Gaucher disease is an inherited lysosomal disorder in which a deficiency of the enzyme glucocerebrosidase leads to the accumulation within lysosomes of its major metabolite, glucosylceramide (GL-1), and glucosylsphingosine (lyso-GL-1), the deacylated form of GL-1, a minor substrate of the enzyme.
The most common form of this rare disease is Gaucher disease type 1 (GD1) and its current treatment options include 3 enzyme replacement therapies (ERTs)—Cerezyme (imiglucerase), VPRIV (velaglucerase alfa), Elelyso (taliglucerase alfa)—and 2 substrate reduction therapies—Zavesca (miglustat) and Cerdelga (eliglustat).
Of these medications, the most recently approved is oral Cerdelga, made by Genzyme; it is the first non-ERT that can be used instead of ERT (unlike Zavesca, which is only approved for patients who cannot take ERT).
Poster at WORLDSymposium
At the WORLDSymposium meeting held in San Diego, CA, February 29-March 4, 2016, Genzyme researchers presented data showing that the reductive effect Cerdelga has on lyso-GL-1 concentrations seems to be correlated with Cerdelga’s efficacy.1
In the study, lyso-GL-1 extracted from dried blood spots was measured, as were changes in spleen and liver volumes, hemoglobin, platelet count, and chitotriosidase concentrations in 26 patients (10 males and 16 females) with Gaucher disease who had participated in a phase 2 clinical trial.2
At baseline, all patients with available data showed lyso-GL-1 concentrations (mean: 942 ng/mL; range: 248-2418) that were elevated 165-fold compared with normal controls (mean: 5.7 ng/mL; range 3.0-14.8).
Following treatment with Cerdelga, the median lyso-GL-1 concentrations decreased by 61% (SD: 11.0%) after 1 year, with continued decreases through year 3 and a final median reduction of 83% (SD: 11.8%) after year 4.
The decrease in lyso-GL-1 concentration paralleled the decrease in concentrations of chitotriosidase, a biomarker for Gaucher disease. Reductions were also observed in other biomarkers, including CCL18 (median level at baseline and year 4: 3560.20 ng/mL, 475.45 ng/mL), and GL-1 (median level at baseline and year 4: 18.80 mcg/mL, 2.00 mcg/mL).
Preliminary analyses indicate that the decreases in lyso-GL-1 concentrations correlated with the decreases in spleen and liver volumes and chitotriosidase concentrations, and with the increases in hemoglobin concentration and platelet count over time. Investigators recorded a mean 95% increase in platelet counts (P
= .0003), a 2.3 g/dL average increase in hemoglobin levels (P
<.0001), a 28% average reduction in liver volume (P
<.0001), and a 63% average reduction in spleen volume (P
The lyso-GL-1 biomarker has several advantages over other biomarkers in monitoring GD. For instance, unlike chitrosidase levels, which cannot be interpreted without genotypic testing (4% to 30% of patients with GD do not express chitrosidase), no genotypic testing is required to interpret lyso-GL-1 levels. Additionally, unlike chitrosidase levels and CCL18 levels, Lyso-GL-1 elevations are highly specific to patients with GD. Lyso-GL-1 is also an intermediate in the causal pathway of GD, which is not true of chitrosidase or CCL18 biomarkers.
Authors evaluated several correlations between outcome measures and Lyso-GL-1 levels and other markers of disease, including:
Spleen volume and Lyso-GL-1 levels (r = 0.690, P <.0001)
Hemoglobin levels and Lyso-GL-1 levels (r = –0.515, P <.0001)
Chitrosidase levels and Lyso-GL-1 levels (r = 0.386, P <.0001)
Liver volume and Lyso-GL-1 levels (r = 0.065, P = .0006)
Platelet count and Lyso-GL-1 levels (r = 0.279, P = .0001)
GL-1 levels and Lyso-GL-1 levels (r = 0.074, P = .0499)
Although correlations between liver volume and GL-1 levels were statistically significant, the strength of these correlations was weak. However, stronger and significant correlations were noted for other outcome measures.
The authors concluded that the decrease in lyso-GL-1 concentrations correlated with improvements of the major clinical manifestations of the disease. In addition, lyso-GL-1 may be a more useful marker of treatment response to eliglustat than chitotriosidase.
1. Peterschmitt MJ, Zhang K, Liu L, Cox GF. Evaluation of glucosylsphingosine as a biomarker of the eliglustat treatment response in patients with Gaucher disease type 1 (GD1). Mol Genet Metabol
. 2016;117;S94-S95. doi:10.1016/j.ymgme.2015.12.404.
2. Lukina E, Watman N, Dragosky M, et al. Eliglustat, an investigational oral therapy for Gaucher disease type 1: phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis