{"id":27748,"date":"2024-04-24T16:12:08","date_gmt":"2024-04-24T10:42:08","guid":{"rendered":"https:\/\/www.delveinsight.com\/blog\/?p=27748"},"modified":"2024-04-24T16:12:09","modified_gmt":"2024-04-24T10:42:09","slug":"soticlestat-for-epilepsy","status":"publish","type":"post","link":"https:\/\/www.delveinsight.com\/blog\/soticlestat-for-epilepsy","title":{"rendered":"Soticlestat (TAK-935): A Paradigm Shift in Epilepsy Treatment Strategies"},"content":{"rendered":"\n<ul class=\"wp-block-list\">\n<li><em>Takeda and Ovid Therapeutics with soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, holds promise for transformative therapy marking a milestone in advancing treatment options for individuals with refractory epilepsies associated with Dravet syndrome and Lennox-Gastaut syndrome.&nbsp;<\/em><\/li>\n\n\n\n<li><em>Soticlestat by modulating cholesterol homeostasis and glutamatergic pathways, presents a pioneering approach to reducing seizure susceptibility and improving seizure control.&nbsp;&nbsp;<\/em><\/li>\n<\/ul>\n\n\n\n<p>Current treatments for epilepsy predominantly address symptomatic seizure control, frequently falling short in targeting fundamental disease mechanisms, thus leaving approximately one-third of patients without adequate seizure management. Bridging this clinical gap for disease-modifying therapies requires dedicated research concentrating on targets that achieve a nuanced equilibrium between efficacy and safety.&nbsp;<\/p>\n\n\n\n<p>At the 76th annual meeting of the <strong>American Academy of Neurology (AAN) 2024<\/strong>, held in Denver from April 13 to 18, the company presented posters detailing soticlestat\u2019s mechanism of action as an anti-seizure medication, and its in-vitro metabolism and drug-drug interactions, shown in DS and LGS patients up to 2 years. It also presented details about the physiologically based pharmacokinetic (PBPK) model, developed to predict drug-drug interactions.&nbsp;<\/p>\n\n\n\n<p>Soticlestat (TAK-935) by Takeda and Ovid Therapeutics, targets brain-specific cholesterol 24-hydroxylase (CH24H) enzyme, crucial in regulating neuronal functions linked to seizure hyperexcitability. The enzyme primarily found in the brain, facilitates the conversion of cholesterol into 24S-hydroxycholesterol (24HC), thus regulating brain cholesterol homeostasis. This 24HC serves as a positive regulator of the NMDA receptor, impacting glutamatergic signaling. Activation of CH24H decreases excitatory amino acid transporter 2 function, which in turn reduces glutamate reuptake from the peri-synaptic space and potentially contributes to exaggerated neuronal hyperexcitability.&nbsp;<\/p>\n\n\n\n<p>Reduced postsynaptic levels of 24HC correlate with reductions in tumor necrosis factor-alpha (TNF-\u03b1) levels, and an increase in functional excitatory amino acid transporter 2 (EAAT2) in peri-synaptic astrocytes. These decrease extrasynaptic glutamate, decrease neuronal hyperexcitability, and reduce seizure susceptibility<\/p>\n\n\n\n<p>According to the data from the PBPK model, offering predictions on potential DDIs involving soticlestat, the simulated area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) and maximal drug concentration (C<sub>max<\/sub>) based on the final PBPK model for all doses evaluated were within 2-fold of observed values from single- and multiple-rising-dose studies. For soticlestat 300 mg, the model-simulated AUC0-inf and C<sub>max<\/sub> geometric mean ratios (GMRs) were 0.88 and 0.78\u2011fold of the observed values, respectively, which were not clinically significant. For soticlestat administered with and without itraconazole (strong CYP3A4 inhibitor), the model-simulated versus observed AUC0-inf and C<sub>max<\/sub> GMRs were 1.05 and 1.10-fold, respectively. For soticlestat with and without coadministration of rifampin (strong CYP3A4 inducer), the model under-predicted the DDI, with simulated AUC0-inf and C<sub>max<\/sub> GMRs of &gt;2.9-fold of observed values, representing a&nbsp; weak-to-moderate interactions. This PBPK model accurately predicted DDIs and will help with the clinical development and regulatory submissions of soticlestat.&nbsp;&nbsp;<\/p>\n\n\n\n<p>Takeda also provided information on the metabolism of soticlestat. The in-vitro investigations conducted in human hepatocytes (HHep), in human hepatocytes (HHep), liver microsomes (HLM), embryonic kidney (HEK), and colon adenocarcinoma clone 2 (Caco-2) cells using standard methodology, established that soticlestat has well-characterized metabolism, with limited victim and perpetrator DDI potential leading to minimal concern of clinical DDI risk. It demonstrated that soticlestat-glucuronide accounted for about 66% of total metabolism after 6 hours, with 34% attributed to cytochrome P450 and CYP3A being the only CYP responsible for soticlestat metabolism. Studies in human liver microsomes stated that UGT2B4 accounted for maximum UGT metabolism, almost 89.7%. Reversible CYP inhibition studies with soticlestat in HLMs showed notable inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4, but were not time-dependent.&nbsp;<\/p>\n\n\n\n<p>Soticlestat\u2019s unique mechanism as a CH24H inhibitor represents an innovative avenue in treating epilepsy, with a significant impact on neurosteroid synthesis regulation. Its advancement for conditions like Dravet Syndrome and Lennox\u2013Gastaut syndrome suggests a potential breakthrough in addressing rare epilepsies with transformative therapeutic prospects.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Current treatments for epilepsy predominantly address symptomatic seizure control, frequently falling short in targeting fundamental disease mechanisms, thus leaving approximately one-third of patients without adequate seizure management. Bridging this clinical gap for disease-modifying therapies requires dedicated research concentrating on targets that achieve a nuanced equilibrium between efficacy and safety.&nbsp; At the 76th annual meeting of [&hellip;]<\/p>\n","protected":false},"author":14,"featured_media":27750,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_editorskit_title_hidden":false,"_editorskit_reading_time":0,"_editorskit_is_block_options_detached":false,"_editorskit_block_options_position":"{}","advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","footnotes":""},"categories":[17126],"tags":[22059,22060,22061],"industry":[17225],"therapeutic_areas":[17245],"class_list":["post-27748","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-others","tag-aan","tag-aan-2024","tag-aan-2024-conference","industry-pharmaceutical","therapeutic_areas-neurology"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v25.8 (Yoast SEO v25.8) - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Soticlestat for Epilepsy | AAN 2024<\/title>\n<meta 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