Zogenix Ready to Resubmit Fintepla for Rare Epilepsy to FDA

In April, the FDA issued a Refuse to File (RTF) letter to Zogenix for its New Drug Application (NDA) for Fintepla (fenfluramine hydrochloride). The drug was developed to treat seizures associated with Dravet syndrome, a rare form of epilepsy characterized by frequent and prolonged seizures.

The company at the time indicated the application, which was submitted in February, was not “sufficiently complete to permit a substantive review.” The FDA had two concerns, the first over non-clinical studies that were not submitted over chronic administration of the drug, and what Zogenix indicated as an incorrect version of a clinical dataset.

Now, the company announced that after its Type A meeting with the FDA on May 30, it plans to resubmit its NDA for Fintepla. Based on the meeting, the company will resubmit the NDA without the inclusion of the new chronic toxicity studies requested in the original RTF letter. In terms of the second issue, Zongenix ran a root cause analysis to explain the incorrect clinical dataset originally submitted and discussed that analysis with the agency.

“We are very pleased with the outcome of our meeting with the FDA and appreciate their thoughtful approach in considering the totality of the data from our drug development program, along with additional clinical and non-clinical literature that will be referenced in our re-submission,” stated Stephen J. Farr, president and chief executive officer of Zogenix. “We now have the clarity required to successfully resubmit our Fintepla NDA, which we will anticipate will occur in the third quarter.”

Drugs Used for Epilepsy May Increase Risk of Dementia, Study Shows

Scientists have long found a possible link between anticholinergic drugs and an increased risk of dementia.

A study published in the journal JAMA Internal Medicine suggests that the link is strongest for certain classes of anticholinergic drugs — particularly antidepressants such as paroxetine, bladder antimuscarinics such as oxybutynin, antipsychotics such as chlorpromazine or olanzapine and antiepileptic drugs such as oxcarbazepine [sold under the brand name Trileptal] or carbamazepine [sold under the brand name Tegretol among others].

Researchers wrote in the study that “there was nearly a 50% increased odds of dementia” associated with a total anticholinergic exposure of more than 1,095 daily doses within a 10-year period, which is equivalent to an older adult taking a strong anticholinergic medication daily for at least three years, compared with no exposure.

It has been well known that anticholinergic agents and confusion or memory issues are linked, but the new study investigated this association over a long period of time, said Dr. Douglas Scharre, director of the division of cognitive neurology at the Ohio State University Wexner Medical Center in Columbus, who was not involved in the study.

He encouraged any patients who might have questions about this association to talk to their physicians.

Encoded Therapeutics Bags $104M to Propel ‘Precision Gene Therapy’ for Dravet Syndrome

Encoded Therapeutics reeled in $104 million in series C cash to bankroll the development of its lead program: a precision gene therapy for Dravet syndrome, a rare form of epilepsy. The Bay Area biotech will also use the funds to push its preclinical programs and come up with new treatments for severe genetic disorders.

The company’s work is based on a platform designed to overcome hurdles it has identified in the gene therapy space. Gene therapies tend to work in one of three ways: They deliver a healthy copy of a faulty gene, introduce a new gene into the body or “knock out” a defective gene. But they can run into problems with cell selectivity, potency and the ability to control endogenous genes, Encoded CEO Karthik Ramamoorthi, Ph.D., told FierceBiotech.

“We’ve developed a series of technologies that are both computational and genomics- or sequencing-based that allow us to screen for and identify sequences in vivo that control where and when genes are able to be expressed,” Ramamoorthi said. “We take these sequences and place them in gene therapies—such as adeno-associated viruses (AAVs)—that allow us to control where the adeno-associated viruses are able to express the payload.”

Eisai Presents Data To Assess Seizure Freedom With FYCOMPA® Monotherapy In Newly Diagnosed Or Untreated Patients With Partial Onset Seizures

Results of the FREEDOM Study (Study 342) presented at the 33rd International Epilepsy Congress (IEC)- In a single-arm study, 63% of patients treated with FYCOMPA 4mg/day achieved seizure freedom at 26 weeks

Eisai Inc. announced results from its FREEDOM Study (Study 342), a Phase III open-label study conducted in Japan and South Korea evaluating the efficacy and safety of FYCOMPA® (perampanel) CIII as monotherapy in new onset or untreated patients with partial-onset seizures (POS). The data was presented at the 33rd International Epilepsy Congress (IEC) taking place in Bangkok, Thailand.

“Through research and development of compounds in our epilepsy franchise, Eisai is committed to shifting the conversation from seizure control to seizure freedom whenever possible. Results from this first investigation of FYCOMPA as monotherapy in patients with partial-onset seizures are an example of this shift,” said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai Inc. “Data from the FREEDOM study showed a seizure freedom rate of 63% with a 4mg/day dose of FYCOMPA as monotherapy in newly diagnosed or untreated  patients with POS.”

Seizure freedom for partial-onset seizures was achieved in 63% of patients (46/73) treated with FYCOMPA at Week 26 (95% CI: 50.9–74.0). Of those patients who had secondarily generalized seizures 65% (n=31/48) were convulsive seizure free. The most common adverse events (occurring in >5% of patients) out of 68 patients were dizziness (n=18 [26.5%]), nasopharyngitis (n=9 [13.2%]), somnolence (n=9 [13.2%]) and headache (n=7 [10.3%]).

CU Professor Helping Those with Severe Epilepsy

An approved epileptic drug to treat seizures has been modified by a University of Colorado Anschutz Medical Campus professor and is currently being used in a clinical trial in Australia for medically refractory epilepsy.

Tom Anchordoquy, PhD, professor at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences, and Dan Abrams, MD, CEO of Cerebral Therapeutics, have developed a proprietary reformulated specialty pharmaceutical, which bypasses the blood-brain barrier using a chronic implantable infusion system, to improve the lives of patients with severe medically refractory epilepsy. The two have worked together for over a decade developing drug formulations to be injected directly into the brain where it is needed.

Cerebral Therapeutics is conducting a proof-of-concept study in adult patients at Australia’s University of Melbourne using its proprietary anti-epileptic specialty formulation via direct intracerebroventricular (ICV) administration. This proof-of-concept study has demonstrated potentially enhanced efficacy and reduced toxicity in patients with medically refractory epilepsy. Proceeds from the financing will be used to file an IND with the U.S. Food and Drug Administration (FDA) to initiate a Phase 2 clinical trial.

Pregabalin (Lyrica) Associated with Increased Suicidal Behavior and Other Hazards: Population-Based Study in Sweden

Objective: To examine associations between gabapentinoids and adverse outcomes related to coordination disturbances (head or body injuries, or both and road traffic incidents or offences), mental health (suicidal behaviour, unintentional overdoses), and criminality.

Design: Population based cohort study.

Setting: High quality prescription, patient, death, and crime registers, Sweden.

Participants: 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for gabapentinoids (pregabalin or gabapentin) during 2006 to 2013.

Main outcome measures: Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics.

Results: During the study period, 10,026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17,144 (8.9%) experienced an unintentional overdose, 12,070 (6.3%) had a road traffic incident or offence, 70,522 (36.7%) presented with head/body injuries, and 7,984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behavior and deaths from suicide, unintentional overdoses, head/body injuries (, and road traffic incidents and offences. Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years.

Conclusions: This study suggests that gabapentinoids are associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

Summaries of all highlighted studies follow below. I’ve organized the findings into three categories: Treatment Advances, Research Discoveries, and Also Notable.

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
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The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
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In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
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Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
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A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
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The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
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A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
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Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
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Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
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A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
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Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
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Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
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Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
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The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
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Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

Zebinix Effective as Adjunctive Therapy in Epilepsy Patients with Psychiatric Comorbidities

Bial and Eisai have announced clinical practice data from the Euro-Esli study demonstrating clinical effectiveness of eslicarbazepine acetate, and that it is generally well tolerated as an adjunctive therapy in focal epilepsy patients with psychiatric comorbidities, including intellectual disability, compared with people with no psychiatric comorbidities.

The data, which add to the body of evidence on eslicarbazepine acetate as adjunctive therapy from Phase III studies, were published in Journal of the Neurological Sciences.

Psychiatric comorbidities, including intellectual disability and depression, are common for adults who have epilepsy. Prevalence of psychiatric comorbidities may be twofold higher in adult patients with epilepsy compared to the general public, and up to a quarter of people diagnosed with epilepsy are estimated to have an intellectual disability. Psychiatric comorbidities can exacerbate the effects and increase the impact of epilepsy. Furthermore, antiepileptic treatments can interfere with treatments for the psychiatric comorbidities, and thus adversely affect these psychiatric conditions. There are many considerations for treating this patient population, thereby complicating treatment choice.

Increased Behavioral Problems in Children of Mothers with Epilepsy Prenatally Exposed to Antiepileptic Drugs, as Reported by Parents

OBJECTIVE: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.

METHODS: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential.

RESULTS: Of the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to lamotrigine, and significantly more attention problems than levetiracetam-exposed children. Lamotrigine-exposed children had significantly more attention deficit, but significantly less anxious behavior when compared to levetiracetam-exposed children.

SIGNIFICANCE: Compared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common antiepileptic drugs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all antiepileptic drug exposure groups. It is important that prenatally antiepileptic drug-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy

Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalised tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks.

Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo.

The safety profile was similar to that observed in other studies.

The trial was conducted as a post-marketing requirement by the FDA.

Pfizer is investigating the drug as part of its wider Lyrica Pediatric Epilepsy Program, which is composed of six studies in patients with epilepsy evaluating Lyrica as adjunctive therapy, five of which have been completed.

Another phase 3 trial in May 2018 was successful, showing that in paediatric patients with epilepsy a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo – however no statistically significant reduction was observed with a 7 mg dose.