Therapeutics with Intravail® technology

• Neurelis acquires Aegis Therapeutics with innovative drug delivery technologies including Intravail® absorption enhancement technology
• During this period, Neurelis also initiates pre-clinical activities for second and third investigational product candidates
• New Drug Application (NDA) for lead investigational product candidate filed

Approval of Sumatriptan with Intravail®

• Formulation with Intravail® mucosal absorption enhancer approved
• Tosymra® (sumatriptan), a serotonin receptor (5-HT_1B/1D) agonist (triptan), was approved by the US Food and Drug Administration in January 2019 for acute treatment of migraine with or without aura in adults

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Diazepam Nasal Spray Approved January 2020

• Valtoco® (diazepam nasal spray) approved by the US Food and Drug Administration
• Indicated for 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 patient's with epilepsy aged ≥6 years
• Includes the absorption enhancer Intravail® and vitamin E

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Healthy Volunteer Diazepam Pharmacokinetic Study

• Phase 1 bioavailability study of diazepam in healthy adults
• Time to maximum plasma concentration was similar to diazepam rectal gel, slower than oral diazepam
• Interpatient variability was lowest with oral diazepam; nasal spray was lower than rectal gel
• Most treatment-emergent adverse events (n=131) were mild
• Diazepam nasal spray has predictable pharmacokinetics with reliable bioavailability

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Ictal/Interictal Pharmacokinetic Study of Diazepam Nasal Spray

• Phase 1 pharmacokinetic study of diazepam nasal spray in patients with epilepsy during ictal/peri-ictal and interictal conditions
• Pharmacokinetic profiles were similar under both conditions
• 17/49 patients (29.8%) reported TEAEs; 8 (14%) had treatment-related TEAEs
• There were no clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain

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Patient and Care Partner Survey: Subanalysis from the Phase 3 Safety Study

• A subgroup of patients and caregivers completed a survey for the long-term, phase 3 safety study
• 78.8% of patients (n=67) were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% returned to their usual selves within an hour
• 27 patients self-administered diazepam nasal spray
• 93.8% of 84 caregivers found diazepam nasal spray extremely or very easy to use

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• Final Results of the Phase 3 Long-term Safety Study of Diazepam Nasal Spray
• Long-term, phase 3 safety study of diazepam nasal spray in patients with epilepsy and seizure clusters
• Administered for 3853 seizure clusters
• Low use of second doses within 24 h (12.6% of clusters) suggests effectiveness
• Safety was consistent with rectal diazepam
• No serious TEAEs were considered treatment related
• 1 death and 1 withdrawal owing to a TEAE were not treatment related
• Nasal irritation was uncommon (7.9%)
• Figure. Key Safety Results View Figure

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• Recommendation for Development of an Acute Seizure Action Plan
• Many patients with epilepsy do not have a written seizure action plan (SAP) to guide appropriate treatment of seizure emergencies
• Epilepsy experts recommended a format for an easy-to-use but comprehensive acute seizure action plan
• SAPs could empower patients and caregivers and diminish seizure burden, fear, and healthcare burden
• Figure. Sample Acute Action Plan Acute Action Plan

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• Concomitant Benzodiazepine Use: Interim Analysis from the Phase 3 Safety Study
• An interim subgroup analysis in patients and without concomitant benzodiazepines
• Of 158 patients, 119 received concomitant benzodiazepines (60, chronic; 59, intermittent)
• Use of second doses to control a seizure cluster was low (<12%) in both groups
• The safety profile was consistent between patients with and without concomitant benzodiazepines

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• Use of Second Doses: Subanalysis from the Phase 3 Safety Study
• Use of a second dose within 24 hours was a proxy for effectiveness
• About half of patients (79/163) ever used a second dose, and 33 (41.8%) used only one
• Only 12.6% of clusters (485/3853) were treated with a second dose
• Rates of treatment-emergent adverse events (TEAEs; 15.2%) and treatment-related TEAEs (5.1%) within 1 day of a second dose were low
• Figure. Use of Second Doses Within 24 Hours of the First Dose View Figure

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• Pediatric Subgroup Analysis from the Phase 3 Safety Study
• This subanalysis evaluated safety and tolerability in patients aged 6-17 years
• Only 11.4% of treated seizure clusters (186/1634) used a second dose within 24 hours
• Treatment-emergent adverse events (TEAEs) occurred in 87.2% and serious TEAEs in 35.9%
• Treatment-related TEAEs were reported in 14.1%; none were serious, and no patients discontinued because of TEAEs

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• Epilepsia Supplement on Seizure Clusters
• This Epilepsia supplement is a practical resource to foster communication about seizure clusters for clinicians, caregivers, and people with epilepsy
• It integrates fundamental, translational, and clinical trial data with family insights, expert practical experience, and pharmacoeconomic approaches
• Articles also provide guidance on development and use of acute seizure action plans
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• Rapid Treatment Leads to Faster Seizure-Cluster Termination: Subanalysis from the Phase 3 Safety Study
• This post hoc analysis characterized time from seizure start to treatment and from treatment to seizure end
• In seizure clusters treated in <5 minutes, median time from dose to seizure end was 2 minutes
• For seizure clusters treated in ≥5 minutes, median time to seizure end was 10 minutes
• Figure. Shorter Median Time to Seizure Termination With Shorter Median Time to Treatment in Adult Patients Aged ≥18 Years (1567 observations) View Figure

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• Concomitant Use of Cannabidiol: Subanalysis from the Phase 3 Safety Study
• Intermittent diazepam nasal spray with/without cannabidiol (CBD) was assessed post hoc
• Of 163 treated patients, 119 (73.0%) did not receive CBD, 14.1% (23/163) received highly purified CBD, and 12.9% (21/163) other forms of CBD
• Treatment-related treatment-emergent adverse event rates were lowest with highly purified CBD (13.0%), 18.5% with no-CBD, and 23.8% with other CBD products
• Use of second doses showed a similar trend: 8.2%, 11.6%, 20.3%, respectively

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• Approval of Nalmefene with Intravail®
• Formulation with Intravail® mucosal absorption enhancer approved
• Opvee® (nalmefene hydrocholoride), an opioid antagonist, was approved by the US Food and Drug Administration in May 2023 for emergency treatment of known or suspected overdose induced by natural or synthetic opioids in patients aged ≥12 years, as manifested by respiratory or central nervous system depression

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• Subanalysis of Pediatric Developmental and Epileptic Encephalopathies from the Phase 3 Safety Study
• This was a post hoc analysis safety and effectiveness in patients with developmental epileptic encephalopathies (n=64)
• 10.6% of seizure clusters were treated with a second dose, and was similar in patients with Rett, Lennox-Gastaut, and Dravet syndromes
• The safety profile was consistent with that of the larger pediatric study population (aged 6-17 years) and the full study population (aged 6-65 years) with seizure clusters

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• Treatment of Prolonged Seizures in a Cluster: Subanalysis from the Phase 3 Safety Study
• An exploratory post hoc analysis assessed treatment of prolonged seizures (i.e., treated 5-15 minutes after seizure start) within seizure clusters
• Median time to treatment was 6 minutes and time from treatment to seizure end was 7 minutes
• Second doses were used in 9.3% of episodes, similar to the full study
• Figure. Median Times to Seizure Termination for Prolonged Seizures in Pediatric and Adult Subgroups View Figure

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• Approval of Epinephrine with Intravail®
• Formulation with Intravail® mucosal absorption enhancer approved
• Neffy® (epinephrine), an alpha and beta-adrenergic receptor agonist, was approved by the US Food and Drug Administration in August 2024 emergency treatment of type I allergic reactions, including anaphylaxis in adult and pediatric patients who weigh ≥30 kg

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