Migalastat Demonstrated Statistically Significant (p=0.013) and Durable Substrate Reductions on 12-Month Pre-Specified Primary Analysis in Fabry Patients with Amenable Mutations
Statistically Significant (p < 0.0001) Reduction Also Seen in Important Fabry Disease Biomarker, Plasma Lyso-Gb3
Kidney Function Remained Stable Up to 24 Months in Fabry Patients with Amenable Mutations
85% of Patients with Amenable Mutations Completing Month 24Remain in Ongoing Voluntary Extension Study (Study 041)
Conference Call and Webcast Today at
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
Summary of Study 011 12- and 24-Month Data in GLP HEK Amenable Patients
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.
Study 011 Stage 1 Data
(Baseline to Month 6)
Study 011 Stage 2 Data
(Month 6 to Month 12)
|Mean Change in GL-3 (SEM) (Baseline Corrected)3||
-0.25 ± 0.10
|+0.07 ± 0.13 (n=20)||0.008**||
+0.01 ± 0.011
|-0.31 ± 0.10 (n=17)||0.013*|
|Plasma Lyso-Gb3 (SEM)||
-11.2 ± 4.8
+0.6 ± 2.4
+1.2 ± 1.3
-15.5 ± 6.2
Study 011 Kidney Function Data in GLP HEK Amenable Patients
Among patients with GLP HEK amenable mutations in Study 011, kidney function by various measures of glomerular filtration rate (GFR) has remained stable for up to 24 months following treatment with migalastat. Decline in kidney function is a key cause of mortality in patients with Fabry disease.
Mean Annualized Change in GFR (ml/min/m2/yr) (SEM)
Over 18 to 24 Months (Preliminary Data)
|Estimated GFR (eGFR) (CKD-EPI) (n=41)||-0.30 (0.66)|
|eGFR (MDRD) (n=41)||+0.79 (1.03)|
|Iohexol (Measured) GFR (n=37)||-1.51 (1.33)|
About Study 011 Statistical Analyses
The primary endpoint in Study 011 analyzed the percent change in kidney interstitial capillary GL-3 inclusions from baseline to month 6 (responder analysis with a 50% reduction threshold). As previously reported, the variability and low levels of GL-3 at baseline contributed to a higher-than-anticipated placebo response at month 6. Following the unblinding of the 6-month data, and while still blinded to the 12-month data, Amicus identified the mean change in GL-3 as a more appropriate way to control for the variability in GL-3 levels in Study 011 and to measure the biological effect of migalastat.
Amicus analyzed and previously reported the mean change in GL-3 from baseline to month 6 as a post-hoc analysis, including a subgroup analysis in patients with GLP HEK amenable mutations that further supports use of the GLP HEK assay in predicting responsiveness to migalastat. Following a Type C Meeting with the
About GLP HEK Amenable Mutations
Amenable mutations are 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. All subjects enrolled in Study 011 had amenable mutations in the clinical trial human embryonic kidney (HEK) assay available at study initiation ("clinical trial assay"). Following the completion of enrollment, a GLP HEK assay was developed with a third party to measure the criteria for amenability with more quality control and rigor. However, approximately 10% of mutations in the HEK database switched categorization between "amenable" and "non-amenable" when moving from the clinical trial assay to the GLP HEK assay. Therefore there were changes in categorization from amenable to non-amenable in 17 patients in Study 011.
Overall based on results from mutations tested in the GLP HEK assay, Amicus continues to believe that approximately 30% to 50% of the Fabry population have mutations that are amenable to migalastat.
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1Patients with GLP HEK amenable mutations who received migalastat from baseline to month 24
2Patients with GLP HEK amenable mutations who received placebo from baseline to month 6 and switched to migalastat after month 6
3Mean change in number of inclusions per capillary as a continuous variable (assessed by histology in kidney biopsies). Scores averaged across all reads at baseline, month 6 and month12.
*MMRM analyzing change in placebo group from month 6 to month 12
**ANCOVA model with covariate adjustment for baseline value and treatment-by-baseline interaction
This press release contains, and the accompanying conference call will contain, "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of Amicus' candidate drug products, the timing and reporting of results from preclinical studies and clinical trials evaluating Amicus' candidate drug products and the projected cash position for the Company. Words such as, but not limited to, "look forward to," "believe," "expect," "anticipate," "estimate," "intend," "potential," "plan," "targets," "likely," "may," "will," "would," "should" and "could," and similar expressions or words identify forward-looking statements. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. The inclusion of forward-looking statements
should not be regarded as a representation by Amicus that any of its plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong. They can be affected by inaccurate assumptions Amicus might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing and outcomes of discussions with regulatory authorities and the potential goals, progress, timing and results of preclinical studies and clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in the business of Amicus, including, without limitation: the potential that results of clinical or pre-clinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our
clinical trials; the potential that regulatory authorities may not grant or may delay approval for our product candidates; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we will need additional funding to complete all of our studies and, our dependence on third parties in the conduct of our clinical studies. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. With respect to statements regarding projections of the Company's cash position, actual results may differ based on market factors and the Company's ability to execute its operational and budget plans. In addition, all forward looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended
Sara Pellegrinospellegrino@amicusrx.com (609) 662-5044 Media: Dan Budwickdan@purecommunicationsinc.com (973) 271-6085
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