Lyso-Gb1 (glucosylsphingosine) may be a sensitive marker of disease burden and treatment response in patients with Gaucher disease type 1, argue researchers from the biotechnology company Shire and Zedek Medical Center at the Hebrew University-Hadassah Medical School.
Unlike other markers of treatment response, Lyso-Gb1 reflects changes in disease processes, and may, therefore, complement current measures used in the development of new Gaucher therapies.
The study, “Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials,” was published in the journal Molecular Genetics and Metabolism.
To assess the value of Lyso-Gb1 as a biomarker, researchers analyzed data from two Phase 3 clinical trials of velaglucerase alfa (NCT00430625 and NCT00478647). The studies included 22 patients who had not received Gaucher treatment, as well as 21 patients who switched from treatment with Cerezyme (imiglucerase).
The analysis showed that the treatment lowered Lyso-Gb1 levels by 82.7 percent on average, over 209 weeks in previously untreated patients. Those who switched treatments lowered their levels by 52.0 percent over 161 weeks.
Researchers noted that treatment-naive patients who had Gaucher caused by a mutation in the N370S gene had higher levels of Lyso-Gb1 when the study began. But this difference did not translate to a difference in relative reductions of Lyso-Gb1 with treatment.
Such differences also were seen in previously treated patients at the study’s start, but the difference in relative reductions remained with treatment.
But to show that Lyso-Gb1 acts as a marker of improvement, researchers also needed to link the reductions to improvement in symptoms.
Analyses showed that Lyso-Gb1 reductions among previously untreated patients correlated with increasing platelet counts and decreasing spleen volumes. The link between Lyso-Gb1 and platelet counts was, however, not seen among those who completed 209 weeks of treatment.
In contrast, there was no correlation between changes in Lyso-Gb1 and platelet counts or spleen volumes among patients who switched treatments. Researchers said the lack of correlation likely is caused by the small number of patients studied and the relatively small changes in Lyso-Gb1 these patients experienced.
Lyso-Gb1 is a downstream metabolite of glucosylceramide — accumulated in Gaucher because of a faulty β-glucocerebrosidase gene. In the absence of the functional enzyme lacking in GD, glucosylceramide forms Lyso-Gb1.
While studies suggest that Lyso-Gb1 is linked to symptoms of the condition, more studies are needed to understand the potential of Lyso-Gb1 as a biomarker. Such studies, including a clinical trial (NCT02416661), are ongoing.