Pharmacological Chaperone Therapy for the Treatment of Gaucher Disease: Results of Phase 1 Clinical Trials and a Clinical Ex Vivo Response Study with a Survey of Blood Markers for 53 Gaucher Patients.
Authors: Weinreb Neal J. , Grabowski G.A. , Pastores G.M. , Fernhoff P.M. , Kaplan P.B. , Palling D. , Pine C.W. , Raines B.E. , Insinga F. , Lockhart D.J. , Do H.V. , Wustman B.A. 
Published: April 2020

Abstract
Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase (GCase). Deficient GCase activity leads to symptoms such as anemia, thrombocytopenia, hepatosplenomegaly, bone necrosis, infarcts and osteoporosis, and in some cases, neuropathic disease. The pharmacological chaperone AT2101 (isofagamine tartrate) selectively binds and stabilizes GCase in the ER and increases trafficking of the enzyme to the lysosome. In single- and repeat-dose Phase 1 clinical trials involving 72 healthy volunteers, AT2101 was well tolerated with no serious adverse events. In the repeat-dose study, a dose-dependent increase in GCase levels in white blood cells (up to 3.5-fold) was observed during the 7 day treatment period, and enzyme levels remained elevated for more than a week after removal of the drug. To evaluate the effects of AT2101 on a range of different GCase variants, we conducted an ex vivo response study using macrophages and EBV-transformed lymphoblasts derived from GD patients. The study was conducted on samples from 53 patients enrolled at 5 sites in the United States. The study included 26 males and 26 females with type I GD, and one male with type III GD. Patients ranged in age from 7 to 83 years; 50 of 53 patients were receiving imiglucerase and blood was drawn prior to enzyme infusion. Incubation of cells with AT2101 (5 days) increased GCase levels in macrophages or lymphoblasts derived from 52 of 53 patients representing 18 different genotypes (mean: 2.6-fold, range: 1.4- to 8.6-fold). Plasma was also screened for potential biomarkers associated with inflammation, bone metabolism, multiple myeloma and neurodegeneration. Analysis of 40 markers showed elevated levels of chitotriosidase activity, TRACP 5b, PARC, IL-8, IL-17, VEGF, MIP-1α and α-synuclein and reduced bone-specific alkaline phosphatase levels in some patients. These results show that an imbalance between osteoclast and osteoblast activities may remain even though treatment with imiglucerase (Wenstrup et al. 2007. Journal of Bone and Mineral Research, 22: 119–26) and bisphosphonates (Wenstrup et al. 2004. Blood, 104: 1253–7) have been shown to increase bone mass in GD patients. Interestingly, increases in IL-8, IL-17, VEGF, MIP-1α, impaired osteoblast activity and increased osteoclast activity have also been implicated in the pathogenesis of multiple myeloma, and it has been reported that GD patients have an increased risk of developing multiple myeloma (Rosenbloom et al. 2005. Blood, 105: 4569–72). To determine if these biomarkers respond to treatment with AT2101, they are being monitored in an ongoing 6-month Phase 2 clinical trial with AT2101 in GD patients. Additionally, a 4-week Phase 2 clinical trial with AT2101 is being conducted in GD patients and preliminary results are expected by the end of 2007.