FDA Review: Clobazam Oral Soluble Film for Treating Lennox-Gastaut Syndrome

The U.S. Food and Drug Administration has accepted for review a New Drug Application for clobazam Oral Soluble Film (clobazam OSF) for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients two years of age or older. The target date for completion of the FDA review is the third-quarter of 2018.

Clobazam OSF is administered using Aquestive’s PharmFilm drug delivery technology. Similar in size and thickness to a stamp, Aquestive’s PharmFilm dissolves instantly after being placed on the tongue and can be administered without water.

Two multicenter controlled studies were conducted to evaluate the bioequivalence of clobazam OSF with clobazam tablets, a benzodiazepine currently on market, at the same dosage strengths. Based on the studies, clobazam OSF was demonstrated to be bioequivalent to clobazam tablets and have comparable safety.

Drug Repurposing Database for Epilepsy

A database focused on repurposing drugs to treat epilepsy has been released by the University of Liverpool. The aim of the project is to help prioritize the most promising candidates for drug repurposing.

Repurposing drugs offers the potential of significant savings in the time and cost of drug development by discovering new indications for approved drugs. Given that 20 to 30 percent of individuals with epilepsy do not respond to traditional medications, there is a need to identify new antiepileptic drugs.

The database is reliable: 94 percent of the included drugs have corroborative evidence of efficacy in animal models. The database includes many drugs that are appealing candidates for repurposing, as they are widely accepted by prescribers and patients.

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy

A total of 40,443 patients with vagus nerve stimulation (VNS) therapy were followed up to 10 years post-implantation, accumulating 277,661 person-years of follow-up. There were 3,689 deaths, including 632 SUDEP, with 84% classified as possible and 16% as probable or definite. Age-adjusted SUDEP rates decreased significantly over time (by over 30%) from years 1-to-2 to years 3-to-10.

Several mechanisms could account for these findings including attrition and natural evolution, aging, changes in medications or medical practice over time, or VNS Therapy; the respective impacts cannot be disentangled due to study limitations.

Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy

We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy.

Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis.

These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy.

Growth hormone releasing hormone may play a role in inhibiting seizures

According to the study, “Interactions between GHRH and GABAARs in the brains of patients with epilepsy and in animal models of epilepsy” [1]:

[Researchers] propose that growth hormone releasing hormone (GHRH) may exert an antiepileptic effect.

The primary finding of this study is that growth hormone releasing hormone expression was significantly increased in the brains of both patients with temporal lobe epilepsy and in two mouse models of epilepsy induced by either kainic acid or pentylenetetrazol.

In addition, growth hormone releasing hormone co-localized with presynaptic and postsynaptic inhibitory neurons. Interestingly, [researchers] confirmed that growth hormone releasing hormone and activate ?-aminobutyric acid (GABA) receptors (GABAARs) interacted.

Therefore, [researchers] propose that growth hormone releasing hormone participates in anti-epileptic processes by increasing ?-aminobutyric acid levels and activating ?-aminobutyric acid receptors.

Ablation of hippocampal granule cells could halt progression of epilepsy

According to a study from Bethany E. Hosford et al., “Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression,” [1]:

Targeted ablation of newborn granule cells can produce a striking improvement in [temporal lobe epilepsy] disease course, and the treatment can be effective when applied months after disease onset.

Ablation halted epilepsy progression relative to untreated epileptic mice; the latter showing a significant and dramatic 300% increase in seizure frequency. This increase was prevented in treated mice.

Ablation did not, however, cause an immediate reduction in seizures, suggesting that peri-insult generated cells mediate epileptogenesis, but that seizures per se are initiated elsewhere in the circuit.

Clobazam Clinical Trial: Use for Epilepsy and Anxiety

This study is an open label, adjunctive, proof of concept, pilot clinical trial. Pediatric patients with epilepsy and clinically significant anxiety will be recruited and if enrolled will receive active treatment, involving flexible dose titration of clobazam and will be monitored for a period of four months. The study will be monitored and overseen by the Johns Hopkins Hospital Institutional Review Board.

Eligibility Criteria

Ages Eligible for Study: 6 Years to 17 Years (Child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Established diagnosis of epilepsy, characterized by focal seizures with suspected or documented localization in the temporal lobe. All participants will have active epilepsy that requires treatment with anticonvulsant medication.
    • Although it is not necessary to be seizure free, a seizure baseline period will be established in the 60 days prior to enrollment into the study.
    • Current regimen of anticonvulsant drugs must have been stable for 30 days prior to entry into the study.
  • No episodes of seizure clusters of status epilepticus within 30 days prior to entry into the study.
  • Established symptoms of anxiety with functional impairment.
  • Baseline behavioral criteria for inclusion will include subscale scores above the norm for age and gender on one of the following:
    • Pediatric Anxiety Rating Scale (PARS).
    • Multidimensional Anxiety Scale (MASC)
  • Male or female participants equal to or above age 6 and below age 18 at the start of the study. No exclusion will be made on the basis of gender or minority status.
  • Good general health as determined by medical history and physical examination.
  • Ability to swallow pills (participant will receive pill swallowing instruction if necessary). The medicine may be cut into pieces and/or mixed with applesauce.
  • If female of childbearing age, a negative urine or serum pregnancy test must be established or assured at baseline. Additionally, the participant must agree to use abstinence or appropriate contraception methods or be otherwise incapable of pregnancy for the duration of the study. Pregnancy test results will be shared with parent or guardian. Pregnancy status (or prevention) and abstinence or contraception methods will be addressed throughout the study for females of childbearing age as well as for post-pubertal males.
  • Previous subjects who failed at any point to meet continuation criteria and withdrew early may be considered for re-enrollment by the PI on a case-by-case basis.
  • Participant or legal caregiver capable of providing informed consent and fully capable of monitoring the subject’s disease process and compliance with treatment.

 

Exclusion Criteria:

  • Previous allergic or hypersensitivity reactions to Onfi® or benzodiazepines
  • Active substance abuse or dependence within 30 days of enrollment
  • DSM-V diagnosis of psychotic illness or imminent risk of harm to self or others.
  • Current use of antidepressants
  • Current standing use of benzodiazepines (except as “rescue” medicine)
  • Serious or unstable medical or neurologic conditions such as HIV, liver or kidney disease, cancer or diabetes.
  • Participation in a previous experimental drug study within 30 days of baseline visit.
  • Estimated IQ<70 as indicated by initial clinical assessment (rendering rating scales invalid)
  • Insufficient capacity of caregiver or legal guardian to understand and appropriately consent for study procedures

Vigabatrin evaluated for focal seizures in tuberous sclerosis in recent study

A study, “Vigabatrin for focal seizures in tuberous sclerosis,” found that [1]:

Vigabatrin (VGB) is used for focal seizures in tuberous sclerosis (TS) and may be an effective therapy in patients who fail to respond adequately to other anti-seizure medications while awaiting definitive epilepsy surgery.

Vigabatrin is well-established as the first-line therapy for infantile spasms in association with tuberous sclerosis, but less is known about its role in focal seizures due to tuberous sclerosis.

[Researchers] retrospectively identified 22 patients with tuberous sclerosis who received Vigabatrin for focal seizures, starting Vigabatrin in June 1989 and continuing through the present time. Nineteen (86%) had a history of infantile spasms and all except the two oldest, born in 1986, received Vigabatrin for infantile spasms. Eleven of these individuals exhibited improvement in or resolution of infantile spasms. Sixteen out of 17 with infantile spasms remained on Vigabatrin to treat focal seizures.

The risk for vision loss due to photoreceptor toxicity continues to limit prolonged use.

Vagus nerve stimulator placement, corpus callostomy, or ketogenic diet initiation could help children with pharmacoresistent epilepsy

According to a study, “Seizure control and quality of life in children with epilepsy after vagus nerve stimulator placement, corpus callostomy, or ketogenic diet initiation” [1]:

Vagus nerve stimulator placement, corpus callostomy, and ketogenic diet was successful in reducing both generalized and focal seizure types, [with] ketogenic diet showing a trend towards slightly better success.

Parents of 210 patients, who had 292 (VNS, n=150; CC, n=44; KD, n=98) treatment modalities, agreed to participate in a phone interview. 60% were male with ages ranging from 8 months to 20 years. Seizure control, cognitive and behavioral factors, quality of life and treatment satisfaction was rated via a 9-item telephone questionnaire.

Improvements observed in cognitive and behavioral domains, better seizure control and less falls positively affected quality of life. Parent overall satisfaction was greater than 75%, which far outweighed seizure reduction or behavioral improvements.

These findings support palliative management for those with pharmacoresistant epilepsy who are not candidates for surgical resection.