Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers

Peterschmitt, Michel; Crawford, Nigel P.S.; Gaemers, Sebastiaan J.M.; Ji, Allena J.; Sharma, Jyoti; Pham, Theresa T.

doi:10.1002/cpdd.865

Cited by 79 publications

(58 citation statements)

References 23 publications

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“…Based on results from phase 1 clinical studies and nonclinical studies evaluating the safety and tolerability, pharmacokinetic, and pharmacodynamic profiles, oral administration of venglustat was generally well-tolerated with minimal side effects and off-target pharmacological effects (Suppl. Tables 3 and 4 ) 32 .…”

Section: Resultsmentioning

confidence: 99%

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Viel

Clarke

Kayatekin

et al. 2021

Sci Rep

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Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson’s disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.

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Section: Resultsmentioning

confidence: 99%

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Viel

Clarke

Kayatekin

et al. 2021

Sci Rep

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“…In addition, Venglustat as a GCS inhibitor demonstrated a favorable safety and tolerability profile (Sanofi Genzyme; NCT01674036; NCT01710826) [57].…”

Section: Substrate Reduction Therapymentioning

confidence: 99%

Fabry Disease: The Current Treatment Landscape

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2021

Drugs

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Fabry disease (FD) is a rare X-linked lysosomal storage disease based on a deficiency of α-galactosidase A (AGAL) caused by mutations in the α-galactosidase A gene (GLA). The lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (Gb 3) and globotriaosylsphingosine (lyso-Gb 3 , deacylated form), leads to a multisystemic disease with progressive renal failure, cardiomyopathy with potentially malignant cardiac arrhythmias, and strokes, which considerably limits the life expectancy of affected patients. Diagnostic confirmation in male patients is based on the detection of AGAL deficiency in blood leukocytes, whereas in women, due to the potentially high residual enzymatic activity, molecular genetic detection of a causal mutation is required. Current treatment options for FD include recombinant enzyme replacement therapy (ERT) with intravenous agalsidase-alfa (0.2 mg/kg body weight) or agalsidase-beta (1 mg/kg body weight) every 2 weeks and oral chaperone therapy with migalastat (123 mg every other day), which selectively and reversibly binds to the active site of AGAL, thereby correcting the misfolding of the enzyme and allowing it to traffic to the lysosome. These therapies enable cellular Gb 3 clearance and improve the burden of disease. However, in about 40% of all ERT-treated men, ERT can lead to infusion-associated reactions and the formation of neutralizing antidrug antibodies, which reduces the efficacy of therapy. In chaperone therapy, there are carriers of amenable mutations that show limited clinical success. This article provides a brief overview of the clinical picture in FD patients, diagnostic confirmation, and interdisciplinary clinical management of FD. The focus is on current and future therapeutic options. Key Points Diagnosis of Fabry disease in males includes the detection of decreased α-galactosidase A activity and in females the determination of a disease-causing mutation. Current treatment options of enzyme replacement therapy and chaperone therapy can improve disease burden and quality of life. New therapy options include modified enzyme replacement therapy, substrate reduction therapy, and gene therapy.

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“…Both drugs inhibit GCS, which blocks the first step in glycosphingolipid biosynthesis [118]. In particular, venglustat/ibiglustat [119] and lucerastat [120] are currently under evaluation as oral GCS inhibitors for FD (NCT02228460 and NCT02930655 are the respective clinical trials). Efforts and directions towards SRT for FD with specific inhibition of A4GALT, the responsible glycosyltransferase for the synthesis of Gb3, will be further discussed in this review.…”

Section: Present α-Gala-centered Therapy Approachesmentioning

confidence: 99%

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

et al. 2021

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Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.

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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers

Cited by 79 publications

References 23 publications

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Fabry Disease: The Current Treatment Landscape

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

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