Ospolot (sultiam) / AOP Orphan Pharma - LARVOL DELTA

Sultiame once per day in obstructive sleep apnoea (FLOW): a multicentre, randomised, double-blind, placebo-controlled, dose-finding, phase 2 trial. (PubMed, Lancet) - P2 | "Sultiame caused consistent, dose-dependent improvements of OSA, nocturnal hypoxia, sleep quality, and excessive daytime sleepiness. These findings offer perspectives for a pharmaceutical approach to treatment of patients with obstructive sleep apnoea."

Journal • P2 data • Excessive Daytime Sleepiness • Infectious Disease • Novel Coronavirus Disease • Obstructive Sleep Apnea • Pain • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Developmental and epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS): Clinical and treatment insights from a cohort of 50 children. (PubMed, Seizure) - "D/EE-SWAS is a spectrum disorder with variable severity and prognosis depending on etiology. Early recognition and tailored treatment, especially in children with SeLFE, are essential to mitigate neurocognitive decline. This large single-center cohort provides new insights into the therapeutic challenges and outcome variability in D/EE-SWAS."

Journal • CNS Disorders • Epilepsy • Pediatrics

Pharmacotherapy for obstructive sleep apnea: a critical review of randomized placebo-controlled trials. (PubMed, Sleep Med Rev) - "Weight-loss agents, particularly tirzepatide, represent a promising and now clinically viable treatment option. While endotype-targeted approaches are conceptually attractive, many agents were too early in their testing/re-purposing phase to demonstrate improvements in sleepiness, quality of life or sustained reductions of OSA severity; or were insufficiently targeted at the endotype they might best treat."

Journal • Review • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Reduction of carbonic anhydrase activity is associated with amelioration of obstructive sleep apnea. (PubMed, Sleep Breath) - "CA-inhibitory drugs reduced CA activity in whole blood suggesting a therapeutic role of CA inhibition in OSA. The findings also suggest that an activated CA system may constitute a pathophysiological mechanism in some forms of OSA."

Journal • CNS Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Apnea-hypopnea duration changes after Sulthiame - a new biomarker for treatment efficacy? (WSS 2025) - P2 | "STM is associated with a reduction in sleep-disordered breathing, improved nocturnal oxygenation, and a mild prolongation of residual events. The extension of AH event duration with STM should be further explored as a potential biomarker of treatment efficacy in OSA."

Biomarker • Clinical • CNS Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients. (PubMed, Clin Genet) - "Her clinical symptoms were more severe than those of previously reported female patients, but they improved with ethosuximide and sulthiame treatment. The strength of the X-chromosome inactivation skewing may be related to severity. These novel pathogenic CNKSR2 variants have expanded the phenotypic spectrum of this disease."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation

SURF: Effect of Sulthiame on EEG in Childhood Epilepsy Syndromes (clinicaltrials.gov) - P=N/A | N=15 | Recruiting | Sponsor: University Hospital, Angers | Trial completion date: Nov 2024 ➔ Dec 2025 | Trial primary completion date: Oct 2024 ➔ Dec 2025

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

Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and nocturnal seizures. (PubMed, Seizure) - "Our results propose KCNH3, which is primarily expressed in the nervous system, as a new disease gene associated with a neurodevelopmental phenotype including seizures."

Journal • Cardiovascular • CNS Disorders • Developmental Disorders • Epilepsy • Insomnia • Mental Retardation • Sleep Disorder • KCNH2 • KCNH3

The effect of sulthiame on potential biomarkers in moderate to severe obstructive sleep apnoea. (PubMed, ERJ Open Res) - "STM treatment in OSA induced a reduction of both CA activity and HIF-1α concentration. The effects remained 2 weeks after treatment completion, suggesting prolonged effects of STM in OSA."

Biomarker • Journal • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder • HIF1A

Late Breaking Abstract - A randomized, double-blind, placebo controlled, dose-finding trial of sulthiame in obstructive sleep apnea (ERS 2024) - "STM, in the evaluated dose range, provides a consistent reduction of sleep disordered breathing and improvement of sleep quality, hypoxia, and daytime sleepiness. STM is a promising candidate for drug therapy in OSA."

Clinical • Late-breaking abstract • Cardiovascular • Fatigue • Obstructive Sleep Apnea • Pain • Respiratory Diseases • Sleep Disorder

The effect of sulthiame on potential biomarkers in moderate to severe obstructive sleep apnea (ERS 2024) - "STM treatment in OSA induced a reduction of both CA activity and HIF-1α concentration. The effects remained two weeks after treatment completion, suggesting prolonged effects of STM in OSA."

Biomarker • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder • HIF1A

SURF: Effect of Sulthiame on EEG in Childhood Epilepsy Syndromes (clinicaltrials.gov) - P=N/A | N=15 | Recruiting | Sponsor: University Hospital, Angers | Trial completion date: Sep 2024 ➔ Nov 2024 | Trial primary completion date: Jul 2024 ➔ Oct 2024

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

The epilepsy phenotype of KCNK4-related neurodevelopmental disease. (PubMed, Seizure) - "Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental syndrome."

Journal • CNS Disorders • Dermatology • Developmental Disorders • Epilepsy • Mental Retardation • Pain • Psychiatry • KCNK4

Sulthiame use in children with pharmacoresistant epilepsies: A retrospective study. (PubMed, Epileptic Disord) - "These data demonstrate the therapeutic potential of sulthiame, even in patients with highly pharmacoresistant epilepsy. Improvements may be seen in both seizure frequency and sleep SWI."

Journal • Retrospective data • CNS Disorders • Epilepsy • Vascular Neurology • NDUFS1 • SATB1

Retrospective Study Of Sulthiame In Treatment Of Pediatric Epilepsy (CNSF 2024) - "These data indicate that sulthiame is effective and well-tolerated in children with CSWS, regardless of the etiology and type of epilepsy."

Retrospective data • CNS Disorders • Epilepsy

Efficacy, Safety, and Tolerability of Three Doses of Sulthiame in Patients With Obstructive Sleep Apnea. A Randomized, Double-blind, Placebo Controlled, Dose-ranging Study (STM-042/K) (ATS 2024) - P2 | "Treatment with STM in the evaluated dose range provides a consistent reduction of sleep disordered breathing together with improvement of sleep quality, hypoxia, and excessive daytime sleepiness. STM is a promising candidate for drug therapy in moderate to severe OSA. Keywords: RCT; carbonic anhydrase inhibition; drug therapy; obstructive sleep apnea; pharmacology.: 1."

Clinical • Late-breaking abstract • Cardiovascular • Excessive Daytime Sleepiness • Fatigue • Obstructive Sleep Apnea • Pain • Respiratory Diseases • Sleep Disorder

Use of Acetazolamide for Electrical Status Epilepticus During Slow-wave Sleep (AAN 2024) - "Sulthiame has been used to treat ESES successfully but is unavailable in the United States...Eight patients were prescribed AZM as a second-line medication for ESES, first being a benzodiazepine - diazepam or clobazam...The literature is limited on AZM use for ESES. We note that AZM has shown efficacy (66%) comparable to BZDs (60% in other studies), both clinically and electrographically. Since, it is better tolerated we support the consideration of an AZM trial as a second-line medication in patients who have failed or did not tolerate BZDs, prior to initiation of steroids."

CNS Disorders • Epilepsy • Metabolic Disorders • Rare Diseases

Use of Dextrose containing fluids and intralipids in a patient with KCNA1 related neuromyotonia (ACMG 2024) - "Treatment to prevent attacks is limited by lack of clinical trials but commonly used or proposed treatments include Acetazolamide, Phenytoin, Sulthiame, Carbamazepine, and Lamotrigine...She has required antiepileptic medication since presentation of symptoms with most presently being treated with carbamazepine and Ativan... Our patient presents with a familial VUS in KCNA1, which segregates with affected family members with episodic myotonia which is a described phenotype associated with pathogenic variants in KCNA1. Current management includes avoidance of triggers, antiepileptic medication, and acetazolamide which is effective in some patients, but acute management during attacks of myotonia is lacking. In addition to recommended treatment of KCNA1 related disorders which our patient has responded well to for prevention of attacks, our patient and her father have had success in acute treatment of attacks with dextrose containing fluids and intralipids."

Clinical • Ataxia • CNS Disorders • Epilepsy • Gastroenterology • Gynecology • Movement Disorders • Nephrology • Otorhinolaryngology • Renal Calculi • Vertigo

SURF: Effect of Sulthiame on EEG in Childhood Epilepsy Syndromes (clinicaltrials.gov) - P=N/A | N=15 | Recruiting | Sponsor: University Hospital, Angers | Initiation date: Jul 2023 ➔ Oct 2023 | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • CNS Disorders • Epilepsy

Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug-Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy. (PubMed, Ther Drug Monit) - "This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment."

Journal • PK/PD data • CNS Disorders • Epilepsy • CYP2C19

Cannabidiol Effect on the Antiepileptic Drug Serum Levels – Experience from the Danish Epilepsy Center (AES 2023) - "In polytherapy with Cannabidiol with or without clobazam were used: valproic acid (17 case), topiramat (11), perampanel (8), lacosamide (8), rufinamide (8), levetiracetam (7), zonisamid (7), lamotrigine (5), bivaracetam (4), ethosuximide (4), stiripentol (4), eslicarbazepin (2), oxcarbazepine (2), pregabalin (2) and sultiame (1)...Topiramate level in all cases was the same or only slightly increased or decreased... There seems to be no simple relationship between Cannabidiol and most antiepileptic drugs. Cannabidiol politherapy with antiepileptic drugs requires control of serum antiepileptic drug levels especially in polytherapy in such medicine as valproic acid, brivaracetam, lacosamide, and perampanel but also rufinamide."

CNS Disorders • Developmental Disorders • Epilepsy • Movement Disorders

Efficacy, Safety and Tolerability of Sulthiame in Patients With Obstructive Sleep Apnea (OSA) (clinicaltrials.gov) - P2 | N=298 | Completed | Sponsor: Desitin Arzneimittel GmbH | Active, not recruiting ➔ Completed

Trial completion • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Modification of endotypic traits in obstructive sleep apnea by the carbonic anhydrase inhibitor sulthiame. (PubMed, Chest) - "The effect of STM in OSA may be explained by a reduction of ventilatory instability (LG) as well as upper airway collapsibility (V / V)."

Journal • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Modification of OSA endotypic traits by sulthiame (ERS 2023) - "STM reduced AHI in OSA already in the lower concentration range. The effect of STM in OSA may be explained by reduced ventilatory instability and improved upper airway collapsibility.; General respiratory patient care; Physiology; Epidemiology; Cell and molecular biology"

Cardiovascular • Hypertension • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Efficacy, Safety and Tolerability of Sulthiame in Patients With Obstructive Sleep Apnea (OSA) (clinicaltrials.gov) - P2 | N=298 | Active, not recruiting | Sponsor: Desitin Arzneimittel GmbH | Recruiting ➔ Active, not recruiting | Trial completion date: May 2023 ➔ Aug 2023 | Trial primary completion date: Mar 2023 ➔ Aug 2023

Enrollment closed • Trial completion date • Trial primary completion date • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder