Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan

Abstract

Background Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD. Methods All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed. Results In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results. Conclusion PMS data from patients with types 1–3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan. Trial registration: NCT03625882 registered July 2014.

Real-Life Experience with Oral Eliglustat in Patients with Gaucher Disease Previously Treated with Enzyme Replacement Therapy

“…Although, some patients improved after the switch, and others deteriorated ( Supplementary Table S2 ), our data confirms that in the majority of the patients, switching from ERT to SRT maintained stability in the key disease parameters. Variable responses were also seen by Kleytman et al [ 12 ], however, in this study, the improvements in spleen volume, platelet count, chitotriosidase, and lyso-Gb1 following the switch seems to be more significant. Since the characteristics of the patients in the two studies are rather similar, we speculate that the differences in the results could be explained by the different nature of the report.…”

“…For example, Deegan and Cox reported in 2012 that only 3 of 262 (1.1%) patients discontinued imiglucerase due to AE [ 11 ]. A study from Japan showed that only one of 53 patients, including all three types of GD, stopped Velaglucerase alfa due to an AE (1.9%) [ 12 ]. These numbers support our basic approach towards eliglustat as a second-line therapy as previously discussed [ 5 ].…”

Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency

“…In particular, IFN-γ administration did not lead to an inflammatory syndrome with a high temperature or to a recurrence of HLH-like manifestations. The main risk of providing exogenous protein to compensate for the genetic deficiency of the endogenous protein is the development of neutralizing antibodies, which have been observed in a subset of patients with inherited deficiencies of coagulation proteins (e.g., factors VII, VIII, and IX) [ 58 ], ß-glucocerebrosidase factor deficiency underlying Gaucher disease [ 59 ], and adenosine deaminase deficiency underlying severe combined immunodeficiency [ 60 ]. No neutralizing anti-IFN-γ auto-Abs were detected in the serum of the patient during the 30 months of treatment administration.…”

Newborn screening for Gaucher disease in Japan

“…No case of GD with the p.L483R variant has been reported in Nepal, and it is unclear whether p.L483R is a common variant in Nepalese. ERT has been approved as the first-line treatment for GD2 in Japan [ 31 ]. The first patient's hematological abnormalities and hepatosplenomegaly improved after ERT but her neurological symptoms gradually worsened.…”