Fabry is an inherited disease in which a genetic mutation stops an enzyme from breaking down a fatty substance known as globotriaosylceramide, or GL3. The buildup of GL3 in cells throughout body causes severe damage to kidneys, heart, brain, and other organ systems. By definition, Fabry patients lack sufficient enzyme to break down GL3, but their inability to do so is highly variable.

Amicus, like other companies conducting Fabry disease clinical trials, tried to enroll patients with severe disease burden, defined as higher levels of GL3 in kidneys at baseline. The reason is fairly simple: Patients with more measurable disease at the start of the study tend to have a greater magnitude of response to treatment. The primary endpoint of Amicus' study compared response to Amigal versus placebo at six months, with response defined as a 50% reduction in GL3 levels measured via a kidney biopsy. Enrolling patients with more GL3 in their kidneys gave Amigal a better chance of demonstrating a superior response rate over placebo.

As reported last December, the Amigal study failed. Forty-one percent of Amigal patients were counted as responders (meaning they had a 50% decrease in GL3 in their kidneys. By comparison, 28% of placebo patients were responded. The response trend clearly favored Amigal but the difference was not statistically significant.

Amicus also measured the absolute percent change in kidney GL3 from baseline to six months. The result: Amigal 41% reduction compared to placebo 6% reduction. Again, the difference favored Amigal but was not statistically significant.

Which brings us back to the new data presented Friday at the Lysosomal Disease Network World Symposium. To get a better understanding of why Amigal missed the primary and secondary endpoints of the study, researchers used the results of the kidney biopsies taking after six months to divide patients into groups by the level of GL3 in their kidneys at the the start of the trial.

The results of this analysis are illustrated in the chart below:

Thirty-five of 60 (58%) Fabry patients in Amicus' study had baseline GL-3 levels between 0 and 0.3, representing low disease burden that is difficult to measure. In these patients, 32% treated with Amigal were classified as responders compared to 44% of patients treated with a placebo. This is where the Amigal study failed, Amicus believes.

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