padsevonil (UCB0942) / UCB - LARVOL DELTA

Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily. (PubMed, Nat Commun) - "Here, we report sub-3 Å resolution cryo-electron microscopy (cryo-EM) structures of human SV2A in its apo form and in complex with FDA-approved antiseizure medication levetiracetam; PET imaging tracer UCB-J; experimental antiseizure drug padsevonil; and allosteric modulator UCB1244283. Notably, padsevonil occupies both orthosteric and allosteric sites, functionally precluding modulation. These findings uncover an allosteric mechanism of regulation and provide a structural framework for the development of modulators targeting SV2A and related MFS transporters."

Journal • CNS Disorders • Epilepsy

SV2B Promotes the Progression of TFE3-Rearranged Renal Cell Carcinoma by Interacting with HERC2 to Impede the Degradation of NF-κB Subunits. (PubMed, Adv Sci (Weinh)) - "The drug padsevonil, targeting SV2B, selectively inhibits the growth of TFE3-RCC cells and organoids, similar to the NF-κB inhibitor Withaferin A. Clinically, RELA/NFKB1 expression positively correlates with SV2B levels but negatively with HERC2 expression, confirming the activation of TFE3-SV2B-NF-κB axis in TFE3-RCC. These findings establish SV2B as a novel diagnostic biomarker for TFE3-RCC and validate SV2B-NF-κB signaling as a therapeutic target, providing potential strategies for managing TFE3-RCC."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • RELA • TFE3

Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A). (PubMed, Proc Natl Acad Sci U S A) - "Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an experimental anticonvulsant; while UCB1244283 acts as an allosteric modulator for BRV and LEV binding but not for these other ligands. Structural comparison of multiple SV2A complexes reveals that primary site occupancy shapes the conformation of the lumenal half of the transmembrane domain, influencing how UCB1244283 binds via a connected network that differentially stabilizes TM1 in either an open or closed conformation and repositions key allosteric and primary site residues. These insights provide a foundation for developing therapeutics targeting the allosteric site and modulating SV2A function."

Journal • CNS Disorders • Epilepsy

Padsevonil suppresses seizures without inducing cell death in neonatal rats. (PubMed, Pharmacol Rep) - "PSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures."

Journal • Preclinical • CNS Disorders • Epilepsy • CDKN1A

Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil. (PubMed, Expert Opin Drug Metab Toxicol) - P1 | "A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed. The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing. https://www.clinicaltrials.gov/identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409."

Journal • PK/PD data • Preclinical • CNS Disorders • Epilepsy • CYP1A2 • CYP2C19 • CYP2C9 • CYP3A4 • SLC22A1

THERAPEUTIC TARGETING OF SYNAPTIC VESICLE GLYCOPROTEIN 2C (SV2C) IN PARKINSON'S DISEASE (ADPD 2024) - " Functional assays identified inhibitory effects (-39%) of the -racetam compound Padsevonil on FFN206 uptake at high (e.g., 100μM) dose, although no effects were identified with Levetiracetam. Theoretical modeling can be paired with functional assays to identify and test putative compounds for SV2C activity. Future studies will expand this catalogue of potential SV2C-modifying compounds for translation into in vivo models of PD."

CNS Disorders • Epilepsy • Movement Disorders • Parkinson's Disease

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development. (PubMed, AAPS J) - "Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration)."

Journal • CNS Disorders • Epilepsy

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. (PubMed, Neurosci Bull) - "Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs."

Journal • Review • CNS Disorders • Epilepsy

Pharmacokinetics and safety of Padsevonil in healthy Chinese subjects and comparison of two sampling methods for Padsevonil quantification. (PubMed, Eur Rev Med Pharmacol Sci) - "PSL has a favorable PK profile after single-dose oral administration and good safety properties in healthy Chinese volunteers. The regression analysis results of VAMS and plasma indicated that the application of VAMS for therapeutic drug monitoring in novel antiepileptic drug development is promising and needs further validation."

Clinical • Journal • PK/PD data • CNS Disorders • Epilepsy

Current and future pharmacotherapy options for drug-resistant epilepsy. (PubMed, Expert Opin Pharmacother) - "Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder...For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium..."

Journal • CNS Disorders • Epilepsy • Genetic Disorders • Immunology • Inflammation

Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials. (PubMed, Epilepsia Open) - P2, P3 | "In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated and no new safety signals were identified."

Clinical • Journal • CNS Disorders • Epilepsy

Study to Test the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P2; N=406; Terminated; Sponsor: UCB Biopharma SRL; Phase classification: P2/3 ➔ P2; Completed ➔ Terminated; Based on available data, UCB has decided to stop development of padsevonil as adjunctive treatment of focal-onset seizure

Clinical • Phase classification • Trial termination • CNS Disorders • Epilepsy

Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy. (PubMed, Front Pharmacol) - "Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms...At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs...In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy."

Journal • Preclinical • Review • CNS Disorders • Epilepsy

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy. (PubMed, J Exp Pharmacol) - "The best results were obtained for clobazam (already marketed), ganaxolone (in phase III trials), CVL-865 (in phase II trials), and padsevonil (in phase III trials). Several compounds with more selective action on GABA A receptors, perhaps only in certain brain regions, have the potential to become effective drugs against specific subtypes of focal-onset epilepsy. However, their development needs time, and in the near future we can expect only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy, an advance that would be of use for just a fraction of patients with drug-resistant epilepsy."

Journal • Review • CNS Disorders

Study to Test the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P2/3; N=406; Completed; Sponsor: UCB Biopharma S.P.R.L.; Enrolling by invitation ➔ Completed; N=1000 ➔ 406

Clinical • Enrollment change • Trial completion • CNS Disorders • Epilepsy

ARISE: Study to Test the Efficacy and Safety of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adults With Drug-resistant Epilepsy (clinicaltrials.gov) - P2; N=515; Completed; Sponsor: UCB Biopharma S.P.R.L.; Trial primary completion date: Jan 2019 ➔ Jan 2020

Clinical • Trial primary completion date • CNS Disorders • Epilepsy

An Open-label Extension Study of UCB0942 in Adult Patients With Highly Drug-resistant Focal Epilepsy (clinicaltrials.gov) - P2; N=42; Completed; Sponsor: UCB Biopharma S.P.R.L.; Active, not recruiting ➔ Completed

Clinical • Trial completion • CNS Disorders • Epilepsy

Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach. (PubMed, Brain Commun) - P2 | "Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy."

Clinical • Journal • P2a data • CNS Disorders • Epilepsy • Pain

[VIRTUAL] Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal seizures: a double-blind, randomized, placebo-controlled dose-finding trial (AES 2020) - P2 | "Both primary outcomes did not reach statistical significance in any dose group. Numerical improvements were observed for PSL dose groups vs PBO; however, these did not show a dose-dependent response. PSL was generally well tolerated and the safety profile was as expected based on its pharmacology and previous trials."

Clinical • CNS Disorders • Epilepsy • Fatigue • Hematological Disorders

Study to Test the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P2/3; N=1000; Enrolling by invitation; Sponsor: UCB Biopharma S.P.R.L.; Trial completion date: Apr 2021 ➔ Nov 2020; Trial primary completion date: Apr 2021 ➔ Nov 2020

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

DUET: A Study to Test the Efficacy and Safety of Padsevonil as Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P3; N=230; Completed; Sponsor: UCB Biopharma SRL; Active, not recruiting ➔ Completed; Trial completion date: Jan 2021 ➔ Sep 2020; Trial primary completion date: Jan 2021 ➔ Sep 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

An Open-label Extension Study of UCB0942 in Adult Patients With Highly Drug-resistant Focal Epilepsy (clinicaltrials.gov) - P2; N=42; Active, not recruiting; Sponsor: UCB Biopharma S.P.R.L.; Trial completion date: Dec 2021 ➔ Nov 2020; Trial primary completion date: Dec 2021 ➔ Nov 2020

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Study to Test the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P2/3; N=1000; Enrolling by invitation; Sponsor: UCB Biopharma S.P.R.L.; Trial completion date: Mar 2023 ➔ Apr 2021; Trial primary completion date: Jul 2022 ➔ Apr 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

DUET: A Study to Test the Efficacy and Safety of Padsevonil as Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy (clinicaltrials.gov) - P3; N=230; Active, not recruiting; Sponsor: UCB Biopharma SRL; Suspended ➔ Active, not recruiting; N=500 ➔ 230

Clinical • Enrollment change • Enrollment closed • CNS Disorders • Epilepsy

Pharmacological profile of the antiepileptic drug candidate padsevonil - characterization in rodent seizure and epilepsy models. (PubMed, J Pharmacol Exp Ther) - "Further results in the 6 Hz model showed that padsevonil provided significantly greater protection than the combination of diazepam with either 2S-(2-oxo-1-pyrrolidinyl)butanamide (levetiracetam) or 2S-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (brivaracetam), both selective SV2A ligands. Furthermore, in one rodent model, its efficacy extended beyond the combination of drugs interacting separately with SV2 or the benzodiazepine site. Padsevonil displayed a high therapeutic index, potentially translating into a favorable safety profile in humans; tolerance to antiseizure effects was not observed."

Journal • Preclinical • CNS Disorders • Epilepsy