Consistent safety and tolerability of Valtoco® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long-term, open-label, repeat-dose safety study

Ian Miller, James W Wheless, Robert E Hogan, Dennis Dlugos, Victor Biton, Gregory D Cascino, Michael R Sperling, Kore Liow, Blanca Vazquez, Eric B Segal, Daniel Tarquinio, Weldon Mauney, Jay Desai, Adrian L Rabinowicz, Enrique Carrazana, DIAZ.001.05 Study Group, Ian Miller, James W Wheless, Robert E Hogan, Dennis Dlugos, Victor Biton, Gregory D Cascino, Michael R Sperling, Kore Liow, Blanca Vazquez, Eric B Segal, Daniel Tarquinio, Weldon Mauney, Jay Desai, Adrian L Rabinowicz, Enrique Carrazana, DIAZ.001.05 Study Group

Abstract

Objective: Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement.

Methods: This phase 3, open-label, repeat-dose, safety study of diazepam nasal spray enrolled patients (6-65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (<2, moderate frequency; 2-5, high frequency; >5, very-high frequency). Safety was evaluated based on treatment-emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness.

Results: Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment-related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate-, high-, and very-high-frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use.

Significance: Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.

Trial registration: ClinicalTrials.gov NCT02721069.

Keywords: acute repetitive seizure; diazepam; dosing frequency; intranasal; nasal spray; seizure cluster.

Conflict of interest statement

Dr Miller is currently an employee of Marinus Pharmaceuticals and has served as a consultant/advisor to GW Pharmaceuticals; Insys Therapeutics; Visualase; NeuroPace; and Neurelis, Inc; and as a study investigator for GW Pharmaceuticals. Dr Wheless has served as an advisor or consultant for: CombiMatrix; Eisai Inc; GW Pharmaceuticals; Lundbeck, Inc; Neurelis, Inc; NeuroPace, Inc; Supernus Pharmaceuticals, Inc; and Upsher‐Smith Laboratories, Inc Dr Wheless has served as a speaker or a member of a speakers bureau for: Cyberonics, Inc; Eisai Inc; Lundbeck, Inc; Mallinckrodt; Neurelis, Inc; Supernus Pharmaceuticals, Inc; Upsher‐Smith Laboratories, Inc, and has received grants for clinical research from: Acorda Therapeutics; GW Pharmaceuticals; Insys Therapeutics, Inc; Lundbeck, Inc; Mallinckrodt; Neurelis, Inc; NeuroPace, Inc; Upsher‐Smith Laboratories, Inc; and Zogenix, Inc Dr Hogan has received research support from UCB Pharmaceuticals, Neurelis, Inc; and Biogen Inc, and is an advisor for Neurelis, Inc Dr Dlugos receives salary support from NIH, Commonwealth of Pennsylvania Department of Health, Pediatric Epilepsy Research Foundation, and The Epilepsy Study Consortium. He is an investigator on research grants awarded to CHOP from Zogenix, Greenwich Biosciences, UCB, Brain Sentinel, Neurelis, Q‐State, USL, Aquestive, Bio‐Pharm, Insys, SK Life Sciences, and Encoded Therapeutics. He has received travel expenses for protocol development conferences or investigator meetings from Marinus, Ovid/Takeda, Ultragenyx, USL, Pfizer, and Zogenix. He received honoraria and/or travel support for CME and other educational programs from Wake Forest University School of Medicine, American Epilepsy Society, American Academy of Neurology, Epilepsy Foundation of America, Epilepsy Foundation of North Carolina, Medscape, Miller Medical Communications, Ecuador Neurology Project, Ministry of Health of the United Arab Emirates, and Seoul National University. Dr Biton has nothing to disclose. Dr Cascino has nothing to disclose. Dr Sperling has received personal compensation for speaking from NeurologyLive and Eisai, is an advisor for Neurelis, Inc, and consulting with payments to Thomas Jefferson University from Medtronic. Dr Sperling has received research support from Eisai; Medtronic; Neurelis, Inc; SK Life Science; Takeda; Sunovion; UCB Pharma; Xenon; and Engage Pharmaceuticals. Dr Liow has received research support from Intracellular Therapies, SK Life Sciences, Genentech, Biotie Therapies, MonoSol, Aquestive Therapeutics, Engage Therapeutics, Xenon, Lundbeck, Biogen, Eli Lilly, Pfizer, Novartis, Sunovion, Acorda, Eisai, UCB, LivaNova, Axsome, and Acadia. Dr Vazquez is an advisor for Neurelis, Inc Dr Ayala has nothing to disclose. Dr Segal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Eisai, Lundbeck, Nutricia, Novartis, Greenwich, Epitel, Encoded Therapeutics and QBioMed, and is an advisor for Neurelis, Inc Dr Tarquinio has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Marinus, Avexis, and Neurelis, Inc Dr Mauney has nothing to disclose. Dr Desai has received research funding from the Epilepsy Foundation of Greater Los Angeles; Neurelis, Inc; Novartis; Ovid; Aquestive; and UCB. Dr Rabinowicz is an employee and has received stock options from Neurelis. Dr Carrazana is an employee of and has received stock and stock options from Neurelis, Inc Dr Carrazana has received compensation for serving on the boards of directors of Marinus and Hawaii‐Biotech. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Population and retention rates for the usage groups

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