Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

Abstract

Gaucher disease type 3 (GD3) is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease, and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once daily in combination with maintenance dose of imiglucerase ERT during one year of treatment in eleven adults with GD3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Week 26 and Week 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI (vMRI) using tensor-based morphometry, and resting functional MRI (fMRI) analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•hr/mL; Cmax of 58.1 (26.4) ng/mL was achieved at a median tmax 2.00 hours. After once-daily venglustat, plasma concentrations (4 hours post dose) were higher compared with Day 1, indicating approximately 2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/mL in plasma and 6.14 (3.44) ng/mL in CSF. After one year of treatment, median (IQR) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (IQR) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified SARA score decreased from 2.68 (1.54 [0.0 to 5.5]) at baseline to 1.55 (1.88 [0.0 to 5.0]) at Week 52 (mean change: -1.14 [95% CI: -2.06 to -0.21]). Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (-13894.8 mm3). fMRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with GD3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research.

A rare disease in adult women: Gaucher disease

“…8 GD type 3 (chronic neuronopathic), is a subacute neurological form with a slower progression of neurological symptoms and later onset of the disease. 9 The diagnosis of GD is often accompanied by delays because its diagnosis requires the use of invasive and resource-intensive procedures, such as pathological biopsies, molecular genetic tests, and enzyme activity assays. 10 A multidisciplinary combination of internal medicine, paediatrics, radiology, pathology, and molecular biology is beneficial in the treatment of GD.…”

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective

“…However, the authors of the study do not recommend an off-label use of the compound outside clinical studies. [128] Finally, in a recent study Venglustat, beside its ability to inhibit the activity of GCS, has been shown to competitively bind at the N-terminal methyltransferase 1 (NTMT1) substrate binding site, displaying an IC 50 value of 0.5 μM in both biochemical and cellular inhibition assays. Therefore, it has been selected as lead compound for the development of novel inhibitors of NTMT1 which has physiopathological implications in neurogenesis, retinoblastoma and cervical cancer.…”

“…In addition, amelioration of ataxia and neurocognitive deficits in GD3 patients have been observed. However, the authors of the study do not recommend an off‐label use of the compound outside clinical studies [128] …”

Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model

“…Of the LSDs, Gaucher disease (GD) has received particular attention over the past 15 years or so due to the genetic association between mutations in GBA, which encodes the defective lysosomal enzyme in GD, acid-beta-glucosidase (GCase), and Parkinson's disease (PD) 3 , although little data is available to permit delineation of the cellular and biochemical basis of this association 4 . GD is typically divided into three clinical subtypes, with the juvenile neurological form (type 3) the target of novel forms of therapeutic intervention, such as substrate reduction therapy which partially inhibits synthesis of the accumulating substrate 5 .…”