Top-line six-month primary treatment period results from first Phase III Fabry monotherapy study

GlaxoSmithKline plc (GSK) and Amicus Therapeutics (Nasdaq: FOLD) today announced the six-month primary treatment period results from the first Phase III 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 randomised a total of 67 patients to receive oral migalastat HCl 150 mg or placebo on an every-other-day (QOD) dosing schedule during a six-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 six months of treatment with migalastat HCl compared to placebo. During a six 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 utilised for the evaluation of the kidney biopsies at month 12. GSK and Amicus 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 six was performed. Taken alone, this analysis showed a median reduction of 41% in the migalastat HCl group versus a median reduction of six percent 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 (nine percent; 12%). The 4 dropouts in this portion of the study were deemed by the investigators to be unrelated to study medication.

The six-month secondary endpoints in Study 011 continue to be analysed 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 II experience, the six-month results from Study 011 demonstrate notable trends in kidney interstitial capillary GL-3 reduction in favour of migalastat HCl monotherapy compared to placebo. We look forward to announcing additional six-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 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 analyse the six-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 six-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 six-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 six-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 six-month data in the placebo crossover group.

A second Phase III 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 III 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 III studies of migalastat HCl monotherapy being conducted by GSK and Amicus. 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 six-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 six-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 six-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.

About Migalastat HCl

GSK, in collaboration with Amicus, is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world. As a monotherapy, migalastat HCl is designed to bind to and stabilise, 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. Oral migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with amenable mutations. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 is comparing open-label migalastat HCl to ERT to primarily support global registration.

For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form. Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development. Migalastat HCl is subject to evaluation by regulatory authorities before being made available as a treatment for patients.

About Fabry Disease

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 α-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. This accumulation of GL-3 is believed to cause the various manifestations of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.