FDA Approves New Therapy for Dravet Syndrome

FDA Press Release

On June 25, 2020, the U.S. Food and Drug Administration approved Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients age 2 and older.

“Dravet syndrome is a debilitating disease that takes a tremendous toll on both patients and their families,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy.”

The effectiveness of Fintepla for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages 2 and 18. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with Fintepla had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment). These reductions were seen within 3-4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.

Fintepla labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Because of these risks, patients must have cardiac monitoring using echocardiograms performed before treatment, every six months during treatment, and once three to six months after treatment is discontinued. If the echocardiogram shows signs of VHD, PAH, or other cardiac abnormalities, health care professionals must consider the benefits and risks of continuing treatment with Fintepla for the patient.

Because of the risks of VHD and PAH, Fintepla is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). The Fintepla REMS requires health care professionals who prescribe Fintepla and pharmacies that dispense Fintepla to be specially certified in the Fintepla REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive Fintepla.

The most common adverse reactions in clinical studies were decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.

The FDA granted this application Priority Review. Fintepla received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Fintepla to Zogenix, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Comparison of Phenytoin (Dilantin®) Versus Fosphenytoin (Cerebyx®) for Second-Line Treatment of Status Epilepticus

Abstract, published in Seizure

Purpose: For status epilepticus, the choice of antiepileptic drugs for second-line treatment after benzodiazepine remains controversial: although both phenytoin and fosphenytoin are recommended, it not unknown which is better. Using a nationwide inpatient database in Japan, we compared the efficacy and safety of these two drugs.

Method: An observational study identified adult patients who had been admitted for status epilepticus and who had received intravenous diazepam (Valium®) on the day of admission from January 1, 2011 through December 31, 2015.

Results: The analysis examined data from 5265 patients: 2969 patients received phenytoin; 2296 received fosphenytoin, on the day of admission. No significant difference was found for use of a vasopressor, which is a drug to treat low blood pressure, or for mechanical ventilation, on the day of admission; in-hospital mortality; length of hospital stay; or total hospitalization cost. Higher age, comorbidity of cardiac diseases and lower body mass index were associated significantly with increased vasopressor use, whereas the dose of phenytoin equivalents and the choice of fosphenytoin were not.

Conclusions: This nationwide observational study found no evidence that fosphenytoin provides higher efficacy or safety than phenytoin for treatment of status epilepticus in adults after diazepam. Age, cardiac disease, and low body mass index were identified as independent risk factors for vasopressor use in both phenytoin and fosphenytoin.

Relationship Between Saliva and Plasma Rufinamide (Banzel®) Concentrations in Patients with Epilepsy

Abstract, published in Epilepsia

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Also investigated were the relationships between plasma rufinamide concentrations and dose as well as the influence of “add-on” medications

Assay results in the two tested fluids correlated well, but concentrations in saliva were moderately lower than those in plasma. In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. However, patients receiving valproic acid (Depakote®) “add-on” medication had higher dose-normalized plasma rufinamide levels than patients taking “add-on” medications metabolized by a different enzyme than that for rufinamide.

Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Nevertheless, because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.

Changes in Cognition After Introduction or Withdrawal of Zonisamide (Zonegran®) Versus Topiramate (Topamax®) in Epilepsy Patients

Abstract, published in Epilepsia

Objective: This study aims to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive.

Methods: In this retrospective observational study, the team analyzed patients’ records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions verbal memory and subjective health was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn.

Results: There was decisive evidence for a negative effect of “add-on” antiseizure therapy with ZNS and TPM on executive function and a positive effect of their withdrawal. The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance.

Significance: This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function. Comparable to the well-known TPM effect, cognition worsens when ZNS is used as add-on therapy and recovers when it is withdrawn. However, most patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Clinical Factors Associated with Suicide Risk Independent of Depression in Persons with Epilepsy

Summary, published on MDLinx

In individuals with epilepsy, researchers assessed if epilepsy-related factors are correlated with suicide risk independent of depression. Participants in the cross-sectional study were adults (n = 212; 52.4% men) with epilepsy. Study participants were divided into two age groups (under 40 vs over?40 years). The risk of suicide was reported in 31.6% of candidates, while risk of depression was reported in 22.2% of candidates. Independent of depression and a past or family history of psychiatric disorders, there was a significant link between an antiepileptic drug load greater than one and suicide risk. Independent of current depression, use of pregabalin (Lyrica®) in the younger group and frequent seizures in the older group were associated with a risk of suicide.

The risk of suicide in people with epilepsy may be linked to epilepsy-related factors such as high antiepileptic drug load, frequent seizures (over one per month), and pregabalin use, regardless of depression. Such risk factors can vary according to the patient’s age.

Cognitive Behavioral Therapy reduces the impact of Psychogenic Nonepileptic Seizures

Press Release from NIHR Maudsley Biomedical Research Centre 

Scientists have found that adding cognitive behavioral therapy (CBT) to standardized medical care gives patients with dissociative seizures longer periods of seizure freedom, less bothersome seizures and a greater quality of life, in a study published in Lancet Psychiatry today and by the Cognitive behavioral therapy for adults with dissociative seizures (CODES) study group funded by National Institute for Health Research (NIHR).

Psychogenic nonepileptic seizures, also called functional and dissociative seizures, look similar in appearance to epileptic seizures or fainting but are related to a different type of involuntary blackout that is typically distressing and disabling for patients and their carers. Up to 1 in 5 adults presenting in epilepsy clinics have this hidden condition which is one of several types of Functional Neurological Disorder (FND). Historically patients with dissociative seizures have often been ignored or disbelieved by doctors and research on treatment is limited. They are more likely to be found in women and usually have a poor outcome with a worse quality of life than people with epilepsy alone. People with dissociative seizures have a marked increase in health service use.

In the largest treatment trial to date for dissociative seizures, 368 patients from centers across England, Scotland, and Wales were followed up 6 months and 12 months after treatment courses began. Researchers found patients treated with dissociative seizure specific CBT alongside standardized medical care reported the highest number of consecutive dissociative seizure-free days in the previous 6 months, along with greater functional status, self-rated and doctor-rated change in global impression scores, and satisfaction with treatment when compared with standardized medical care alone.

Hand holding Valtoco Nasal Spray

Neurelis Announces Rapid and Broad Payer Coverage of Valtoco (diazepam nasal spray)

Neurelis Press Release

  • More than 176 million lives in the U.S. now covered by payers/managed care/insurance plans within months of FDA approval of VALTOCO, the first and only nasal spray treatment of seizure clusters in patients 6 years of age and older
  • Neurelis’ patient assistance program supports eligible patients who have no health insurance
  • Co-pay program for VALTOCO helps commercial patients lower their out-of-pocket costs to as low as $20

Neurelis, Inc., announced today that insurers and managed care plans now provide coverage for more than 176 million lives for the company’s lead product, VALTOCO® (diazepam nasal spray). VALTOCO was approved by the U.S. Food and Drug Administration (FDA) on January 10, 2020, for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in adult and pediatric patients 6 years of age and older.

“It is a very positive signal that insurers are quickly providing coverage for VALTOCO,” said Chuck DeWildt, the company’s Chief Commercial Officer. “We’ve accomplished in just over four months what takes many companies up to a year to do. I’d like to commend our market access team and the payers for understanding that this is a large unmet need for people with epilepsy and we look forward to even more lives being covered in the coming months to provide this important product to the people who need it.”

In the United States, there are over 3.4 million people with epilepsy, with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, as many as 170,000 are at risk for episodes of frequent seizure activity, also known as cluster or acute repetitive seizures, representing a significant unmet need in the epilepsy community.

DeWildt added that Neurelis has initiated a patient assistance program to support eligible patients who do not have access to insurance. In addition, he said, the company’s co-pay plan has been able to help eligible commercial insurance patients to pay as little as $20 for VALTOCO. “These plans take on even more importance at a time when the COVID-19 pandemic has economically hurt so many people, including those in the epilepsy community,” DeWildt said.

One other important program initiated by the company is myNEURELIS™. myNEURELIS provides individualized support for VALTOCO patients, including access to nurse educators, insurance coverage checks, financial assistance for those who need it, and more. For more information, please visit www.myNEURELIS.com.

“We understand that the epilepsy community has been waiting more than two decades for a version of diazepam that is delivered in an effective combination of reliability, safety, and tolerability in a ready-to-use nasal spray,” DeWildt said. “We are so grateful to be able to bring VALTOCO to the community and remain dedicated to providing access to this vital medication for everyone who needs it.”

About VALTOCO

VALTOCO is a proprietary formulation of diazepam incorporating the science of Intravail®. Intravail transmucosal absorption enhancement technology enables the noninvasive delivery of a broad range of protein, peptide, and small-molecule drugs. In its approval of VALTOCO, the FDA recognized VALTOCO’s intranasal route of administration as clinically superior to the previously approved standard of care treatment (a rectal gel formulation of diazepam). In a long-termopen-labelrepeat-dose clinical trial, the safety of VALTOCO was evaluated and more than 4,000 seizures were treated. The clinical trial included adult and pediatric patients aged 6 and older. VALTOCO was generally safe and well tolerated during clinical studies. The most common adverse reactions for diazepam (at least 4%) were somnolence, headache, and nasal discomfort. For more information on VALTOCO, please visit www.valtoco.com.

About Neurelis

Neurelis, Inc. is an innovation-driven neuroscience company providing a highly differentiated approach to target unmet medical needs. Neurelis is focused on the development and commercialization of product candidates for epilepsy and the broader central nervous system (CNS) market. On January 10, 2020, the U.S. Food and Drug Administration (FDA) approved Neurelis’ VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from an individual’s usual seizure pattern in adult and pediatric patients 6 years of age and older. In addition to VALTOCO, the company is developing NRL-2 for intermittent use to control acute panic attacks, NRL-3 as a noninvasive acute therapy to stop seizures that have progressed to status epilepticus, and NRL-4 as a noninvasive rescue therapy to address the escalation of psychomotor agitation (PMA) symptoms outside of the medical setting. The Neurelis technology platform includes Intravail®, ProTek® and Hydrogel™, three proprietary, noninvasive drug-delivery and stabilization technologies applicable to a wide range of molecules, including therapeutic proteins, peptides, non-peptide macromolecules, and small molecules. For more information on Neurelis, please visit www.neurelis.com.

Important Safety Information about VALTOCO:

Indication

VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older.

IMPORTANT SAFETY INFORMATION

RISK FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
  • Limit dosages and durations to the minimum required
  • Follow patients for signs and symptoms of respiratory depression and sedation

Contraindications: VALTOCO is contraindicated in patients with:

  • Known hypersensitivity to diazepam
  • Acute narrow-angle glaucoma

Central Nervous System (CNS) Depression

Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle, until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.

The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Advise patients and caregivers to be alert for these behavioral changes and to immediately report them to a healthcare provider.

Glaucoma

Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative

VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions, including “gasping syndrome,” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs, including VALTOCO. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Adverse Reactions

The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort.

Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance.

To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see full Prescribing Information, including Boxed Warning, for additional important safety information.

Healthcare Utilization and Associated Costs Following Initiation of Perampanel (Fycompa®) in Patients with Epilepsy

Abstract, published in Epilepsy & Behavior

Purpose: This study compared health service utilization and costs for patients with epilepsy before and after initiation of perampanel and compared with matched controls.

Results: Three hundred and forty-three patients treated with perampanel were identified. One hundred and eighty-three (53.4%) were male, with an average age of 39 and an average epilepsy duration of 21 years. Two hundred and eighty-seven (83.7%) were matched to controls. Inpatient admissions with a primary diagnosis of epilepsy and neurology specific outpatient appointments were significantly reduced following initiation with perampanel. Total costs attributable to epilepsy and overall secondary costs were also significantly reduced. There was no significant difference in primary care, outpatient, or general inpatient admissions. Compared with controls, there was a significant reduction in primary epilepsy admissions but a significant increase in outpatient appointments and accident and emergency contacts for patients treated with perampanel.

Conclusion: Treatment with perampanel is associated with reduced epilepsy-related inpatient admissions and accident and emergency contacts.

Study Shows that Birth Defects Attributed to Valproate (Depakote®) Do Not Involve a Genetic Component

Abstract, published in Epilepsia

Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), that is, generalized epilepsy cause by a mutation,  dramatically increases the risk of a range of birth defects. Although the mechanisms underlying these birth defects are not known, they may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.

Results: The team used three different rat models of epilepsy, each of which had a different genetic mutation. VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls. Specifically, VPA treatment altered the distances between individual vertebrae in the backbone in all three rat models, more frequently than in controls.

Significance: Exposure of embryos to VPA during pregnancy results in similar developmental and morphological abnormalities in three different rat models, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. These models may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects.

Influence of Stiripentol (Diacomit®) on Perampanel (Fyncompa®) Serum Levels

Abstract, published in Epilepsy Research

Stiripentol is an orphan drug successfully used in combination with valproate (Depakote®) and clobazam (Onfi®) in the treatment of Dravet syndrome. Perampanel has also been added by experts. In this study, we investigated the influence of stiripentol on perampanel serum levels by using the doses and corresponding perampanel serum levels of 10 patients. The impact of stiripentol on the perampanel serum levels was significant, with perampanel serum levels increasing linearly with the stiripentol doses.

Researchers conclude that dose adjustments of stiripentol and perampanel when administered together, should be done carefully to avoid side effects or even severe intoxication. Hence, perampanel serum level monitoring seems advisable.