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.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

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.

Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

  • SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptorLearn More

    This research was supported by the Benninghoven family in memory of Cameron Benninghoven.

  • Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
  • Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
  • New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
  • Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
  • Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
  • SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Illustration of an RNS device after being implanted in a patient.

FDA Approves MRI Labeling for Neurostimulation System Designed to Prevent Seizures

The Food and Drug Administration (FDA) has approved MRI labeling for the RNS® System (NeuroPace), a closed-loop brain-responsive neurostimulation system indicated as adjunctive therapy to reduce the frequency of seizures in adults with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to 2 or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and / or secondarily generalized seizures).

With this approval, an MRI scan may be safely performed on patients with the RNS-320 neurostimulator model under the specific conditions of safe use detailed in the MRI Guidelines for the RNS System, providing an additional option for patients with focal onset seizures with brain anomalies that require frequent monitoring (ie, patients with tuberous sclerosis, brain tumors, and multiple sclerosis).

“MRI conditional labeling opens up valuable medical imaging possibilities for our patients treated with the model RNS-320 neurostimulator, who can now receive full-body 1.5T magnetic resonance imaging scans under appropriate conditions,” said Michael Favet, President and CEO of NeuroPace. “I’m pleased that we have removed a potential barrier to treatment and increased the number of patients who can benefit from this life-changing therapy.”

Engage Therapeutics Announces Phase 2b StATES Study of Staccato® Alprazolam for Seizure Cessation Meets Primary Endpoint

Engage Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on developing an orally inhaled therapy designed to terminate an active epileptic seizure, today announced that its Phase 2b StATES study of Staccato® alprazolam met its primary endpoint which was proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours.

“With statistically significant and clinically meaningful Phase 2 results in this randomized, placebo-controlled trial, Staccato alprazolam has demonstrated the ability to rapidly terminate seizures in patients with epilepsy in two minutes or less and prevent recurrence of seizure within two hours,” said Jaqueline French, MD, the study’s principal investigator and professor of neurology and co-director of epilepsy research and epilepsy clinical trials at NYU Langone Health’s Comprehensive Epilepsy Center, and founder/director of the Epilepsy Study Consortium. “We are now one step closer to bringing to patients an EpiPen®-like rescue treatment that works fast enough to terminate an active seizure episode. We look forward to initiating a Phase 3 study in the outpatient setting later this year.”

Drug Shows Promise in Reducing Seizures in Those with Severe Epilepsy

Featuring the work of former CURE Grantee, Dr. Angelique Bordey

People who suffer severe and recurring seizures have few good treatment options, but an experimental drug can reduce seizures in mouse models of two underlying disorders that can cause chronic epilepsy, Yale researchers report in the journal Science Translational Medicine.

Severe forms of epilepsy caused by brain lesions or malformations are usually treated with surgeries and anti-seizure medication. However, the prognosis for many of these patients remains poor, said Angelique Bordey, professor of neurosurgery and of cellular and molecular physiology.

“This is a completely new treatment with unexpected benefits,” Bordey said.

In a study led by first author Longbo Zhang, the Bordey lab reports the elevated expression of actin-cross linking protein filamin A (FLNA) in the brain tissue of many patients with two genetic disorders linked to intractable seizures: tuberous sclerosis complex (TSC) and a subset of focal cortical dysplasia type II. Both disorders are associated with disruption of a regulator of cell growth and cortical malformations with enlarged, dysmorphic cells that are responsible for seizures. Using a drug targeting FLNA to treat mice models of the disorders, Bordey’s lab found that cell enlargement and seizures could be prevented or reduced.

Bordey said her lab plans to explore whether the drug will be effective in treating people with epilepsy and perhaps other symptoms of TSC, such as behavioral problems, including social and intellectual deficits.

The work was primarily funded by the National Institute of Neurological Disorders and Stroke.