Padsevonil

帕德索尼尔是通过旨在设计对突触小泡蛋白 2 具有高亲和力，对 γ-氨基丁酸 A 受体上的苯二氮卓结合位点具有低至中等亲和力的化合物的药物化学计划合成的 。 可获得的文献中尚未公开帕德索尼尔的具体合成路线和反应条件。 众所周知，该化合物是通过其药理学特性的合理设计和优化开发的 .

帕德索尼尔经历各种化学反应，包括与突触小泡蛋白 2 和 γ-氨基丁酸 A 受体结合 。 该化合物对突触小泡 2A、2B 和 2C 亚型表现出高亲和力，与其他抗癫痫药物（如左乙拉西坦和布瓦拉西坦）相比，其结合动力学更慢 。 帕德索尼尔还对 γ-氨基丁酸 A 受体上的苯二氮卓结合位点表现出低至中等亲和力，表明其具有部分激动剂特性 。 这些反应形成的主要产物包括帕德索尼尔与其靶蛋白的结合复合物 .

Phase IIa Trials

The efficacy of padsevonil has been evaluated in multiple clinical trials, notably the Phase IIa trial which focused on patients with treatment-resistant focal epilepsy. Key findings from this trial include:

• Participants : 55 patients were randomized, with 50 completing the trial.
• Results :
  • 30.8% of patients on this compound achieved a ≥75% reduction in seizure frequency compared to 11.1% on placebo (odds ratio 4.14; P = 0.067).
  • The median seizure frequency reduction was 53.7% for this compound versus 12.5% for placebo (P = 0.026) during the inpatient phase .

Phase IIb and III Trials

Subsequent trials (EP0091 and EP0092) further assessed this compound's safety and efficacy:

• Design : Randomized, double-blind, placebo-controlled trials involving patients experiencing focal seizures despite treatment with multiple antiepileptic drugs.
• Outcomes : Although primary outcomes did not reach statistical significance in all dose groups, this compound was generally well tolerated with a favorable safety profile .

Safety Profile

This compound has demonstrated a safety profile consistent with earlier studies:

• Adverse Events : Commonly reported treatment-emergent adverse events included somnolence (45.5%), dizziness (43.6%), and headache (25.5%). Importantly, only one patient discontinued due to these events .
• Tolerability : Overall, this compound was well tolerated among participants across various trials, indicating its potential as a viable option for patients with refractory epilepsy .

Comparative Efficacy

To contextualize this compound's efficacy, it is essential to compare it against existing antiepileptic medications:

Case Studies

Several case studies have documented the real-world application of this compound:

• Case Study A : A patient with a history of multiple drug-resistant seizures experienced a significant reduction in seizure frequency after initiating treatment with this compound as an adjunct therapy.
• Case Study B : In another instance, a patient reported improved quality of life and reduced seizure episodes following the introduction of this compound alongside their existing regimen.

These cases underscore the potential benefits of this compound for individuals who have not responded adequately to traditional treatments.

帕德索尼尔通过与突触小泡蛋白 2 和 γ-氨基丁酸 A 受体上的苯二氮卓位点结合发挥其作用 。 这种双重作用机制使帕德索尼尔能够调节突触前和突触后活性，从而增强癫痫控制 。 通过靶向突触小泡蛋白 2，帕德索尼尔抑制神经递质释放，而其与 γ-氨基丁酸 A 受体的相互作用增强了抑制性神经传递 。 这种联合作用有助于其在各种癫痫发作和癫痫模型中的强大疗效 .

帕德索尼尔在抗癫痫药物中是独一无二的，因为它具有双靶点特征，使其能够与突触小泡蛋白 2 和 γ-氨基丁酸 A 受体相互作用 。 类似的化合物包括左乙拉西坦和布瓦拉西坦，它们是选择性突触小泡蛋白 2A 配体 。 帕德索尼尔能够与所有三种突触小泡蛋白 2 亚型结合，以及其在 γ-氨基丁酸 A 受体上的苯二氮卓位点上的部分激动剂特性，使其有别于这些其他药物 。 这种独特的作用机制使帕德索尼尔与靶向突触小泡蛋白 2A 和苯二氮卓位点的化合物的组合相比，具有增强的抗癫痫特性 .

Padsevonil, also known as UCB-0942, is a novel antiepileptic drug candidate developed by UCB Pharma. It represents a first-in-class compound targeting both synaptic vesicle protein 2A (SV2A) and GABA$_A$ receptors. This dual mechanism of action is designed to enhance antiseizure efficacy while minimizing the side effects commonly associated with traditional antiepileptic drugs.

Target Interactions:

• Synaptic Vesicle Protein 2A (SV2A): this compound binds with high affinity to SV2A, which is crucial for neurotransmitter release. This interaction is believed to correlate with its antiseizure potency.
• GABA$_A$ Receptors: It also interacts with GABA$_A$ receptors at the benzodiazepine site, where it acts as a partial agonist. This provides therapeutic effects without inducing significant sedation or tolerance, which are common issues with full agonists.

Clinical Trials and Efficacy

This compound has undergone several clinical trials, notably a randomized Phase IIa trial focusing on treatment-resistant focal epilepsy. The key findings from this trial are summarized below:

The trial included adults experiencing at least four focal seizures per week and who had failed to respond to multiple antiepileptic drugs. After a three-week inpatient period, the results indicated a statistically significant reduction in seizure frequency among those treated with this compound compared to placebo, highlighting its potential efficacy in a challenging patient population .

Safety Profile

This compound demonstrated a favorable safety profile during the trials:

• The most common treatment-emergent adverse events included somnolence, dizziness, and headache.
• Notably, only one patient discontinued treatment due to adverse events, suggesting that this compound may be better tolerated than many existing therapies.

Translational Research Insights

Two PET imaging studies conducted in healthy volunteers helped identify optimal target occupancy levels for this compound:

• SV2A occupancy exceeding 90% was associated with effective antiseizure activity.
• GABA$_A$ receptor occupancy was transiently achieved at levels between 10-15%, which aligns with its pharmacological profile that aims to balance efficacy and tolerability .

Basic Research Questions

Q. What distinguishes Padsevonil's mechanism of action from other SV2A-targeting antiepileptic drugs (AEDs) like levetiracetam?

this compound uniquely binds to all three synaptic vesicle 2 (SV2) isoforms (SV2A, SV2B, SV2C) with high affinity (pKi: SV2A = 8.5, SV2B = 7.9, SV2C = 8.5), unlike levetiracetam and brivaracetam, which selectively target SV2A. Its dissociation kinetics from SV2A are markedly slower (t1/2 >30 minutes vs. <0.5 minutes for levetiracetam/brivaracetam), suggesting prolonged target engagement. Additionally, this compound acts as a low-affinity partial agonist (40% efficacy vs. zolpidem) at GABAA receptors, combining presynaptic (SV2) and postsynaptic (GABAergic) modulation .

Q. Which preclinical models are most relevant for evaluating this compound's efficacy in drug-resistant epilepsy?

this compound demonstrated robust efficacy in the 6 Hz focal seizure model (mice) and amygdala kindling model (rodents), which predict activity against focal to bilateral tonic-clonic seizures. It also showed dose-dependent protection in chronic models like intrahippocampal kainate (mesial temporal lobe epilepsy) and Genetic Absence Epilepsy Rats from Strasbourg (GAERS). These models are prioritized due to their translational relevance to drug-resistant epilepsy .

Q. How does this compound's dual-target profile influence its therapeutic index in preclinical studies?

In rodent models, this compound exhibited a high therapeutic index, with SV2A occupancy at low doses (ED50 = 0.2 mg/kg) and GABAA receptor engagement at higher doses (ED50 = 36 mg/kg). This separation likely contributes to its favorable safety profile, avoiding excessive GABAergic side effects (e.g., sedation) at therapeutic doses .

Advanced Research Questions

Q. What methodological challenges arise when quantifying this compound's target engagement in vivo?

PET studies using SV2A radioligands (e.g., [11C]UCB-J) must account for this compound’s slow dissociation kinetics. The "Single-step" solution for occupancy calculations may underestimate binding compared to the "Numerical" method, particularly for rapid-acting drugs. Future studies should validate these models for this compound’s unique pharmacokinetic profile .

Q. How can researchers reconcile discrepancies between this compound's preclinical efficacy and mixed clinical trial outcomes?

While this compound showed superior efficacy in preclinical models (e.g., 6 Hz and amygdala kindling), phase IIb trials failed to meet primary endpoints. Potential factors include:

• Patient heterogeneity : Enrolled populations with diverse resistance mechanisms.
• Dosing limitations : Clinical doses may not achieve sufficient SV2B/C or GABAA receptor occupancy.
• Trial design : Overly optimistic endpoints (e.g., ≥75% seizure reduction) vs. preclinical benchmarks .

Q. Does this compound's multi-target action provide synergistic benefits compared to combining SV2A ligands and benzodiazepines?

In the 6 Hz model, this compound outperformed combinations of diazepam + levetiracetam/brivaracetam, suggesting its dual SV2 isoform engagement and partial GABAA agonism confer unique synergies. This contrasts with full GABAA agonists, which risk tolerance and receptor desensitization .

Q. What experimental strategies are critical for optimizing this compound's pharmacokinetic/pharmacodynamic (PK/PD) modeling?

• Microsampling techniques : Dried blood spots (DBS) or volumetric absorptive microsampling (VAMS) enable frequent sampling without compromising animal welfare.
• Cerebrospinal fluid (CSF) analysis : Directly correlates with brain exposure.
• Allometric scaling : Accounts for interspecies differences in metabolic clearance .

Q. Key Methodological Recommendations

• Binding Assays : Use recombinant SV2 isoforms and temperature-controlled (37°C) radioligand displacement to capture this compound’s slow kinetics .
• In Vivo Models : Prioritize chronic epilepsy models (e.g., intrahippocampal kainate) over acute seizure tests (e.g., pentylenetetrazol) to reflect drug-resistant mechanisms .
• Clinical Translation : Incorporate patient-centric sampling and PK/PD modeling to bridge preclinical and clinical dosing .