First-in-human single-dose data show favorable safety and dose-proportional exposure for the oral GCS inhibitor, presented at the IWGGD Symposium 2026 in Italy
Dr. Yukyung Kim, Director of Clinical Science at Yuhan Corporation, presenting the Phase 1 clinical trial results for the Gaucher disease treatment YH35995. (Photo courtesy of Yuhan Corporation)
Yuhan Corporation announced on May 6 that it presented the results of its Phase 1 single-dose trial for YH35995, a glucosylceramide synthase (GCS) inhibitor, in an oral presentation at the 3rd International Working Group on Gaucher Disease (IWGGD) Symposium 2026 held in Trieste, Italy.
Gaucher disease is a rare genetic disorder caused by a GBA1 gene mutation, which leads to reduced function of the lysosomal enzyme glucocerebrosidase, causing the accumulation of glucosylceramide (GL1) in various organs. Particularly in neuronopathic Gaucher disease (Types 2/3), which involves central nervous system (CNS) symptoms, there is a significant unmet medical need as existing treatments have difficulty sufficiently crossing the blood-brain barrier (BBB) to address these CNS symptoms.
YH35995 is a new drug pipeline secured through a joint research agreement with GC Biopharma in 2018. Yuhan is currently conducting its clinical development independently, and it is an oral, small-molecule GCS inhibitor classified as a Substrate Reduction Therapy (SRT). Its most significant feature is its ability to penetrate the BBB. In preclinical studies, it was confirmed to significantly reduce GL1 in both plasma and the brain, improve behavioral abnormalities, and suppress the increase of neuroinflammation-related markers, such as glial cell activation in brain tissue.
The oral presentation shared the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) results, focusing on the First-in-Human (FIH) Single Ascending Dose (SAD) part of the Phase 1 trial conducted in healthy adult males. The trial was conducted as a randomized, double-blind, placebo-controlled study.
In these results, YH35995 demonstrated a generally favorable safety profile across the administered dose range. No serious adverse events (SAEs) or Grade 3 or higher drug-related adverse events were reported, and the incidence of adverse events did not increase in proportion to the dose.
Pharmacokinetically, the drug’s systemic exposure increased proportionally with dose escalation, with low inter-individual variability. It also showed an unusually long half-life of approximately 21-24 days for an oral drug. Pharmacodynamically, the biomarker plasma GL1 showed a dose-dependent reduction, and the target GL1 inhibition rate was achieved in dose cohorts 4 and 5, confirming a potent and sustained GL1 inhibitory effect. Based on these PK/PD results, it was predicted that a dosing regimen of every 4 weeks (Q4W) or even longer intervals could be established.
Based on these SAD results, Yuhan Corporation plans to proceed with the Multiple Ascending Dose (MAD) part of the trial, administering repeated doses every 4 weeks (Q4W) to evaluate safety and tolerability, and to confirm GL1 changes in plasma and cerebrospinal fluid (CSF), as well as target engagement within the CNS.
Dr. Yeol-hong Kim, President and Head of R&D at Yuhan Corporation, stated, “This announcement is a significant achievement that confirms the potential for a new treatment option to address the unmet medical needs of Gaucher disease patients, especially those with neuronopathic forms. Moving forward, we will accelerate clinical development through close cooperation with regulatory authorities in various countries and do our best to provide a tangible treatment alternative for patients.”
Choi Mun-hee
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