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Collection of eight posters include analyses of data from studies of diazepam nasal spray in treatment of episodes of frequent seizures in people with epilepsy aged 2-65 years SAN DIEGO, Dec. 5, 2025 /PRNewswire/ -- Neurelis, Inc., the innovator behind VALTOCO® (diazepam nasal spray), today announced it will participate in the American Epilepsy Society (AES) Annual Meeting December 5-9, 2025 in Atlanta. The Company will present a collection of eight posters focused on evaluation of diazepam nasal spray for the treatment of episodes of frequent seizures in people with epilepsy aged 2-65 years. Six of Neurelis' posters include analyses of data from the completed Stellina study, which was a long-term, Phase 1/2a, open-label pharmacokinetics (PK) and safety study that investigated diazepam nasal spray for the treatment of episodes of frequent seizures in patients with epilepsy aged 2-5 years, an age group now included in the indication for diazepam nasal spray. These presentations examine safety, single-dose effectiveness, time to seizure cessation, interval between treated seizure episodes over time, and caregiver responses to seizure severity and quality of life assessments. Additionally, one presentation explores administration of diazepam nasal spray for status epilepticus (SE), as defined by International League Against Epilepsy (ILAE) criteria, occurring within an episode of frequent seizures. This analysis uses pooled data gathered from the Stellina study in patients aged 2-5 and a long-term, Phase 3 safety study of diazepam nasal spray in patients aged 6-65 years. The final presentation reports findings from an exploratory post hoc analysis of the long-term safety study in patients aged 6-65 years. This analysis specifically examined the minute-by-minute relationship between the timing of diazepam nasal spray administration and the associated timing of seizure termination, when administered within five minutes of seizure cluster onset. "We are proud to present multiple posters this year highlighting data from our studies of diazepam nasal spray and its safety and effectiveness in treatment of episodes of frequent seizures," said Adrian L. Rabinowicz, MD, Neurelis Chief Medical Officer. "The AES Annual Meeting is an important opportunity for the epilepsy community to come together with a shared focus on improving health outcomes for people with epilepsy. We look forward to engaging fellow clinicians, researchers, and epilepsy advocates to discuss the latest scientific and clinical advances." Neurelis' presentations at the Annual Meeting include the following. December 7th, Session 2, 12-2:00 PM ET Prehospital Treatment of Impending Status Epilepticus with Diazepam Nasal Spray (Poster #2.35) Pooled patient diary data from the two long-term safety studies of diazepam nasal spray for episodes of frequent seizures were analyzed to assess the treatment of early status epilepticus in patients aged 2-17 years and 18-65 years. The analysis mapped seizure types to established ILAE criteria, using two critical time points: t1, when seizures are abnormally prolonged, and t2, when long-term consequences may occur. Overall, median total seizure durations were ≤t2 for most seizure categories, with a high proportion of patients achieving SE termination by or before t2. There were low rates of seizure recurrence 24 hours post-SE termination, use of >1 dose of diazepam nasal spray per episode, and hospitalization for SE. Collectively, these analyses demonstrate that treatment with diazepam nasal spray provided consistent and rapid control of early SE. Examining Nasal and Respiratory Safety of Diazepam Nasal Spray and Device Suitability for Children with Epilepsy Aged 2-5 Years (Poster #2.335) Data from the Stellina study were analyzed for nasal tolerability and device appropriateness, revealing that local treatment-emergent adverse events (TEAEs) were uncommon, with the few that were reported being mild and transient. Additionally, there was a low rate of dosing errors (<1%) in these young patients. No serious treatment-related TEAEs, including respiratory depression, were observed. These findings are comparable to those seen in studies in older children and adults, further supporting the diazepam nasal spray safety profile in the 2-5 year age group. Rapid Termination of Seizures in a Cluster: Minute-by-Minute Subgroup Analysis of Prompt Treatment with Diazepam Nasal Spray (Poster #2.336) An expert consensus recommends rapid and early seizure termination to avoid progression to a seizure emergency. In this analysis using data from the long-term safety study of diazepam nasal spray in patients aged 6-65 years, time to administration in the first 5 minutes after seizure cluster onset and associated seizure termination was examined. Among 2169 treated seizure clusters, earlier administration was associated with a shorter time to seizure termination and shorter seizure duration for generalized, focal, and indeterminable seizure types, in patients aged 6-17 years and 18-65 years, providing therapeutic support for the consensus recommendation. December 8th, Session 3, 12-1:45 PM ET Second Dose Usage as a Proxy for Effectiveness of Diazepam Nasal Spray in Patients with Epilepsy Aged 2-5 Years: Final Results of a Phase 1/2a Study (Poster #3.35) Seizure diary data from the Stellina study were evaluated using >1 dose of diazepam nasal spray within 24 hours as a proxy for effectiveness in patients aged 2-5 years. Results showed 82% of 339 total episodes of frequent seizures were treated with a single dose of diazepam nasal spray (based on patient age and weight (0.5 mg/kg)), similar to observations in patients aged 6-65 years in the separate long-term safety study of diazepam nasal spray. These findings support the effectiveness of the 0.5 mg/kg dose in patients aged 2-5 years. Interval Between Seizure Clusters (SEIzure interVAL) in Children Aged 2-5 Years: Final Analysis from a Phase 1/2a Study of Diazepam Nasal Spray (Poster #3.348) The interval between treated seizure clusters (SEIVAL) was examined in a presentation of data from the Stellina study. Data showed substantial lengthening of mean SEIVAL using both 70-day periods and 90-day periods, consistent with results in patients aged 6-65 years. These findings suggest a beneficial long-term treatment effect of diazepam nasal spray as an intermittent seizure medication. Temporal Patterns of Dosing and Seizure Cessation in Children Aged 2-5 Years: Final Results from a Phase 1/2a Study of Diazepam Nasal Spray (Poster #3.349) Seizure diary data from the Stellina study were evaluated for patterns of dosing and seizure cessation. Earlier treatment with diazepam nasal spray was associated with more rapid seizure cessation and shorter overall seizure duration. For seizures treated within 5 minutes, 5-15 minutes, and >15 minutes, median times to seizure cessation were 1, 3, and 9 minutes, respectively. These data were consistent with temporal patterns observed in older children and adults treated with diazepam nasal spray in the long-term safety study of patients aged 6-65 years. Final, Long-Term Safety Results for Diazepam Nasal Spray in Patients Aged 2-5 Years from a Phase 1/2a Study (Poster #3.357) Final safety results from the Stellina study were reported in 36 children with epilepsy, aged 2-5 years, who received at least one dose of diazepam nasal spray. The mean duration of participation in the study was >15 months. Treatment-related TEAEs were reported in 7 patients during the Open Label Safety Period (N=36) and 1 patient during the Optional Extension Period (N=27), with no serious treatment-related TEAEs reported. There were no study discontinuations or deaths due to TEAEs. Overall, the safety profile of diazepam nasal spray for seizure clusters in children aged 2-5 years was consistent with that seen in older children and adults. Caregiver Perceptions of Diazepam Nasal Spray Treatment in Children Aged 2-5 Years (Poster #3.358) During Stellina site visits, the validated Seizure Severity Questionnaire and a novel Caregiver Assessment instrument were administered to document the experiences of caregivers of epilepsy patients aged 2-5 years, treated with diazepam nasal spray. Caregivers' responses reflected improvement in their activities of daily living for themselves and their families. These insights reinforce the value of appropriate seizure cluster management. About Neurelis Neurelis, Inc., is a neuroscience company focused on the development and commercialization of therapeutics for the treatment of epilepsy and neurologic disorders characterized by high unmet medical need. The FDA has approved Neurelis' VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from an individual's usual seizure pattern in adult and pediatric patients 2 years of age and older. VALTOCO is a proprietary formulation of diazepam incorporating the science of INTRAVAIL®, a transmucosal absorption enhancement technology that enables the noninvasive delivery of a broad range of protein, peptide, and small-molecule drugs. For more information on VALTOCO, please visit . For the latest scientific information on VALTOCO, please visit . Neurelis is also developing NRL-1004, an investigational, Phase 1 stage intranasal olanzapine for treatment of acute agitation episodes associated with schizophrenia and bipolar disorder. In addition, Neurelis is also developing NRL-1049 (previously known as BA-1049), an investigational, Phase 1 new chemical entity Rho kinase (ROCK) inhibitor, for the treatment of cerebral cavernous malformations (CCMS), a rare disorder of the central nervous system (CNS). For more information on Neurelis, please visit . Important Safety Information about VALTOCO: Indication VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 2 years of age and older. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although VALTOCO is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO. Contraindications: VALTOCO is contraindicated in patients with: Hypersensitivity to diazepam Acute narrow-angle glaucoma Central Nervous System (CNS) Depression Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle, until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Glaucoma Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma. Neonatal Sedation and Withdrawal Syndrome Use of VALTOCO late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly. Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions, including "gasping syndrome," can occur in neonates and low-birth-weight infants treated with benzyl alcohol–preserved drugs, including VALTOCO. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Adverse Reactions The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort. Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance. To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (). Please read full Prescribing Information , including Boxed Warning. Contacts: Brittany Bradrick, Chief Operating Officer and Chief Financial Officer, +1 858 251 2100 SOURCE Neurelis, Inc. 21% more press release views with Request a Demo

点击蓝字 关注我们 本 期 看 点 随着CLDN18.2靶向药物Zolbetuximab（佐妥昔单抗）的成功研发和获批，晚期胃癌治疗领域迎来了新的转折点，即在经典的Her2靶点之后，CLDN18.2靶点成为第二个得到成药性检验的靶点，也会进一步促进其他在研CLDN18.2单抗、双抗、ADC及CAR-T相关创新产品的研发速度。而这也让临床抉择变得更加复杂，本文就两项最新研究进行梳理（文献来源1：European Journal of Cancer 224(2025) 115521。文献来源2：Chin J Cancer Res 2024;36(1):78-89），两篇文献分别从不同角度深入探讨了CLDN18.2阳性胃癌的临床特征和治疗策略，尤其在免疫联合化疗已经成为晚期胃癌一线SOC的基础上，如何进行CLDN18.2靶向治疗方案与免疫的抉择进行了分析，为临床实践提供了重要依据。 本期内容 01 治疗选择困境：靶向治疗还是免疫治疗？ 02 CLDN18.2阳性胃癌的独特临床特征 03 佐妥昔单抗的毒性管理 04 研究意义及展望 【01治疗选择困境：靶向治疗还是免疫治疗？】 胃癌是全球发病率与死亡率均居前的消化道恶性肿瘤，HER2阴性患者长期缺乏精准靶点可供治疗。随着 Claudin 18.2（CLDN18.2） 的发现与检测普及，精准治疗格局被重新定义。Zolbetuximab 作为首个靶向 CLDN18.2 的单克隆抗体，已在两项关键Ⅲ期临床试验——SPOTLIGHT 和 GLOW 中验证了其临床价值。 目前，FDA、EMA、日本MHLW及NMPA等机构已批准Zolbetuximab 联合化疗用于HER2阴性、CLDN18.2阳性的晚期胃或胃食管结合部（G/GEJ）腺癌一线治疗。这标志着胃癌精准治疗进入“CLDN18.2时代”。 然而，在实际临床中，CLDN18.2阳性患者常同时具备PD-L1阳性（CPS ≥1）或MSI-H特征，带来了“免疫与靶向如何取舍”的关键问题。 如何选择：Zolbetuximab vs ICI？ 文章综合SPOTLIGHT、GLOW、CheckMate-649与KEYNOTE系列数据进行间接比较，提出以下个体化策略： 这意味着，PD-L1高表达患者优先免疫治疗，低表达患者则是Zolbetuximab的理想人群。而对于既CLDN18.2阳性又PD-L1中高表达的交叉群体，如何联合或序贯治疗，仍是未来研究的关键方向。  专家点评“Zolbetuximab让HER2阴性人群首次拥有明确靶点，但精准治疗的意义在于‘人群区分’，而非‘药物取代’。理解PD-L1、MSI与CLDN18.2之间的交叉，是走向真正个体化治疗的核心。” 02 CLDN18.2阳性胃癌的独特临床特征 此外，来自北京大学肿瘤医院的回顾性研究系统分析了536例晚期胃癌患者，揭示出CLDN18.2阳性人群在临床特征与免疫反应上的显著异质性。研究显示，CLDN18.2阳性患者多为女性、年轻（<60岁）、弥漫型Lauren组织学、非胃食管结合部（non-GEJ）肿瘤，且呈现出典型的HER2阴性、PD-L1低表达特征。与传统免疫敏感型人群相比，这类患者的肿瘤微环境呈现出独特的“免疫冷漠型（immune-cold）”状态： 一方面，CD8⁺PD-1⁻、CD8⁺LAG3⁻、CD8⁺TIM3⁻等非激活T细胞比例升高，提示肿瘤内缺乏有效的T细胞应答；另一方面，肿瘤相关巨噬细胞（TAMs）大量浸润，形成免疫抑制性微环境，同时PD-L1通路表达显著降低，使PD-1/PD-L1抑制剂难以充分激活免疫反应。 图1. 根据CLDN18.2状态绘制的总体生存（OS）Kaplan-Meier曲线。 （A）CLDN18.2表达阈值为2+、40%（P=0.003）；（B）CLDN18.2表达阈值为2+、70%（P=0.013）。 图2　基于CLDN18.2表达的免疫治疗相关无进展生存期（irPFS）Kaplan-Meier曲线。 总体分析：CLDN18.2表达阈值为2+、40%（P=0.050）（A）；2+、70%（P=0.077）（B）；一线治疗亚组：CLDN18.2表达阈值为2+、40%（P=0.014）（C）；2+、70%（P=0.040）（D）。irPFS：免疫治疗相关无进展生存期 图3　根据CLDN18.2状态绘制的接受标准一线化疗患者的无进展生存期（PFS）Kaplan-Meier曲线。 （A）CLDN18.2表达阈值为2+、40%（P=0.099）；（B）CLDN18.2表达阈值为2+、70%（P=0.021）。 图4　CLDN18.2阳性患者接受标准一线化疗或化疗联合免疫检查点抑制剂（ICI）治疗的无进展生存期（PFS）Kaplan-Meier曲线。 （A）CLDN18.2表达阈值为2+、40%（P=0.540）；（B）CLDN18.2表达阈值为2+、70%（P=0.906）。 这种生物学特征直接转化为临床层面的差异：在接受免疫治疗的患者中，CLDN18.2阳性组的免疫相关无进展生存期（irPFS）显著短于阴性组（6.2 vs. 7.0个月，P≈0.05），且无论PD-L1表达高低，疗效均未显著改善。这表明CLDN18.2阳性胃癌并非典型的免疫敏感型肿瘤，其TME缺乏“热启动”特征，对ICI反应有限。 与之形成鲜明对照的是，Zolbetuximab等靶向CLDN18.2的单克隆抗体或CAR-T疗法在此类患者中表现出更高的客观缓解率与生存获益，成为HER2阴性人群中的新型精准靶点。 图S1　研究设计。 （A）肿瘤组织与正常胃黏膜中CLDN18.2表达的判读示例（×20）。肿瘤细胞膜上CLDN18.2染色强度的评估标准为：1+，弱染色；2+，中等至强染色；3+，强染色。（B）研究流程图。IHC：免疫组织化学；CLDN18.2：紧密连接蛋白18.2同工型；irPFS：免疫治疗相关无进展生存期。 由此形成了清晰的治疗区隔逻辑： PD-L1高表达、免疫活跃型患者更适合免疫治疗；CLDN18.2阳性、PD-L1低表达患者则更可能从靶向治疗中获益。 这一发现不仅为Zolbetuximab的临床定位提供了理论依据，也提示未来的治疗策略应从“单靶选择”走向“靶点协同”——在免疫冷漠型肿瘤中通过CLDN18.2靶向联合免疫激活的方式，重新塑造可反应性肿瘤微环境，实现更精准的治疗匹配。 【03 佐妥昔单抗的毒性管理】 在肯定Zolbetuximab在对症胃癌患者的疗效的同时，需要谨防的是它的“高发生率恶心与呕吐（N/V）”特性。根据SPOTLIGHT与GLOW结果，76%的患者出现恶心、67%出现呕吐，明显高于ICI联合化疗。这一毒性与CLDN18.2在正常胃黏膜的生理表达密切相关，尤其在首周期输注时最为明显。 机制与风险高峰 主要与首剂负荷量、输注速率及药物与胃上皮结合有关； 非胃切除患者更易出现严重N/V； 多在首周期发生，后续疗程可缓解。 管理策略：从预防到干预的全流程方案 预防性止吐方案（NCCN高危级别） 5-HT3受体拮抗剂 + 糖皮质激素± NK-1受体拮抗剂（阿瑞匹坦）± 奥氮平（推荐夜间服用） 输注管理 首周期采用“停—走策略”（Stop & Go）：逐步递增输注速率； 避免首剂快速推注，推荐至少2小时输注； 监测生命体征，必要时暂停。 药物辅助 对非胃切除患者可加用PPI或H₂受体拮抗剂，减少胃酸刺激； 严重N/V者可追加地塞米松或多巴胺受体拮抗剂。 剂量调整 Grade 2–3 N/V： 暂停输注，待缓解后以减速或减量重启； Grade 4或持续性症状： 考虑永久停药。 专家共识 “Zolbetuximab并非不可控毒性药物，关键在于团队的‘预判与干预意识’。首周期止吐策略若执行得当，绝大多数患者可顺利完成治疗。” 04 研究意义及展望 发表于《European Journal of Cancer》的综述，为临床医生提供了清晰的决策框架： 精准检测是前提： HER2、PD-L1、MSI、CLDN18.2应同步检测； 个体化选择是核心： PD-L1高→免疫；PD-L1低或ICI禁忌→Zolbetuximab； 毒性管理是保障： 预防性止吐+输注策略缺一不可。 Zolbetuximab 的出现让胃癌精准治疗迈入新的时代，但它同时提醒我们：精准不仅是选择合适的药，更是掌握管理的细节。未来，随着如 ILUSTRO 等Zolbetuximab联合免疫治疗研究结果公布，或许我们将迎来一个“靶向 × 免疫”并行的新格局。 参考文献： 1. European Journal of Cancer 224(2025) 115521 Chin J Cancer Res 2024;36(1):78-89 ★