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Abstract Details

Safety, tolerability and pharmacokinetics of oral venglustat in Parkinson’s disease patients with a GBA mutation
Movement Disorders
S4 - Clinical Trials in Movement Disorders (1:11 PM-1:22 PM)
002

Mutations in GBA, which encodes glucocerebrosidase, are associated with increased risk of developing PD, characterized by a younger onset, higher prevalence of cognitive impairment, and more rapid disease progression.

 

Assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of once-daily oral venglustat, a CNS-penetrating glucosylceramide (GL-1) synthase inhibitor, in Parkinson’s disease (PD) patients with a GBA mutation.

 

Part 1 of MOVES-PD (NCT02906020) was an up-to 36-week randomized, placebo-controlled, double-blind, sequential-cohort study of the safety/tolerability of once-daily venglustat at 3 escalating doses. PD patients age 18-80 years with symptoms ≥2 years at baseline who were heterozygous carriers of a GBA mutation were eligible. The primary endpoint was the safety/tolerability of venglustat. Secondary endpoints included plasma and cerebrospinal fluid (CSF) PK. Exploratory endpoints included pharmacodynamics. 

 

Seventeen patients were randomized to placebo (n=4) or venglustat (n=13). Mean age at enrollment was 58.4 years. Mean years since symptom onset was 6.7, and since diagnosis was 5.2. GBA mutations included N370S, 84GG, L444P, and E326K. Twelve venglustat-treated and 4 placebo-treated patients reported at least 1 treatment-emergent adverse event; most were mild or moderate and resolved without corrective treatment during the study, and the most common were psychiatric, neurological, and gastrointestinal events. No serious AEs or deaths occurred. Two patients on venglustat discontinued due to TEAEs after the primary analysis period (Week 4). Venglustat exposure in plasma and CSF increased in a close to dose proportional manner, and GL-1 levels decreased in a dose-dependent manner over 4 weeks. CSF GL-1 decreased 74.3% (high-dose).

 

The data demonstrate a favorable safety and tolerability profile of venglustat at all doses investigated for up to 36 weeks of treatment. Dose-dependent plasma and CSF exposure and reduction of plasma and CSF GL-1 were observed. Part 2 of MOVES-PD is ongoing. Funding: Sanofi Genzyme.
Authors/Disclosures
Tanya Fischer, MD, PhD
PRESENTER
No disclosure on file
No disclosure on file
Stuart H. Isaacson, MD, FAAN (Parkinson's Dis & Mov Dis Ctr of Boca Raton) The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Acadia. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sunovion. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for acorda. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Supernus. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurocrine. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kyowa. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for adamas. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neuroderm. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for amneal. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurocrine. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for adamas. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lundbeck. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Supernus. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acadia. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amneal. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie.
Jaime Kulisevsky, MD, PhD (Sant Pau Hospital) Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Esteve. Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Britannia. Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AC Immune. Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial. Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zambon. Dr. Kulisevsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Britannia.
Pablo Mir, MD (Servicio De Neurologia. Hospital Virgen Del Rocio) No disclosure on file
Tanya Simuni, MD, FAAN (Northwestern University Feinberg School of Medicien) Dr. Simuni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for cadia, AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Caraway Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, Michael J Fox Foundation, Neuroderm, Sanofi, Sinopia, Roche, Takeda and Vanqua Bio. Dr. Simuni has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for of Koneksa, Neuroderm, Sanofi, UCB, AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23 and Roche. Dr. Simuni has received research support from Amneal, Biogen, Neuroderm, Prevail, Roche, and UCB and an investigator for NINDS, MJFF, Parkinson's Foundation.
Anne Marie A. Wills, MD (MGH) Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Accordant, a CVS/Caremark company. Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi/Genzyme. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Pharmaceuticals. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Wills has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parkinson's Foundation. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx Pharmaceuticals. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ono Pharmaceuticals. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. The institution of Dr. Wills has received research support from Parkinson's Foundation. The institution of Dr. Wills has received research support from Biogen. The institution of Dr. Wills has received research support from Roche/Genentech. The institution of Dr. Wills has received research support from BioSensics.
No disclosure on file
No disclosure on file
Cheryl H. Waters, MD, FAAN (Columbia University) Dr. Waters has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acadia. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kyowa. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for US world meds. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexza. Dr. Waters has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Acorda. Dr. Waters has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Acadia. Dr. Waters has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurocrine. Dr. Waters has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bial. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for US world meds. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Adamas. Dr. Waters has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Dr. Waters has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Amneal.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
S. Pablo Sardi, PhD (SANOFI) Dr. Sardi has received personal compensation for serving as an employee of Sanofi. The institution of Dr. Sardi has received research support from MJFF.
Stephane Saubadu, MD Dr. Saubadu has received personal compensation for serving as an employee of Sanofi. Dr. Saubadu has stock in Sanofi.
No disclosure on file
M. Judith Peterschmitt, MD (Sanofi) No disclosure on file