Venglustat

Venglustat is represented as a GCS inhibitor strategy, not a GBA activator. The pilot source repeatedly treats GBA activity as mechanistically irrelevant for venglustat while tracking GlcCer, GlcSph, alpha-synuclein, and clinical readouts. Sources: 20240722_181756, 20240722_181800.

Preclinical Evidence

model	source-captured effect	source
GbaD409V/D409V GD model	Residual GBA activity around 20%; venglustat had no effect on GBA activity; GlcCer decreased about 20%; GlcSph decreased about 50%; hippocampal proteinase K-resistant alpha-synuclein decreased toward baseline.	20240722_181756
CBE model	GBA activity treated as irrelevant; GlcCer decreased more than 50%; GlcSph decreased about 50%; behavior row mentions hind-limb splay.	20240722_181756
A53T-SNCA mouse	Related compound GZ667161; GlcCer decreased about 30%; GlcSph was not accumulated / NA; alpha-synuclein decreased about 20%; memory improved in novel object recognition.	20240722_181756
In-house A53T SNCA Tg mouse	Venglustat and T-4043036, PO QD, 30 mg/kg/day for 3 months; source defines tris-soluble, triton-soluble, and SDS-soluble alpha-synuclein fractions.	20240722_181756

Source figures include GD model plots and in-house alpha-synuclein plots. Source: 20240722_181756.

Clinical Trial Map

study	population / design	endpoints / key notes	source
P1 SAD	Healthy volunteers	Safety; source says CSF is not mentioned.	20240722_181756
P1 MAD	Healthy volunteers, 14 days, placebo	Safety and PK; plasma GlcCer, GL-3, GM3; CSF GlcSph not detectable in healthy.	20240722_181756
LEAP P2	GD type 1 and 3 on Cerezyme, adult; later GD3 focus; open-label single-group, 15 mg/day, 52 weeks, n=10	Secondary/exploratory neurological and CSF biomarker endpoints; ILD regression in 4/5; platelet increases; mSST showed no deterioration; SARA improved in later result note.	20240722_181800
MOVES-PD P2 POC	Early GBA+PD heterozygous carriers; placebo-controlled Part 1 dose escalation and Part 2 52-week treatment plus extension	MDS-UPDRS II+III primary. Included mutation distribution includes N370S, L444P, E326K, T369. Source asks whether failure was because population was too mild / N370S-heavy.	20240722_181800

Biomarker / Outcome Notes

area	source-captured detail	source
LEAP LLOQ	Plasma GlcCer 0.1 ug/ml, CSF GlcCer 2.0 ng/ml, plasma GlcSph 5.0 ng/ml, CSF GlcSph 5 pg/ml.	20240722_181800
LEAP 52-week changes	GlcCer decreased 78% in plasma and 81% in CSF; GlcSph decreased 56% in plasma and 70% in CSF, with a note that GlcSph appears slower/smaller than GlcCer.	20240722_181800
MOVES-PD Part 1	GlcCer reduction was 79% in plasma and 74% in CSF; source notes lack of normal control group.	20240722_181800
MOVES-PD 52-week clinical result	Least-squares mean MDS-UPDRS II+III changes were 7.29 for venglustat and 4.71 for placebo, not significant between groups.	20240722_181800
MOVES-PD Part 2 / Giladi 2023	GlcCer reduction 75% in plasma and CSF; CSF NfL about 20% elevated versus baseline in venglustat group but non-significant; plasma NfL no between-group difference; DaTSCAN reduced in both groups with no discernible between-group regional difference; CSF total alpha-syn unchanged versus placebo.	20240722_181800

Uncertainties Carried From Source

issue	source
GbaD409V/D409V styling is flattened from Word superscript/subscript.	20240722_181756
Plot y-axis values and significance marks are retained as images, not exact structured data.	20240722_181756
LEAP biomarker percent changes are high-risk numeric transcriptions.	20240722_181800
MOVES-PD design durations and mutation shorthand require review against adjacent material.	20240722_181800