Pregnancy After Valproate (Depakote®) Withdrawal – Fetal Malformations and Seizure Control

Objective: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug’s dose was reduced before pregnancy.

Methods: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases.

Results: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%), and were only 2.7% where VPA intake was ceased before pregnancy. Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant.

Significance: Prepregnancy reduction in valproate dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Study Shows that Add-On Lacosamide (Vimpat®) is Effective for Epilepsy in Patients with Brain Tumors

Objective

To evaluate the effectiveness and tolerability of lacosamide added to one or two antiepileptic drugs (AEDs) in the treatment of patients with brain tumor–related epilepsy (BTRE), and to evaluate patients’ global impression of change and quality of life (QoL).

Results

Patients were recruited from 24 sites in Europe. Ninety-three patients received lacosamide, of whom 79 (84.9%) completed the study. At 6 months, 66 of 86 (76.7%) patients were 50% responders and 30 of 86 (34.9%) were seizure?free. Improvements were reported by 49 of 76 (64.5%) patients, according to a validated patient self-assessment. Improvements were observed in 52 of 81 (64.2%) patients, according to a clinician’s evaluation. Quality of Life and symptom outcome measures remained stable. The 6-month retention rate was 86.0% (N = 93). Fifteen (16.1%) patients reported adverse drug reactions, which were severe enough for four patients (4.3%) that they had to drop out of the study.

Significance

Results of this prospective, noninterventional study suggest that add-on lacosamide is effective and generally well tolerated in patients with brain-tumor related epilepsy.

Influence of Dose and Antiepileptic Comedication on Brivaracetam (Briviact®) Serum Concentrations in Patients with Epilepsy

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations, the lowest serum concentration reached by BRV before the next dose is taken.

A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel, both in Germany, were retrospectively evaluated. Analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine (Tegretol®), phenytoin (Dilantin®), and/or phenobarbital/primidone (Solfoton®/Mysoline®, -49%), but were not affected by concomitant intake of oxcarbazepine (Trileptal®) or eslicarbazepine (Aptiom®). Age and gender did not have a significant effect. An alternative model analyzing the BRV level-to-dose ratios yielded comparable results.

According to the research team, the results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

Study suggests that the dual mechanism of a new antiepileptic drug may explain its effectiveness in Dravet Syndrome

In addition to promoting the release of serotonin, a brain chemical typically associated with feelings of well-being and happiness, fenfluramine also seems to control the activity of sigma-1 receptors found on the surface of nerve cells, a study has found.

This dual mechanism of action is likely responsible for the deep and sustained effectiveness of the medication at reducing the frequency of seizures in children and young adults with Dravet syndrome, researchers noted.

Results of the study, “Fenfluramine acts as a positive modulator of sigma-1 receptors,” were published in the journal Epilepsy & Behavior.

Ovid Therapeutics Announces Initial Data with Soticlestat in CDKL5 Deficiency Disorder and Dup15q Syndrome

Ovid Therapeutics Inc announced initial data from its ongoing exploratory Phase 2 open-label study of soticlestat (OV935/TAK935) in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome (Dup15q). CDD and Dup15q are two rare, highly refractory developmental and epileptic encephalopathies (DEE) that have no approved treatment options. These early data demonstrate that soticlestat, a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), shows a reduction in seizure frequency compared to baseline levels in individual patients. CH24H plays a major role in clearing cholesterol in the brain, and by blocking this enzyme, soticlestat is thought to reduce activation of a neuronal signaling pathway associated with epilepsy, according to Ovid.

“This initial data set from the open-label study includes the first 11 patients enrolled. This data cut was designed to confirm the safety profile of soticlestat in these patient populations and assess any signals of efficacy. These initial data suggest that soticlestat continues to be safe and well tolerated and appears to reduce seizure frequency in a majority of the individual patients,” said Amit Rakhit, M.D., MBA, President and Chief Medical Officer of Ovid Therapeutics. “These early results are encouraging and are supportive of continuation of the study. We are also encouraged that all ARCADE patients that have completed the study to date have opted to roll over into the ENDYMION open-label extension study. We will work closely to evaluate the full data from the ARCADE study, expected in the first quarter of 2021.”

Matthew During, M.D., D.Sc., Chairman of the Company’s Scientific Advisory Board and Visiting Professor of Translational Neuroscience, University of Oxford, commented, “While this initial data includes only a limited number of patients, these results of the open-label trial are encouraging and support the safety and tolerability of soticlestat in CDD and Dup15q. More data is needed to assess efficacy, but initial data support the potential of soticlestat to provide a clinical benefit for patients with these ultra-rare and treatment-refractory epilepsy disorders. These initial results support continued recruitment and enrollment into the study.”

Study Finds Pregabalin (Lyrica®) Adjunctive Therapy Significantly Reduces Seizure Rate in Children One Month to Over Four Years with Focal Onset Seizures

Objective: To evaluate the efficacy and safety of pregabalin as adjunctive treatment for children (aged 1 month-<4 years) with focal onset seizures (FOS) using video-electroencephalography (V-EEG).

Methods: This randomized, placebo-controlled, international study included V-EEG seizure monitoring (48-72 hours) at baseline and over the last 3 days of 14-day (5-day dose escalation; 9-day fixed dose) double-blind pregabalin treatment (7 or 14 mg/kg/d in three divided doses). This was followed by a double-blind 1-week taper. The primary efficacy endpoint was log-transformed seizure rate (loge[24-hour seizure rate +1]) for all FOS recorded during the double-blind V-EEG monitoring, evaluated in subjects who took at least 1 dose of study medication, experienced at least 1 baseline seizure(s), and had a treatment phase V-EEG. Safety and tolerability were assessed by adverse events (AEs), clinical laboratory data, physical/neurological examinations, vital signs, and electrocardiograms.

Results: Overall, 175 patients were randomized (mean age = 28.2 months; 59% male, 69% white, 30% Asian) in a 2:1:2 ratio to pregabalin 7 or 14 mg/kg/d (n = 71 or n = 34, respectively), or placebo (n = 70). Pregabalin 14 mg/kg/d (n = 28) resulted in a statistically significant 35% reduction of loge(24-hour seizure rate +1) versus placebo (n = 53; P = .022), an effect that was not observed with pregabalin 7 mg/kg/d (n = 59; P = .461). The most frequently reported treatment-emergent AEs for pregabalin 7 mg/kg/d, 14 mg/kg/d, and placebo, respectively, were somnolence (11.3%, 17.6%, and 5.7%) and upper respiratory tract infection (7.0%, 11.8%, and 11.4%). All AEs were mild to moderate in severity.

Significance: Pregabalin 14 mg/kg/d (but not 7 mg/kg/d) significantly reduced seizure rate in children with FOS, when assessed using V-EEG, compared with placebo. Both pregabalin dosages were generally safe and well tolerated in children 1 month to <4 years of age with FOS. Safety and tolerability were consistent with the known profile of pregabalin in older children with epilepsy.

Repurposed Molecules for Antiepileptogenesis: Missing an Opportunity to Prevent Epilepsy?

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify post-injury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. Doctors may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically.

One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury – treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose – blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing.

Here, this research team reviews animal and human antiepileptogenic evidence for these medications. The team highlights the knowledge gaps for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

Study Finds Levetiracetam Not Significantly Better Than Phenytoin in Ending Seizures in Patients with Established Status Epilepticus

OBJECTIVES: To compare the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus.

METHODS: In this systematic review, we searched Medline, Embase, and Cochrane databases from their inception with no language restrictions until May 8, 2019 and updated on February 5, 2020, for randomized controlled trials comparing the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus. A Meta-analysis was conducted to calculate the risk ratio (RR) using random-effects models.

RESULTS: We identified 7 trials with a total of 1028 participants. Levetiracetam was not associated with an increased rate of clinical seizure cessation within 60?min compared with phenytoin (RR, 1.02; 95 %CI, 0.92-1.13; I2?=?3%; 60.0 % [309/515] vs 59.3 % [275/463];12 more events [95 % CI, -48 to 77] per 1000 participants; moderate-quality evidence). Results were similar in the subgroup analysis of adults and children. The sample size met the optimum size in trial sequential analysis. There were also no statistically significant effects on good functional outcome (RR, 1.05; 95 % CI, 0.90-1.23), admission to critical care (RR, 1.09; 95 % CI, 0.95-1.24), or all-cause mortality (RR, 1.09; 95 % CI, 0.55-2.16).

CONCLUSIONS: Moderate-quality evidence suggested that levetiracetam was not significantly superior to phenytoin in seizure cessation in patients with established status epilepticus.

XPhyto Therapeutics Epilepsy Treatment Program

XPhyto is pleased to announce significant progress with respect to development of its cannabidiol (CBD) based epilepsy product. Further to the company’s press release, titled “Epilepsy Treatment to be Developed with XPhyto Therapeutics Thin Film Delivery System,” and based on recent positive product development results, XPhyto will be advancing the program to clinical studies immediately.

In the past three months, Vektor Pharma TF GmbH (“Vektor”), the Company’s wholly owned German subsidiary, has completed the initial stage of product development and established a number of critical parameters necessary for an efficient and well-defined dissolvable oral CBD dosage form. The Company is now finalizing the formulation and preparing for European-based clinical studies in Q2 and Q3 of 2020.

XPhyto’s thin film drug delivery system was developed by Vektor, a narcotics manufacturer, importer, and researcher located in the Upper Swabia region of the German state of Baden-Württemberg. Vektor’s previous development work has included narcotics delivery systems for conventional oncology and non-oncology pain treatment, such as Fentanyl, Hydromorphone, and Oxycodone, and more recently, the development of efficient cannabis delivery and dosage systems.

The Company’s CBD-based Epilepsy treatment program is one of several dissolvable oral drug delivery initiatives for 2020. Oral thin film drug delivery is a large and growing international industry which provides an alternative to conventional solid and liquid oral dosage forms. Transparency Market Research estimates that the global market for thin film drug manufacturing will be worth US$15.984 billion by 2024 and rising at a solid 9.0% CAGR between 2019 and 2024. XPhyto’s additional oral thin film drug delivery programs include both cannabinoid and non-cannabinoid products for pain, neurology and infectious disease.

Further to the Company’s press release on March 3, 2020, XPhyto is planning to announce, in due course, an update on its infectious disease programs, particularly as they relate to products relevant to the COVID-19 pandemic.

ELEKTRA Trial Completes Enrollment to Test Soticlestat in Children With Dravet and LGS

The ELEKTRA clinical trial assessing the investigational oral therapy soticlestat (OV935/TAK-935) in children with Dravet syndrome and Lennox-Gastaut syndrome (LGS) has completed patient enrollment, Ovid Therapeutics recently announced.

“We completed enrollment significantly ahead of schedule in our placebo-controlled Phase 2 ELEKTRA trial in children with Dravet syndrome and Lennox-Gastaut syndrome, and as a result, we now expect data to be available in the third quarter of 2020,” Amit Rakhit, MD, president and chief medical officer of Ovid, said in a press release.

Soticlestat was developed by Takeda Pharmaceuticals in collaboration with Ovid Therapeutics for the treatment of rare developmental and epileptic encephalopathies, including Dravet and LGS.

The investigational therapy is a potent, highly-selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase, which has a major role in clearing cholesterol in the brain. By blocking this enzyme, soticlestat is thought to reduce the activation of a neuronal signaling pathway — glutamatergic signaling via NMDA receptors — potentially reducing seizure susceptibility and improving seizure control in patients with Dravet, according to Ovid.

STAY UP TO DATE