid Inclusion Scoring System with virtual microscopy (BLISS-VM) for the histological evaluation of interstitial capillary GL-3 in Study 011. BLISS is a more sensitive scoring system to measure GL-3 inclusions in PTCs compared to the semi-quantitative methodology used in previous pivotal studies of enzyme replacement therapy (ERT) for Fabry disease. Secondary endpoints for Study 011 include safety and tolerability, urine GL-3 and kidney function.
Reduction of GL-3 Substrate in Kidney Interstitial Capillaries:
Globotriaosylceramide (GL-3) is the lipid substrate that accumulates in tissues of patients with Fabry disease, most notably in the kidney. GL-3 clearance from the kidney interstitial capillaries has been used as a marker of treatment effect in Fabry disease. The pre-designated primary endpoint of Study 011 was a responder analysis evaluating the number of patients who demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 after 6 months of treatment with migalastat HCl compared to placebo. During a 6-month open label follow-up period all patients received migalastat HCl. The FDA has also indicated that it will consider the 12-month efficacy and safety data from Study 011. The paired kidney biopsies from baseline and month 6 were assessed by histological scoring using the published, quantitative Barisoni Lipid Inclusion Scoring System with Virtual Microscopy (BLISS-VM).1 This methodology will also be utilized for the evaluation of the kidney biopsies at month 12. Amicus and GSK remain blinded to the 12-month data.
In Study 011 patients with evaluable baseline biopsies, 13/32 (41%) in the migalastat HCl treatment group demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 after 6 months of study treatment versus 9/32 (28%) in the placebo group. This difference did not achieve statistical significance (p=0.3) according to the pre-specified primary endpoint analysis.
In addition to the binary responder analysis reported above, a pre-specified secondary analysis assessing the absolute percent change in kidney interstitial capillary GL-3 from baseline to month 6 was performed. Taken alone this analysis showed a median reduction of 41% in the migalastat HCl group versus a median reduction of 6% in the placebo group (p=0.093).
To date, no drug-related serious adverse events have been observed. The most common treatment emergent adverse events occurring in 10% or more of subjects were (migalastat; placebo, respectively): headache (35%; 21%); fatigue (12%; 12%); nausea (12%; 9%); nasopharyngitis, or inflammation of the nose and throat (15%; 6%); and parasthesia, or tingling sensation of the skin (9%; 12%). The 4 dropouts in this portion of the study were deemed by the investigators to be unrelated to study medication.
The 6-month secondary endpoints in Study 011 continue to be analyzed and will be presented at the Lysosomal Disease Network WORLD Symposium (LDN WORLD), to be held February 12-15, 2013, in Orlando, Florida. Secondary endpoints include urine GL-3 and renal function (iohexol GFR, eGFR and 24-hour urine protein).
John F. Crowley, Chairman and Chief Executive Officer of Amicus, stated "Consistent with our Phase 2 experience, the 6-month results from Study 011 demonstrate notable trends in kidney interstitial capillary GL-3 reduction in favor of migalastat HCl monotherapy compared to placebo. We look forward to announcing additional 6-month results at the WORLD Symposium in February, including a presentation of important secondary and tertiary endpoints in this study. We also anticipate 12-month results from this study in the first half of 2013. Once we have the 12-month data, we intend to meet with FDA to discuss a U.S. approval pathway. We continue to believe that migalastat HCl may become an important treatment option as an oral monotherapy drug for both men and women with Fabry disease who have amenable mutations."
Marc Dunoyer, Global Head of GSK Rare Diseases added, "GSK and Amicus are committed to advancing migalastat HCl as a monotherapy in Fabry patients with amenable mutations. While these 6-month data are encouraging, there is additional work to be done. We continue to analyze the 6-month results and look forward to receiving the 12-month results from this study. In addition the results of Study 012, our second Phase 3 Fabry monotherapy study, will add to the totality of our data and give us a more complete picture of the clinical effect of migalastat HCl. This study, an 18-month comparison of migalastat to ERT, with iohexol GFR as the primary endpoint, is fully recruited and due to report in 2014."
The 6-month primary treatment period in Study 011 was completed in June 2012 in 63 out of 67 randomized patients. All 63 of these patients entered the 6-month open-label follow-up period in Study 011, to continue to receive migalastat HCl or to switch from placebo to migalastat HCl. In December 2012, a total of 59 patients completed this treatment period and received an additional kidney biopsy at month 12. In addition, 57 out of 59 patients who completed Study 011 continue to receive migalastat HCl in both ongoing open-label extension studies. The results from the 6-12 month period of study 011 are expected in the first half of 2013 and will include 12-month data in the migalastat HCl group and 6-month data in the placebo crossover group.
A second Phase 3 global registration study (Study 012) is also underway to compare open-label migalastat HCl to enzyme replacement therapy (ERT) to primarily support global registration. Study 012 (The ATTRACT, or FAB-AT1001-012 Study) is a randomized, open-label 18-month Phase 3 study investigating the safety and efficacy of oral migalastat HCl 150 mg QOD compared to standard-of-care infused therapy using ERTs (Fabrazyme® and Replagal®). This study achieved final enrollment of 60 total patients in December 2012.
Study 011 Design
Study 011 - also referred to as FACETS - is one of two ongoing Phase 3 studies of migalastat HCl monotherapy being conducted by Amicus and GlaxoSmithKline (GSK). This study was designed based on feedback from the U.S. Food and Drug Administration (FDA), and is primarily intended to support U.S. registration. Study 011 randomized 67 patients (24 males and 43 females) diagnosed with Fabry disease who had genetic mutations amenable to chaperone monotherapy in a cell-based assay. For the 6-month, double-blind primary treatment period patients were randomized to migalastat HCl 150 mg or placebo on an every-other-day (QOD) oral dosing schedule. During a 6-month open-label follow up period, patients continued treatment with migalastat HCl or switched from placebo to migalastat HCl.
The primary analysis compared the number of responders in the migalastat HCl versus placebo groups, based on a 50% or greater reduction in interstitial capillary globotriaosylceramide (GL-3) during the 6-month, double-blind treatment period. GL-3 – also referred to as peritubular capillary (PTC) inclusions – is measured in kidney biopsies. Pathologists blinded to biopsy sequence used the published, quantitative Barisoni Lipid Inclusion Scoring System with virtual microscopy (BLISS-VM) for the histological evaluation of interstitial capillary GL-3 in Study 011. BLISS is a more sensitive scoring system to measure GL-3 inclusions in PTCs compared to the semi-quantitative methodology used in previous pivotal studies of enzyme replacement therapy (ERT) for Fabry disease. Secondary endpoints for Study 011 include safety and tolerability, urine GL-3 and kidney function.
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