Fighting severe epilepsies: A new era for Dravet syndrome treatment?

Dravet syndrome is a rare and severe form of epilepsy that typically manifests in infancy and is characterized by prolonged, frequent seizures that are resistant to standard therapies. It belongs to the broader group of developmental and epileptic encephalopathies (DEEs). Not only is it a complicated condition, but it also results in cognitive and developmental impairments that severely impact quality of life. But the next decade might see new treatments for Dravet syndrome reach the market.

Despite recent advances, many patients rely on multiple medications to control their seizures, which often come with considerable side effects. But biotech isn’t standing idly by and several companies are taking action.

The need for more effective treatments in this space is confirmed by Lundbeck’s recent $2.6 billion acquisition of Longboard Pharmaceuticals. The acquisition gives Lundbeck access to bexicaserin, an investigational therapy targeting the 5-HT2C receptor, which plays a role in regulating seizure severity. 

“Bexicaserin is a highly innovative asset in late-stage development for DEEs. Bexicaserin’s differentiated and potentially best-in-class profile addresses a significant unmet need in severe epilepsies where few treatments exist. We can build on that globally with Longboard. With an estimated peak sales potential between $1.5 and $2 billion, bexicaserin will potentially drive growth well into the next decade, while supplementing our existing pipeline,” said Johan Luthman, Lundbeck’s head of research and development (R&D).

As bexicaserin progresses through its phase 3 clinical trial, and with an estimated launch in 2028, Lundbeck hopes that bexicaserin will not only become a cornerstone of its neuro-rare disease portfolio but also offer a first-in-class treatment for patients suffering from drug-resistant seizures associated with DEEs.

Current therapies for Dravet syndrome

Valproate and clobazam: The longstanding options

The treatment landscape for Dravet syndrome has evolved significantly in recent years but the primary goal of new treatments remains reducing seizure frequency and severity. Initial treatment protocols typically include valproate and clobazam, antiseizure medications that are often used together to provide baseline control of seizures. 

Valproate prolongs the inactivation of voltage-gated sodium channels in neurons, reducing neuronal excitability, which helps prevent the initiation and spread of seizures. Another mechanism is its ability to increase levels of gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter. By enhancing GABA inhibition, valproate helps to counterbalance the over-excitability that characterizes epileptic seizures. 

However, its effectiveness is often limited, particularly as Dravet syndrome progresses, leading to the need for adjunct therapies like clobazam. Like other drugs in this class, clobazam works by enhancing the effect of GABA at the GABAA receptor. Clobazam has a more selective mechanism, meaning it tends to have a lower incidence of sedation compared to other similar treatments, which is why it is often favored as a long-term option.

These drugs have been the cornerstone of Dravet syndrome treatment for many years, though their efficacy is limited, and they come with side effects such as fatigue, gastrointestinal issues, and increased infection risk.

The new wave: Epidiolex, Stiripentol, and Fintepla in Dravet syndrome treatment

In 2018, GW Pharmaceuticals introduced Epidiolex (cannabidiol), the first plant-derived cannabidiol (CBD) treatment approved by the U.S. Food and Drug Administration (FDA) for Dravet syndrome. The precise mechanism of action of CBD in epilepsy isn’t fully understood, but it is believed to work by reducing excessive neuronal excitation by influencing the signaling of certain neurotransmitters, including serotonin and GABA.

Stiripentol, marketed by Biocodex, is another therapy used in combination with valproate and clobazam. In addition to increasing GABA levels as valproate does, Stiripentol also inhibits certain cytochrome P450 enzymes, which helps boost the plasma concentrations of other antiepileptic drugs. 

Another interesting treatment is Fintepla (fenfluramine), developed by Zogenix and approved in 2020. Originally used as an appetite suppressant, it targets the serotonin (5-HT) system, specifically the 5-HT2B and 5-HT2C receptors. By increasing serotonin release, fenfluramine helps regulate the excitatory and inhibitory balance in the brain, reducing hyperexcitability that leads to seizures. 

However, Fintepla’s use is closely monitored due to potential cardiovascular risks, including the possibility of heart valve damage, which is why it carries a black box warning​ – the highest safety warning the FDA can deliver. Bexicaserin, which Lundbeck gained the rights to in Longboard’s acquisition, also targets the 5-HT2C receptor, so it does raise the question of whether it would present the same risks.

Challenges remain in Dravet syndrome treatment

Despite these advances, a considerable unmet need persists. Many patients experience drug-resistant seizures – they either do not respond to available therapies, or suffer from intolerable side effects. Most treatments target seizure reduction but do not adequately address the non-seizure-related symptoms of Dravet syndrome, such as cognitive impairment, developmental delays, and behavioral issues​.

The complexity of managing Dravet syndrome often results in patients taking multiple medications, which increases the risk of drug interactions and cumulative side effects. Additionally, while newer treatments like Epidiolex and Fintepla brought improvements, seizure freedom – the ultimate goal for many families – remains elusive for most patients​.

So is Lundbeck’s recent acquisition of Longboard and bexicaserin the next big thing in the DEEs space and for Dravet syndrome patients?

Longboard Pharmaceuticals’ bexicaserin: A new hope? 

Bexicaserin, developed by Longboard Pharmaceuticals and recently acquired by Lunbeck, is a 5-HT2C receptor super-agonist. A super-agonist is a type of agonist that not only binds to and activates a receptor but does so in a way that produces the maximum possible response, often exceeding the effect of a typical agonist. It holds the potential a new first-line treatment for Dravet syndrome.

The 5-HT2C receptor is critical in modulating neuronal excitability and seizure control. We mentioned another drug targeting this receptor – Fintepla – which comes with significant cardiovascular risks. But what makes bexicaserin unique is its specificity – it does not affect the 5-HT2A and 5-HT2B receptors, which are associated with psychiatric side effects and cardiovascular risks. This selective targeting is a significant advantage over other treatments as it minimizes the risk of heart valve damage​.

Bexicaserin’s mechanism involves enhancing GABAergic transmission, which increases inhibitory signaling in the brain. This helps counterbalance the overactive excitatory signals that cause seizures in patients with DEEs, including Dravet syndrome​.

In earlier phases of trials, bexicaserin demonstrated its potential by reducing seizure activity by up to 85% in preclinical seizure models, both in seizure frequency and duration. In human trials, bexicaserin has been shown to reduce seizures in a wide range of patients, from those with Dravet syndrome to those with Lennox-Gastaut – another drug-resistant epileptic condition – reaching an overall rate of seizure reduction of 57.7%​. 

However, Longboard reported that 21% of participants discontinued treatment due to adverse effects during trials. The most common included somnolence, decreased appetite, and gastrointestinal issues. There were also reports of increased seizures in a small number of participants, which, although rare, is important to note.

Bexicaserin is currently in a pivotal phase 3 trial, but Longboard and Lundbeck aren’t the only hope for Dravet syndrome patients and the field is currently gaining momentum. 

Expanding investment in Dravet syndrome and rare epilepsies

There has been a surge in interest from both biotech companies and large pharmaceutical firms targeting rare neurological diseases, including Dravet syndrome. 

Harmony Biosciences’ EPX-100

Harmony Biosciences acquired Epygenix Therapeutics in mid-2024 to develop its lead candidate – clemizole hydrochloride (EPX-100) – a novel treatment for Dravet syndrome​. The candidate EPX-100 is promising as it functions without affecting histamine receptors, which reduces the sedative side effects commonly associated with other antihistamines. 

EPX-100 was initially developed as an antihistamine and is being repurposed for Dravet syndrome due to its ability to modulate serotonin signaling. The drug works by targeting the 5-HT2A receptor, a receptor involved in modulating brain activity. Harmony Biosciences said they were expecting topline data for EPX-100 in Dravet syndrome in 2026 and that it was on track to initiate a phase 3 trial for Lennox-Gastaut syndrome.

Takeda’s TAK-935

While Harmony focuses on serotonin modulation, Takeda has pursued another path by targeting cholesterol metabolism with soticlestat (TAK-935). TAK-935 works by inhibiting cholesterol 24-hydroxylase (CH24H), an enzyme involved in regulating cholesterol metabolism in the brain. By reducing levels of 24-hydroxycholesterol, TAK-935 can help control excessive excitatory signals in the brain. 

However, Takeda’s candidate has shown mixed results in terms of efficacy. In June 2024, Takeda presented the phase 3 topline results for TAK-935 and it turns out it missed its primary endpoints both in Dravet syndrome and Lennox-Gastaut syndrome. In the press release, Takeda said it would engage with regulatory authorities to determine the next steps while assessing the financial impact of the trial. So there is at least reasonable doubt on whether TAK-935 will reach patients. 

Stoke Therapeutics’ zorevunersen

Perhaps one of the most promising routes in Dravet syndrome is targeting the SCN1A gene. Dravet syndrome is primarily caused by a mutation in this gene, which encodes the NaV1.1 sodium channel – a protein involved in the regulation of electrical activity in the brain. In patients with Dravet syndrome, this gene’s mutation leads to a loss of function, reducing the amount of NaV1.1 protein in GABAergic neurons. In other words, targeting this protein is addressing the root cause of Dravet syndrome. 

This is what Stoke Therapeutics is doing with its antisense oligonucleotide therapy, zorevunersen. The antisense oligonucleotide binds to the messenger RNA (mRNA) transcribed from the healthy copy of the SCN1A gene, increasing its translation into functional NaV1.1 protein. This boosts the expression of the protein in GABAergic neurons, which helps restore the balance of excitation and inhibition in the brain, thereby reducing seizure activity​.

In the phase 1/2 trial, zorevunersen demonstrated positive efficacy results, showing a reduction in convulsive seizure frequency. It also showed that zorevunersen was generally well-tolerated. However, some patients experienced adverse events like increased cerebrospinal fluid (CSF) protein levels and irritability. Despite these challenges, the efficacy signals were strong enough to justify proceeding to a phase 3 trial.

Encoded Therapeutics’ ETX101

Stoke isn’t the only company with an approach targeting the SCN1A gene. Indeed, Encoded Therapeutics recently received FDA clearance to proceed to in-human trials for its gene regulation therapy ETX101. ETX101 uses a gene regulation approach to upregulate the expression of the SCN1A gene to increase the production of the NaV1.1 protein. While the end target of this therapy is the same as Stoke’s, the approach is different. 

ETX101’s mechanism revolves around an engineered transcription factor that is delivered into the patient’s body via an adeno-associated virus (AAV9). Once inside the body, the transcription factor increases the expression of the healthy copy of the SCN1A gene, helping restore the normal levels of NaV1.1 protein and thereby reducing the severity of seizures. The therapy is still in the early clinical stage but it holds the potential of becoming a one-time treatment for Dravet syndrome.

Valued at $400 million in 2023 by Expert Market Research, the global Dravet syndrome treatment market is a relatively niche area of biotech. However, the same research indicates the market will likely grow at a compounded annual growth rate of 10.10% in the next seven to eight years to reach $940 million by 2032. 

Luthman told Labiotech he was anticipating significant advancements in the neuro-rare disease space in the next decade, driven by innovative therapies and a deeper understanding of these conditions. With promising therapies and various approaches either addressing the symptoms or the root cause of the disease, Dravet syndrome patients might finally have a solution improving their quality of life beyond seizure reduction coming their way.