Valtoco (diazepam intranasal) / Neurelis, Aculys Pharma - LARVOL DELTA

Pharmacokinetics Study of VALTOCO® in Pediatric Subjects With Epilepsy (clinicaltrials.gov) - P1/2 | N=35 | Completed | Sponsor: Neurelis, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Aug 2023 ➔ Apr 2025

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

Exploring proposed recommendations for immediate-use seizure medication: Treating both cluster and prolonged seizures with diazepam nasal spray. (PubMed, Epilepsia Open) - "Study data showed that for most seizure clusters only 1 dose of diazepam nasal spray was used over 24 h (fitting ACT), and seizures were treated and ended quickly (fitting REST). One medicine for REST and ACT may make treatment simpler."

Journal • Review • CNS Disorders • Epilepsy

NEURELIS ANNOUNCES FDA APPROVAL FOR IMMEDIATE USE SEIZURE MEDICATION VALTOCO (DIAZEPAM NASAL SPRAY) IN AGES 2 TO 5 (PRNewswire) - "Neurelis, Inc., today announced that the U.S. Food and Drug Administration (FDA) has approved VALTOCO (diazepam nasal spray) for short-term treatment of seizure clusters (also known as 'acute repetitive seizures') that are different from a person's normal seizure pattern in people 2 years of age and older. VALTOCO is a proprietary formulation which utilizes an absorption enhancement technology, INTRAVAIL, to enable the noninvasive, enhanced intranasal delivery of diazepam....Data from the phase 1/2a clinical study evaluating safety and pharmacokinetics demonstrated that VALTOCO is safe and effective with easy nasal administration for patients aged 2 years and older who have episodes of frequent seizures."

FDA approval • CNS Disorders

Exploring Proposed Recommendations for Acute Cluster Treatment and Rapid and Early Seizure Termination Using Data From a Long-Term Safety Study of Diazepam Nasal Spray (P12-9.004). (PubMed, Neurology) - "Safety data for diazepam nasal spray were similar to that for diazepam rectal gel. Rabinowicz has stock in Neurelis, Inc. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff."

Journal • CNS Disorders • Epilepsy

Treatment of Status Epilepticus At and After T1 With Diazepam Nasal Spray: A Combined Cohort Analysis (PRNewswire) - "A post hoc analysis of pooled data from two long-term, open-label safety studies was conducted to investigate treatment of early SE episodes in patients with epilepsy aged 2-65 years. Early SE episodes were defined as seizures continuing after Time Point 1 (t1) (5 minutes for generalized seizures; 10 minutes for focal and unclassified seizures). For patients with seizure episodes reaching t1 (671 events of t1 SE in 97 patients), diazepam nasal spray provided timely control of SE episodes. Overall, safety was generally consistent with the established profile of diazepam nasal spray, and most episodes did not result in hospitalization due to serious treatment emergent adverse events (TEAEs) for SE. Additionally, in a responder analysis, the majority of early SE seizures terminated prior to Time Point 2 (when neuronal injury may occur: 30 and 60 minutes for generalized and focal seizures, respectively)."

Retrospective data • CNS Disorders • Epilepsy

Treatment of Prolonged Seizure with Diazepam Nasal Spray: A Post Hoc Cohort Analysis (PRNewswire) - "To assess effectiveness of diazepam nasal spray in treating prolonged seizures (5-15 minutes post onset) within seizure clusters (727 events), a post hoc subgroup analysis of data from the long-term safety study of diazepam nasal spray in patients aged 6-65 years was conducted. Across age, seizure type, and high treatment usage subgroups, generally similar times to seizure termination were observed. Use of second doses within 24 hours for prolonged seizures was low (9.3%) and generally consistent across subgroups, demonstrating preserved first-dose effectiveness in seizures that have become prolonged."

Retrospective data • CNS Disorders • Epilepsy

Exploring Proposed Recommendations for Acute Cluster Treatment and Rapid and Early Seizure Termination Using Data from a Long-Term Safety Study of Diazepam Nasal Spray (PRNewswire) - P=NA | N=163 | "Clinical data from the long-term safety study of diazepam nasal spray in patients aged 6-65 years was analyzed to determine whether it could support the recent expert consensus recommendations to terminate acute clusters and ongoing seizures that are expected to be prolonged. The effectiveness of diazepam nasal spray to prevent further seizures in a cluster was demonstrated by the low use of second doses across 24 hours. Rapid and early seizure termination was demonstrated in a dataset of 3225 administrations. Notably, for treatment within 5 minutes of seizure onset, rapid time to seizure termination reinforced the importance of early treatment."

Clinical data • Epilepsy

Treatment of Status Epilepticus At and After T1 With Diazepam Nasal Spray: A Combined Cohort Analysis (AAN 2025) - "In patients 2–65y with seizure episodes reaching T1, diazepam nasal spray provided consistent control, and the majority of these episodes were not associated with hospitalization as serious TEAEs. Diazepam nasal spray demonstrated safety and tolerability in patients 2–65y."

CNS Disorders • Epilepsy

The FORESITE Study: FOREcasting Seizures to Initiate ThErapy – Technical Design, Hardware, and Algorithms (AAN 2025) - "Seizure alerts prompt administration of intranasal diazepam, with the goal of preventing seizures before they begin. Seizure forecasting to guide medication is feasible."

CNS Disorders • Epilepsy

Treatment of Prolonged Seizure With Diazepam Nasal Spray: A Post Hoc Cohort Analysis (AAN 2025) - "If treatment is delayed (ie, a prolonged seizure within a SC), diazepam nasal spray rapidly terminates the SC with high first-dose effectiveness and a well-characterized safety profile. Diazepam nasal spray controls SCs when used promptly and when seizures are prolonged."

Retrospective data • CNS Disorders • Depression • Epilepsy • Pediatrics • Psychiatry

Exploring Proposed Recommendations for Acute Cluster Treatment and Rapid and Early Seizure Termination Using Data From a Long-Term Safety Study of Diazepam Nasal Spray (AAN 2025) - "Data from the long-term safety study of diazepam nasal spray demonstrate its benefit in immediate use for both prevention of further seizures in SCs (ACT) and termination of an acute SC and PS in a cluster (REST)."

Clinical • CNS Disorders • Epilepsy

Development of a self-management tool for individuals with seizure clusters: Trial design and methodological report. (PubMed, Epilepsy Behav) - "Integrating RM into an evidence-based epilepsy self-management curriculum offers a comprehensive care package with potential to improve care for PWE with seizure clusters."

Journal • CNS Disorders • Depression • Epilepsy • Psychiatry

Seizure Clusters and Rescue Medication: What Does Youtube Offer? (AES 2024) - "FDA-approved treatment recommendations included rectal Diastat, intranasal Nayzilam, or intranasal Valtoco... Finding informative YouTube videos on seizure cluster management is difficult. While several videos appeared to be effective as patient and provider education, applying less specific terminology returned unrelated or unhelpful videos. Healthcare institutions and pharmaceutical companies should produce brief, helpful videos of rescue therapy and arm patients with search terms to facilitate better navigation of educational resources."

CNS Disorders • Epilepsy

Neurologists Improve Their Knowledge, Competence, and Confidence of Seizure Action Plans and Seizure Rescue Medications Following Participation in an Online Certified Medical Education Program (AES 2024) - "The following areas showed significant (P < .05) pre- vs post-educational improvements: information that should always be included in an acute seizure action plan; clinically relevant differences between intranasal diazepam and intranasal midazolam; and the individualized selection of an appropriate seizure rescue medication for a patient with seizure clusters. The results indicated that this CME-certified 50-minute video discussion between physician experts was effective at improving awareness among neurologists regarding both seizure action plans and seizure rescue medications. Future educational efforts should continue to address the core features of seizure action plans as well as strategies to personalize the selection of seizure rescue medications."

CNS Disorders • Cognitive Disorders • Epilepsy

Treatment of Prolonged Seizure with Diazepam Nasal Spray: A Post Hoc Cohort Analysis (AES 2024) - "While immediate use of diazepam nasal spray (within 5 min) resulted in the fastest seizure termination, if treatment is delayed (as in a prolonged seizure within a cluster), diazepam nasal spray still resulted in rapid termination of the seizure cluster with high first-dose effectiveness and a well-characterized safety profile. These findings suggest that diazepam nasal spray controls seizure clusters that are treated promptly and those with seizures that have become prolonged."

Retrospective data • CNS Disorders • Depression • Epilepsy • Pediatrics • Psychiatry

Second Dose Use as a Proxy for Effectiveness of Diazepam Nasal Spray in Patients with Epilepsy Aged 2-5 Years: Interim Results from a Phase 1/2a Study (AES 2024) - "In this interim analysis of diazepam nasal spray for the treatment of seizure clusters in pediatric patients aged 2–5 y, a low proportion of seizure events (14.0%) was treated with a second dose within 24-hours of the first. Rates were comparable to pediatric patients aged ≥6 y in the prior phase 3, long-term, open-label safety study, in which 11.4% of seizure clusters were treated with second doses, with rates of 11.5% and 11.3% in the 6–11 and 12–17 age groups, respectively (Figure) (Tarquinio D, et al. Pediatr Neurol."

Clinical • P1/2 data • CNS Disorders • Epilepsy • Pediatrics

Safety Profile of Diazepam Nasal Spray in Patients Aged 2–5 Years from an Ongoing, Open-label 180-day Safety Period Following Pharmacokinetic Sampling in a Phase 1/2a Study (AES 2024) - "Rationale: For pediatric patients with epilepsy aged 2 to 5 years, diazepam rectal gel has been the only immediate-use antiseizure medication approved by the US Food and Drug Administration (FDA) for the treatment of seizure clusters; diazepam buccal film was recently approved. Thirty-five patients aged 2 to 5 years were enrolled in a phase 1/2a, open-label, single-dose PK study of diazepam nasal spray with a 180-day open-label safety period. In this ongoing study, 88.6% of patients completed the safety period. Treatment-related TEAEs were reported in 20.0% of patients, none of which were serious."

Clinical • P1/2 data • PK/PD data • CNS Disorders • Depression • Epilepsy • Pediatrics • Psychiatry

Potential Adverse Events of Clinical Interest with Use of Diazepam Nasal Spray in Children: Interim Results from an Ongoing Open-label, Pharmacokinetic and Safety Study (AES 2024) - "In this interim analysis, there were no new safety signals of clinical interest with diazepam nasal spray in children aged 2–5 years. Adverse events associated with benzodiazepines (eg, somnolence) and the route of administration (eg, nasal irritation) were uncommon, and cardiorespiratory adverse events were not related to treatment. Moreover, diazepam nasal spray was not associated with changes in vital signs or laboratory values."

Adverse events • Clinical • PK/PD data • CNS Disorders • Depression • Dry Eye Disease • Epilepsy • Infectious Disease • Ocular Inflammation • Ophthalmology • Otorhinolaryngology • Pain • Pediatrics • Pneumonia • Psychiatry • Respiratory Diseases

Pharmacokinetic Characteristics of Diazepam Nasal Spray in Children with Epilepsy 2 to 5 Years of Age (AES 2024) - "Diazepam nasal spray (Valtoco®) is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years, and diazepam rectal gel has a similar indication for patients aged ≥2 years. In this PK study conducted in children aged 2–5 years, diazepam nasal spray was readily absorbed and exposure was similar, independent of age or dose. These data are consistent with the known PK for older children (0.3 mg/kg dosing) and adults (0.2 mg/kg dosing) and confirm the adequacy of the 0.5 mg/kg dosing paradigm for diazepam nasal spray for children age 2–5 years."

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

Development of Self-management Tool for Individuals with Seizure Clusters (AES 2024) - "Phase 1, now completed, used input from an advisory board (AB) consisting of PWE, caregivers of PWE, and epilepsy care clinicians to modify the SMART curriculum and incorporate education and support for the use of diazepam nasal spray (Valtoco®, FDA approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity), as seizure rescue medication (RM)... Specific and actionable content for integrating the use of immediate use RM into an evidence-based epilepsy self-management curriculum provides a comprehensive package of care that has potential to advance care for PWE with seizure clusters."

Clinical • CNS Disorders • Depression • Epilepsy • Psychiatry

Is Disease Modification in Seizure Clusters Possible? Results from the Long-term Safety Study of Diazepam Nasal Spray (AES 2024) - "In the long-term safety study of diazepam nasal spray, analyses of the SEIVAL metric demonstrated strikingly similar increases in time between treated seizure clusters in all analyses. Although the underlying cause of this observation is unknown and the natural history of SEIVAL is yet to be defined, these consistent findings, even in patients with DEEs, suggest that the reduction is not a statistical artifact and may reflect a disease-modifying process with administration of diazepam nasal spray as needed over 1 year. Additional studies to help elucidate the measuring of SEIVAL are needed."

Clinical • CNS Disorders • Epilepsy • Pediatrics

Exploring Proposed Recommendations for Acute Cluster Treatment and Rapid and Early Seizure Termination Using Data from a Long-term Safety Study of Diazepam Nasal Spray (AES 2024) - "The safety profile for diazepam nasal spray was similar to that for diazepam rectal gel. Findings from the large data set of the long-term study of diazepam nasal spray demonstrate that it is of benefit in immediate use for both termination of an acute SC and prevention of further seizures in SCs and prolonged seizures within SCs regardless of seizure duration (eg, PS), thus supporting the recent expert consensus recommendations. Median treatment administration was 2 min and termination was 3 min, and administration at 5–15 min was still effective in cluster treatment (ACT). Even when use diazepam nasal spray treatment was delayed, it terminated PS in a cluster in an average of 7 min."

Clinical • CNS Disorders • Epilepsy

Effect of Diazepam Intervention on Seizure-cluster Expression in a Rat Model of Epilepsy (AES 2024) - "In this study using the rat KASE model of chronic epilepsy, the decreasing seizure severity over time with DZP treatment and the sustained effect of DZP on SC severity, burden, and size during the washout period supports its disease-modifying potential on SC biology. The observed rebound effect possibly masked a potential greater effect of DZP on SC burden and size during the intervention phase. Future studies are needed to understand and confirm these findings in rats receiving background antiseizure medications to mitigate the rebound effect and better replicate clinical practice where ISMs may be administered."

Preclinical • CNS Disorders • Epilepsy

Benzodiazepine rescue medication administration for seizure clusters: Real-world retrospective outcomes. (PubMed, Epilepsia) - "These retrospective real-world data suggest that the effect of benzodiazepines on termination of seizure clusters may be more pronounced when administration occurs earlier after onset, and support a hypothesis of a possible longer-term effect of benzodiazepines beyond immediate-use acute seizure termination."

Journal • Real-world • Real-world evidence • Retrospective data • CNS Disorders • Epilepsy

Treatment of prolonged seizure with diazepam nasal spray: An exploratory post hoc cohort analysis. (PubMed, Epilepsy Behav) - "Although immediate use of diazepam nasal spray (within 5 min) resulted in quicker seizure termination, a treatment delay of 5 to 15 min still produced rapid termination of the seizure cluster with high first-dose effectiveness and an overall acceptable safety profile. These findings suggest that diazepam nasal spray maintains effectiveness in prolonged seizures within a cluster with delayed treatment."

Journal • Retrospective data • CNS Disorders • Depression • Epilepsy • Psychiatry