the latest long term data from their phase 3 study looking at the efficacy and safety of migalastat monotherapy in patients with Fabry disease who have amenable mutations to migalastat. And the results are promising.
In addition to being good news to investors and patients, it also comes as a bit of a surprise. As we reported
a year and a half ago, the original phase 3 study failed to meet its primary endpoint after 6 months of treatment. Subsequent to that report however, the company continued the study and worked with the FDA to came up with a revised 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").
The previous primary outcome was the percentage of patients with 50% reduction in GL-3 levels (regardless of amenable mutations). The revised patient population in the study only includes those with amenable mutations (defined as having an absolute increase of 3% of wild type alpha-Gal A enzyme activity and a relative increase of 20% when exposed to migalastat in a cell-based in vitro
assay) which meant that 17 patients from the original study were removed from the analysis. In their press release, Amicus stated they believe that approximately 30% to 50% of the Fabry population have mutations that are amenable to migalastat.
By focusing on patients amenable to migalastat, the 12 month and 24 month data was very impressive. Summarizing the results, Amicus stated:
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 (p < 0.0001). Subjects who remained on migalastat demonstrated a durable reduction in lyso-Gb3.
Kidney function (estimated glomerular filtration rate (eGFR), iohexol mGFR) remained stable over 18-24 months
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).
In a press release
, John Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc., stated, "Today is a great day for Amicus and the Fabry community. We are pleased to report that the 12 and 24 month results from Study 011 have met our pre-defined criteria for success in terms of substrate reduction at 12 months, as well as clinical measures of kidney function maintained out to 24 months. We believe these data provide important validation that a small-molecule chaperone can restore the function of a patient's own enzyme in patients with amenable mutations, and that our pharmacogenomic assays can identify these patients. Together these results demonstrate the power of personalized medicine in rare diseases and offer the prospect of a new treatment option that differs from traditional enzyme replacement therapy. Pending positive data from our second Phase 3 study we expect to meet with regulatory authorities to discuss these data and determine the fastest registration pathway for migalastat."
Raphael Schiffmann, M.D., M.H.Sc., Director of the Institute of Metabolic Disease, Baylor Research Institute, stated, "As an investigator experienced in treating patients with migalastat for up to 8 years in clinical studies, I believe the results from Study 011 show a positive treatment effect of migalastat in Fabry patients with amenable mutations. The reductions in substrate levels in the kidney and in plasma, combined with stabilization of renal function, strongly suggest that migalastat may become an important new oral treatment option for Fabry patients."
In a conference call
, Dr Jay Barth, Chief Medical Officer at Amicus said the data from the Study 011, as well as a second phase 3 study (study 012) currently nearing completion, should be sufficient to submit the drug for approval in both United States and Europe. Exact dates when they will submit to the FDA and EMA were not specified but they do hope to have data from the 012 study available in the third quarter of 2014.
About Fabry Disease
Fabry disease is an X-linked lysosomal storage disorder that leads to excessive deposition of glycosphingolipids throughout the body. Skin, eye, kidney, heart, brain, and peripheral nervous system are highly vulnerable. Fabry disease is often difficult to diagnose since signs and symptoms are often nonspecific. For example, common symptoms may be fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, diarrhea etc.
Symptoms do appear in childhood but often go undiagnosed for several years. As the disease progressive, most patients with Fabry disease die in their fourth or fifth decade due to complications arising from renal or cardiovascular problems.
Currently, Genzyme’s Fabrazyme is the only approved treatment for Fabry disease in the United States. Fabrazyme is also approved in Europe and elsewhere, as is Shire’s Replagal.
Image of John Crowley courtesy of Wikimedia Commons.
Graphs obtained from Amicus Therapeutics’ presentation on April 29, 2014