Treatment with oral venglustat demonstrates superior neurologic outcomes compared with standard enzyme replacement therapy (ERT) in patients with Gaucher disease type 3 (GD3), according to the phase III LEAP2MONO trial presented at EHA 2026.
The study met its primary endpoint, demonstrating the superior neurologic benefit of venglustat over that of imiglucerase based on the prespecified global O’Brien test of modified Scale for Assessment and Rating of Ataxia (mSARA) for motor function and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition at week 52, said author Dr Irene Motta from Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
This phase III, multicentre, multinational, double-dummy, active-comparator, double-blind trial enrolled 43 adolescents (aged ≥12 to <18 years) and adults with GD3 who were on ERT for ≥3 years prior to enrolment and had already achieved predefined therapeutic goals. Participants were randomized in a 1:1 ratio to receive either oral venglustat (12 or 15 mg/day for adolescents and 15 mg/day for adults) and placebo saline infusion Q2W (n=21) or intravenous imiglucerase Q2W and placebo tablets once daily (n=22) for 52 weeks.
At 52 weeks, the study’s primary endpoint—global O’Brien ordinary least-square (OLS) test combining motor (mSARA) and cognitive (RBANS) measures—demonstrated a statistically significant benefit of venglustat compared with imiglucerase (OLS, 2.59; one-sided p= 0.007). [EHA 2026, abstract S303]
Patients treated with venglustat achieved a clinically meaningful improvement in the mSARA score, with lower scores indicating better neurologic function, than those treated with imiglucerase (-1.35 vs -0.79 points).
The RBANS score, with higher scores reflecting improved cognitive function, increased by 3.69 points in the venglustat group. In contrast, the imiglucerase group showed a decline of 4.63 points.
With regard to the key secondary endpoints, the percent change in spleen and liver volumes was maintained at week 52 from baseline in the venglustat vs imiglucerase group (median 2.78 vs 2.22 and 0.90 vs 0.84 MN*, respectively), as was the haemoglobin level (median 138 vs 135.3 g/L) but not the platelet count.
Additionally, patients treated with venglustat achieved significant reductions in cerebrospinal fluid (CSF; -64.27 percent vs 9.69 percent [CSF GL-1**] and -57.55 percent vs -4.27 percent [CSF lyso-GL-1] for the adult cohort only) and plasma (-73.05 percent vs 6.19 percent [plasma GL-1] and -15.19 percent vs 7.5 percent [plasma lyso-GL-1] for both the paediatric and adult cohorts) biomarkers than those treated with imiglucerase.
Bone marrow burden and bone mineral density z-scores were similar between treatment groups. However, patients treated with venglustat achieved a greater improvement in bone pain from baseline to week 52 than those treated with imiglucerase (73.7 percent to 100 percent vs 81.8 percent to 95.2 percent).
Safety
The incidence of treatment-emergent adverse events (TEAEs) was comparable between the venglustat and imiglucerase groups (90.5 percent vs 86.4 percent). None of the TEAEs led to permanent treatment discontinuation.
The overall safety findings were consistent with the known safety profile of venglustat observed in all prior studies, Motta noted.
LEAP2MONO is the first phase III study to demonstrate that a brain-penetrant glucosylceramide synthase inhibitor can effectively address this unmet need.
Overall, venglustat showed clinical neurologic efficacy, providing coherent benefit across the motor (mSARA) and cognitive (RBANS) domains based on a prespecified global analysis, Motta said.
These findings position venglustat as a promising therapeutic option capable of targeting both the central nervous system and the systemic manifestations of GD3 in paediatric and adult populations, she added.