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

Abstract

Gaucher disease type 3 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 and substrate reduction therapy 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 enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 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 using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•h/ml; Cmax of 58.1 (26.4) ng/ml was achieved at a median tmax 2.00 h. After once-daily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating ∼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 1 year of treatment, median (inter-quartile range) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (inter-quartile range) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified Scale for Assessment and Rating of Ataxia 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). Functional MRI 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 Gaucher disease type 3 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.

Keywords: CNS; Gaucher disease type 3; glycosphingolipids; substrate reduction therapy; venglustat.

Figure 1

Glycosphingolipid biosynthesis in GD and mechanisms by which treatments correct the underlying metabolic defect. Top: Glucosylceramide (GlcCer) and gluco-series sphingolipids are generated from ceramide and glucose by UDP-glucosylceramide synthase (UCGC) in the cis-Golgi. The reaction is common to the de novo and salvage pathways for glycosphingolipid biosynthesis from glucose (Glc) and ceramide (Cer). GD arises because of impaired activity of the lysosomal enzyme, acid β-glucosidase. As a result, its substrates, GlcCer and glucosylsphingosine (GlcSph), accumulate in the lysosome and in cell membranes and bring about GD. Bottom: Enzyme replacement therapy with recombinant human acid β-glucosidase restores enzymatic function and with it, the recycling of glycosphingolipids. However, enzyme therapy is not readily delivered to the brain. Brain-penetrant inhibitors of glucosylceramide biosynthesis, such as venglustat, attenuate formation of β-glucosylceramide and β-glucosylsphingosine in the brain and allow the lysosome to rebalance synthesis of glycosphingolipids with the rate of recycling—thereby alleviating the toxic build-up of glucosylceramides and their metabolites. Note: after biosynthesis in the Golgi, GlcCer is distributed throughout the cell and dynamically recycled by lysosomes in the constitutive process of membrane fusion.

Figure 2

Individual venglustat concentrations in plasma (A) and CSF (B). Concentrations measured ∼4 h post-dose. *Denotes values < LLOQ entered as 0.

Figure 3

Plasma and CSF concentrations of glucosylceramide (A and B) and glucosylsphingosine (C and D) from baseline to Week 52. LLOQ: plasma glucosylceramide 0.1 μg/ml, CSF glucosylceramide 2.0 ng/ml, plasma glucosylsphingosine 5.0 ng/ml, CSF glucosylsphingosine 5 pg/ml.

Figure 4

Total modified SARA score (A) and TMT-B minus TMT-A score (B) at screening, Weeks 26 and 52. In the total modified SARA score, each item of the SARA scale is scored on a 0 to 4 scale (possible range 0–32) and higher scores indicate more severe ataxia. Normative values for time to complete Trail B minus time to complete Trail A in subjects without any history of neurological or psychiatric symptoms: mean (SD) 30.55 (16.14) s in subjects <20 years of age (n = 10) and 44.61 (27.75) s in subjects 20–29 years of age (n = 66).

Figure 5

Tensor-based morphometry cycle at Week 52 visit. Top 10 regional brain volumes changes. (A) The nine brain regions with the greatest increases in volume for vMRI Group A (patients with adequate venglustat, shown as blue diamonds) compared with decreases in eight of these nine regions in Patient 9 (patient with low-to-undetectable venglustat exposure, shown as red diamonds). (B) The mean volume of the cerebral ventricles decreased in vMRI Group A, while in Patient 9, ventricular volume increased, reflecting a progressive loss of brain tissue. TBM = tensor-based morphometry.

Figure 6

Change in connectivity between functional RSNs in fMRI group A versus Patient 9. Functional MRI Group A patients (i.e. adequate venglustat exposure) (left) demonstrated enhanced connectivity (yellow) within a cluster of spatially and behaviourally disparate nodes (RSNs 1,2,3 and 6,7,8). Patient 9 showed less connectivity (blue). Where apparent, sites of enhanced connectivity in Patient 9 (i.e. low-to-undetectable venglustat exposure) werecloser to the line of identity, reflecting increased correlation between neighbouring sets of brain regions (RSNs 6 and 8, 7 and 9). These results indicate that fMRI Group A demonstrated increasing coherence within a wider spatial distribution than the local changes observed in Patient 9. Note: RSN matrices report full correlation (bottom half) and partial correlation (upper half), with partial correlation reflecting the unique variance accounted for by two RSNs while controlling for the variance from the other eight RSNs. *Patient 9 did not have measurable venglustat exposure and Patient 2 did not have an fMRI performed.