Date: 2016-08-10
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The New English Journal of Medicine
Company: GSK (UK) Amicus Therapeutics (USA - NJ)
Product: migalastat
Action
mechanism: chaperone. Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of alpha-Gal are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. Migalastat HCl is designed to bind to and stabilize, or "chaperone" a patient's own alpha-galactosidase A (alpha-Gal A) enzyme in those patients with genetic mutations that are amenable to this chaperone in a cell-based assay. This assay (Galafold Amenability Assay) was used to classify more than 800 known GLA mutations as "amenable" or "not amenable" to treatment with Galafold. The current label includes all 269 GLA mutations that have been identified and determined to be amenable based on the Galafold Amenability Assay, which represent between 35% and 50% of the currently diagnosed Fabry population.
Disease: Fabry disease
Therapeutic area: Rare diseases - Genetic diseases
Country: USA, Argentina, Australia, Belgium, Brazil, Canada, Denmark, Egypt, France, Germany, Italy, Netherlands, Poland, South Africa, Spain, Turkey, UK
Trial
details: Study 011 - also referred to as FACETS - is one of two ongoing Phase 3 studies of migalastat HCl monotherapy being conducted by Amicus and GSK. This study was designed based on feedback from the 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 period (Stage 1) 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 (Stage 2), 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. (NCT00925301)
Latest
news: * On August 10, 2016, Amicus Therapeutics announced that data from the pivotal Phase 3 Study 011 (FACETS) evaluating the efficacy and safety of the oral pharmacological chaperone migalastat in individuals with Fabry disease were published in the August 11 issue of the New England Journal of Medicine. * On February 10, 2015, Amicus Therapeutics announced positive data on pre-specified patient reported outcomes from both of its Phase 3 studies of migalastat for Fabry disease at WORLDSymposium™ 2015 in Orlando, Florida. Amicus previously reported positive Phase 3 data in both treatment naïve (Study 011, or FACETS) and enzyme replacement therapy (ERT) switch patients (Study 012, or ATTRACT). Results from these studies have shown that treatment with migalastat has resulted in reductions in disease substrate, stability of kidney function and improvement in a key cardiac parameter (left ventricular mass index, or LVMi) in patients with amenable mutations. Pre-specified secondary and tertiary endpoints on patient-reported outcome measures from both Phase 3 studies are being reported for the first time at WORLDSymposium™ 2015. Improvements in Gastrointestinal Symptoms Observed in Phase 3 Study 011 (FACETS): A poster at WORLDSymposium described improvements in gastrointestinal symptoms observed in the Phase 3 Study 011 (FACETS) in treatment naïve Fabry patients with amenable mutations. There was a significant decrease in diarrhea (unadjusted p=0.03) in patients treated with migalastat versus placebo during the 6-month double-blind phase (Stage 1). After 18-24 months of treatment with migalastat, significant improvements in diarrhea and indigestion were observed in addition to favorable trends in reflux and constipation.Gastrointestinal symptoms were assessed in 50 subjects with amenable mutations (28 on migalastat, 22 on placebo) using the Gastrointestinal Symptoms Rating Scale (GSRS), a validated instrument of 15 items that includes 5 domains (diarrhea, reflex, indigestion, abdominal pain and constipation). * On October 19, 2014, Amicus Therapeutics announced additional positive data from a Phase 3 study (Study 011) of the oral small molecule chaperone migalastat HCl in Fabry disease patients with amenable mutations. In a poster at the American Society of Human Genetics (ASHG) Annual Meeting, Daniel G. Bichet, M.D., M.Sc., Professor, Department of Physiology, University of Montreal, presented results from patients in Study 011 including those who continued on migalastat in an open-label extension (Study 041). Assessment of kidney function by various measures of glomerular filtration rate (GFR) for patients receiving migalastat in Study 011 for at least 18 months and continuing migalastat treatment in Study 041 showed continued stability of kidney function for an average of 32 months. Decline in kidney function is a key cause of morbidity and mortality in patients with Fabry disease. Measured (iohexol) GFR (mGFR) showed stability over 18-24 months in Study 011 but was not collected in Study 041; mGFR was previously reported with topline Study 011 results. * On April 29, 2014, Amicus Therapeutics has announced positive 12- and 24-month data from its first Phase 3 study (Study 011) of the oral small molecule chaperone migalastat HCl ("migalastat") monotherapy in Fabry patients with amenable mutations. Study 011 was designed to measure the reduction of disease substrate (Globotriaosylceramide, or GL-3) following treatment with migalastat. The 24-month study began with a 6-month double-blind, placebo-controlled treatment period, after which all patients were treated with migalastat for a 6-month open-label follow-up period and a subsequent 12-month open-label extension phase. The study also measured clinical outcomes, including renal function, as secondary endpoints. As previously reported, patients on migalastat experienced greater reductions in GL-3 as compared to placebo during the initial 6-month period; however, this difference was not statistically significant under the original study primary endpoint (responder analysis with a 50% reduction threshold at month 6). Following a Type C Meeting with the FDA in the second quarter of 2013, and based on feedback from the agency at that meeting, Amicus revised the Statistical Analysis Plan to pre-specify the primary analysis at month 12 as the mean change in GL-3 in patients with amenable mutations in a GLP-validated human embryonic kidney (HEK) cell-based in vitro assay ("GLP HEK amenable"). Subjects who switched from placebo to migalastat after month 6 demonstrated a statistically significant reduction in kidney interstitial capillary GL-3 at month 12 (p=0.013). Subjects who remained on migalastat for 12 months demonstrated a durable reduction in kidney interstitial capillary GL-3. Reduction in disease substrate was also observed in plasma lyso-Gb3, another important biomarker of disease, in subjects who switched from placebo to migalastat. Migalastat was generally safe and well-tolerated. Of 41 subjects with GLP HEK amenable mutations who completed Study 011, 35 (85%) remain in the voluntary extension study (Study 041). Migalastat monotherapy is being investigated in two Phase 3 registration studies (Study 011 and Study 012) and an open-label extension study (Study 041) in Fabry patients with amenable mutations. Top-line data are anticipated in the third quarter of 2014 from Study 012. The primary analysis in Study 012 will evaluate GFR, a clinical measure of kidney function, over 18-months of treatment with migalastat compared to enzyme replacement therapy (ERT), the current standard of care for Fabry disease. Study 011 Substrate Reduction Data in GLP HEK Amenable Patients: Migalastat has demonstrated significant and durable reductions in GL-3 in Study 011 in patients with GLP HEK amenable mutations. Reductions in plasma Lyso-Gb3, another important disease biomarker, were also observed in patients with GLP HEK amenable mutations. GL-3 is the substrate that accumulates in patients with Fabry disease. Reduction in kidney interstitial capillary GL-3 is a surrogate biomarker that was used to support U.S. approval of ERT for Fabry disease. * On February 15, 2013, Amicus Therapeutics has announced additional 6-month (Stage 1) results from the first ongoing Phase 3 global registration study (Study 011) of oral migalastat HCl monotherapy (150 mg, every-other-day) in males and females with Fabry disease who had genetic mutations identified as amenable to migalastat HCl in a cell-based assay. Stage 1 results were highlighted in an oral platform presentation1 at the Lysosomal Disease Network WORLD Symposium (LDN WORLD) by Dr. Fatih Ezgu, Gazi University. Initial top-line Stage 1 results previously reported in December, 2012 for the primary endpoint in Stage 1 did not meet statistical significance (See below). The pre-specified primary and secondary analyses of the primary endpoint numerically favored migalastat HCl over placebo. In the primary responder analysis, 13/32 (41%) in the migalastat HCl group versus 9/32 (28%) in the placebo group demonstrated a 50% or greater reduction in kidney interstitial capillary GL-3 from baseline to month 6 (p=0.3). Taken alone the secondary analysis of the absolute percent change in kidney interstitial capillary GL-3 from baseline to month 6 showed a median reduction of 41% in the migalastat HCl group versus a median reduction of 6% in the placebo group (p=0.093). Study 011 entry criteria, particularly elevated urine GL-3, were intended to enrich for patients with higher interstitial capillary GL-3, and more measurable disease burden. Although all patients had detectable interstitial capillary GL-3 at baseline, a number of patients had low levels of GL-3 at baseline, making it difficult to detect a significant difference in responders between the 2 treatment groups. Clearance of kidney interstitial capillary GL-3, a marker of treatment effect, is being measured by histology2 in evaluable kidney biopsies from baseline to month 6 (Stage 1) as well as baseline to month 12 (Stage 2). Stage 2 results remain blinded at this time. Study 011: Stage 1 (Baseline to Month 6) Updated Data Highlights at LDN WORLD Symposium: Post-Hoc Subgroup Analysis of Primary Endpoint (modified intent-to-treat (mITT), n=60): in a post-hoc sub-group analysis, patients with a higher baseline disease burden (0.3 inclusions or more per interstitial capillary, n=25) were compared to those with a lower baseline disease burden (0.3 or fewer inclusions per interstitial capillary, n=35). In the 25 patients (14 males and 11 females) with higher baseline disease burden, 7/11 (64%) on migalastat HCl and 2/14 (14%) on placebo were classified as responders. Among the 35 patients (8 males and 27 females) with lower baseline disease burden, 6/19 (32%) on migalastat HCl and 7/16 (44%) on placebo were classified as responders.
Stratifying patients for gender and baseline proteinuria demonstrated that patients treated with migalastat experienced less decline in kidney function than untreated patients from a previously published natural history study.
Data from a subgroup analysis comparing the change in GL-3 substrate levels between amenable patients and non-amenable patients based on the GLP HEK cell assay provided additional validation of the sensitivity of the GLP HEK assay for identifying patients who will respond to migalastat monotherapy. Overall, patients with amenable mutations had declining levels of GL-3 when treated for six months with migalastat. In contrast, patients with non-amenable mutations had no change or increasing levels of GL-3 after six months of migalastat treatment.
Urine GL-3: The observed median reduction in urine GL-3 from baseline was 17% for placebo and 12% for migalastat. However due to unexpected variability in the pre-treatment urine GL-3 data (>1.6 fold difference between values at screening and baseline), any potential treatment effects on urine GL-3 cannot be determined.
Renal Function from Baseline to Month 6: Renal function remained stable and changes from baseline were similar in both treatment groups during stage 1. Themean (SD) increase in estimated glomerular filtration rate (eGFR) was 2.7 (15.1) mL/min/1.73m2 in the migalastat HCl group compared to a mean decrease of 2.4 (10.8) mL/min/1.73m2 in the placebo group. No clinically meaningful changes in proteinuria were observed, and iohexol GFR data are currently being analyzed.
Safety: During the first 6 months, no drug-related serious adverse events have been observed. No subjects discontinued migalastat HCl therapy due to a treatment emergent adverse event and the majority of adverse events in both treatment groups were mild in nature.
Study 011 results from Stage 2 are anticipated in the second quarter of 2013. The FDA has indicated that it will consider the entirety of the Stage 1 and Stage 2 efficacy and safety data from Study 011. A meeting with the agency is anticipated in mid-2013 to discuss the U.S. conditional approval pathway for migalastat HCl under subpart H.
* On December 19, 2012, Amicus Therapeutics and GSK have announced the 6-month primary treatment period results from the first Phase 3 global registration study (Study 011) of 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.
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. 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).
GSK and Amicus Therapeutics anticipate 12-month results from this study in the first half of 2013.
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(R) and Replagal(R)). This study achieved final enrollment of 60 total patients in December 2012.
