New in epilepsy: promising therapeutic strategies

New treatment strategies are gaining attention in epilepsy, where current therapeutic options are ineffective for many. Learn more about the novel agents at the forefront of the field.

Novel therapeutic strategies able to control symptoms and/or target the underlying mechanisms of disease in epilepsy are a pressing need. Epilepsy is one of the most frequent neurological diseases, affecting approximately 50 million people worldwide1. Despite the availability of over 30 anti-seizure medications (ASMs), only half of treated patients become seizure-free with their first antiepileptic drug treatment, and a third of patients still suffer with uncontrolled seizures after numerous treatments.2

While the last decades of drug development have effectuated an improvement in the safety and tolerability of epilepsy therapies, there has been no recognizable reduction in the percentage of patients presenting with drug-resistant epilepsy3, defined by the International League Against Epilepsy (ILAE) as patients who do not respond to the treatment of two appropriately selected ASMs.4 Lack of seizure freedom carries a heavy burden, impacting an individual’s physical and mental health. Refractory epilepsy predisposes to numerous neuropsychiatric comorbidities and increases the rates of morbidity and mortality associated with the disease.5

New approaches are urgently needed and to this end, numerous pharmacological and non-pharmacological therapies are currently in the pipeline. The outlook is positive, with a better understanding of the pathophysiology than ever and a sharp focus on moving towards precision medicine approaches. Several notable treatments, both recently approved and in preclinical development, have gained lots of attention, including potentially disease-modifying strategies and new ASMs with activity in refractory disease.

Cenobamate

 

The emergence of cenobamate has been heralded by some as the greatest clinical development in epilepsy in the last decade. Bernhard Steinhoff, MD, PhD, Kork Epilepsy Center, Kehl-Kork, Germany, comments on the unique mechanism of action of cenobamate. Although the precise underpinnings of its activity are not clear, cenobamate is postulated to act through dual inhibition of voltage-gated sodium channels and positive allosteric modulation of GABA-A receptors.6

Adjunctive cenobamate has recently been approved by the FDA and the EMA for the treatment of adult patients with uncontrolled focal-onset seizures. The approval was substantiated by unrivaled efficacy evidence from two Phase II randomized, placebo-controlled clinical trials (NCT01866111; NCT01397968), in which cenobamate proved its ability to reduce focal seizure frequency over a prolonged investigational period.2,7

The larger of these studies, launched in 2013 and published 7 years later, assessed the safety and efficacy of adjunctive cenobamate in adult patients with focal seizures despite the use of 1-3 antiepileptic drugs.2 Over 430 patients from 107 neurology centers worldwide were randomized to receive once-daily cenobamate at doses of 100 mg, 200 mg, or 400 mg, or placebo. Results from the primary endpoint analysis revealed that the median percentage change in seizure frequency was significantly improved in the three treatment groups compared to the placebo arm; a change of -24·0% in the placebo group compared with -35.5% (p=0.0071), -55.0% (p<0·0001), and -55·0% (p<0·0001) for the 100mg, 200mg, and 400mg arms, respectively.2 The proportion of patients achieving ≥50% reduction in seizure frequency followed a similar dose-response relationship, with a responder rate of 25% in the placebo group compared with 40% (p=0·0365), 56% (p<0·0001), and 64% (p<0·0001), in the increasing dosage groups.2

Most remarkably, total seizure freedom during the 12-week maintenance treatment phase was reported by 4% (p=0·3688), 11% (p=0·0022), and 21% (p<0·0001) for the cenobamate 100mg, 200mg, and 400mg arms, compared to 1% for the placebo group.2

Protocol amendments were made after a safety review of the first nine patients, which lowered the starting dose and slowed the titration rate increase, after Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases were reported when cenobamate was titrated rapidly.3 Somnolence, dizziness, headache, fatigue, and diplopia were the most reported treatment-emergent adverse events. Most adverse events were mild or moderate in severity.2

 

A second Phase II trial investigated 200mg daily of cenobamate in a similar population of 222 adult patients with uncontrolled seizures.7 Results revealed a greater median percentage change in seizure frequency and responder rate in the active drug arm compared to those treated with placebo (p < 0.0001 in both cases). During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free (p=0.0001).7 Adverse events were comparable to those seen in the previous Phase II study.

Such significant results in a refractory population have not been achieved with other ASMs. The above-mentioned approval does not mark the end of investigations of cenobamate. Both the pivotal Phase II trials are ongoing, as well as a Phase III investigation and open-label extension, also in partial-onset epilepsy (NCT02535091). Additionally, two Phase III trials in patients with primary generalized tonic-clonic seizures are recruiting (NCT03961568, NCT03678753).

An improved understanding of the mechanisms of action of the agent is imperative, as this may enable optimization of treatment regimens, as well as reveal potential additive or synergistic interactions with other ASMs. With the recent approval, real-world data will also elucidate whether the seizure freedom rates seen in trials will be borne out in clinical practice.

Cannabidiol

 

Cannabidiol (CBD) is another anti-seizure medication with a unique, although poorly understood, mechanism of action. As one of the most abundant and well-characterized cannabinoids, CBD and CBD-enriched cannabis extracts have been in the spotlight in recent years. Isolated CBD was first approved by the FDA for the treatment of pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome, based on data from three Phase III trials.8-10 This was followed by the subsequent approval in Europe for use with clobazam, resulting from data showing greater efficacy when used in combination. In these trials, CBD resulted in a greater reduction in convulsive- and drop-seizure frequency than placebo.8-10 The most common adverse events associated with CBD treatment were decreased appetite, diarrhea, vomiting, somnolence, and pyrexia.

The biology underlying the anti-convulsive activity of these compounds appears complex and multifaceted. Observations of CBD’s low affinity for CB1 and CB2 receptors have led to suggestions that it acts on systems other than the endocannabinoid system. GPR55 antagonism, adenosine regulation, 5HT1A activation, transient receptor potential cation channel interactions, and calcium modulation via voltage-gated calcium channels have all been suggested as potential pathways through which CBD may exert its activity.5

Striking gaps in knowledge remain regarding cannabinoids in the treatment of epilepsy, one of the most significant of which is the efficacy and optimal dose of CBD for adults with focal epilepsies. Very few clinical studies have assessed adult patients. The long-term safety of CBD use is another concern. Cannabis use is associated with executive dysfunction, depression, and psychosis, and thus, cognitive, behavioral, and psychiatric side effects must be explicated.11

 

A major limitation of current evidence is that many patients in the clinical trials that led to CBD’s approval were receiving concomitant treatment with clobazam.3 A recent systematic review of 714 participants from 4 clinical trials of CBD demonstrated that response rates were higher in patients treated with CBD receiving concomitant clobazam, compared to those not receiving clobazam (52.9% versus 29.1%).12 Evidence shows that cannabidiol inhibits cytochrome CYP2C19 and, in doing so, more than triples the concentration of clobazam’s active metabolite. It has therefore come into question if the anti-seizure activity associated with CBD is simply attributable to this interaction and not substantial independent efficacy.3

Another unanswered question regards whether cannabis extracts could be more effective and tolerable than purified components. Some studies have demonstrated improved efficacy of the whole extract compared to CBD alone. A recent meta-analysis of 670 individuals treated with CBD-based products for refractory epilepsy showed that the average daily dose for CBD-rich cannabis extract was substantially lower than that reported for purified CBD – 6.0mg/kg/day compared to 25.3mg/kg/day – while the percentage of patients achieving a ≥50% reduction in seizure frequency was comparable across the two groups.13 Thought to be due to the entourage effect, these findings of increased potency indicate that complex interactions between cannabinoids may responsible for the anti-epileptic properties of cannabis rather than an individual compound.5

In this interview, Andreas Schulze-Bonhage, PhD, University Medical Center Freiburg, Freiburg im Breisgau, Germany, shares his thoughts on some of the major questions surrounding the use of cannabinoids for the treatment of epilepsy.

Overall, cannabinoids are a very promising avenue for further development in the epilepsy field. While high-quality evidence from clinical trials is restricted to rare and specific indications, there is much potential to assess wider applications for CBD, including tuberous sclerosis complex, and more cannabinoid compounds, such as cannabidivarin (CBDV). New randomized clinical trials in other isolated epilepsies may widen the field of use in years to come.

Gene therapy

 

Gene therapy is a promising treatment option on the horizon. The approach inserts genetic material into the body to boost gene expression, correct or knock out defective genes, or create new functions. The most widely trialed approach uses viral vectors to modulate gene expression through exogenous nucleic acid introduction. Viral vectors such as adenovirus, adeno-associated virus, and lentivirus have been shown to achieve high levels of transgene delivery in in vivo disease models and clinical trials, enabling robust and sustained expression.14

Non-viral strategies are also under heavy investigation as a possible way to overcome several issues associated with viral vectors. Firstly, non-viral carriers, lipids or polymer-based vectors, can be designed in such a way that enables crossing of the restrictive blood-brain barrier, circumventing the need for direct infection as is commonly required for viral vectors.14 Additionally, these synthetic particles can have a large carrying capacity and are conducive to cost-effective, large-scale manufacturing.14 Unfortunately, the delivery efficiency achieved with this approach to date has been poor due to rapid clearance and poor stability. Research is ongoing to improve the sustainability of transgene expression.6

A newer approach is the use of antisense oligonucleotides (ASOs). Short single-stranded DNA sequences are designed to hybridize to specific mRNAs, causing their degradation or steric blockage.6 Whilst highly promising, several hurdles must be faced to bring ASOs to a place where they could be used clinically.

Numerous therapeutic strategies using gene therapy are showing encouraging findings in epilepsy, including modulation of neuropeptide expression, neurotrophic factor enhancement, and ion channel regulation.14 Simona Balestrini, MD, PhD, University College London, London, UK, talks on the promise of gene therapy in epilepsy, highlighting various treatment options under investigation.

Using gene therapy to enhance the expression of inhibitory neuropeptides that can act as endogenous anticonvulsants has been explored. Inhibitory peptides act via the inhibition of glutamate release to prevent ictogenesis or limit the spread of seizures.14 One such peptide is NPY, which has shown promising results in numerous epilepsy studies. The observation of augmented NPY and NPY receptor expression in seizure models and human epileptic tissue suggests that the brain may increase NPY to counter hyperexcitability.14 As such, it is logical to assume that further NPY augmentation through gene therapy may be beneficial. This is an area of active research, with mounting literature suggesting NPY overexpression can suppress seizures in animal models.

Altering neurotransmitter signaling through the manipulation of ion channels or synaptic receptors to reduce neuronal excitability is another promising approach. For example, overexpression of Kv1.1 has been shown to prevent epileptogeneisis in mouse models.6

 

AAV9-mediated delivery of CRISPRa to increase the expression of KCNA1, which encodes the pore-forming subunit of the voltage-gated Kv1.1 channel, has also been shown to decrease seizures in a rat model of temporal lobe epilepsy.14

Finally, upregulating NaV1.1 through sodium voltage-gated channel alpha subunit 1 (SCN1A) normalization is a hypothesis that is currently in clinical trials. Dravet syndrome is most often caused by a loss-of-function mutation in the SCN1A gene, resulting in a reduction in SCN1A protein. STK-001 is an ASO complementary to the functioning SCN1A gene, able to boost SCN1A production to normal levels and restore expression of NaV1.114 In a mouse model of DS, STK-001 injection was able to reduce seizure severity and frequency and prevent epilepsy-associated death.14 The MONARCH study (NCT04442295), a Phase I/IIa study of STK-001 in pediatric and adolescent patients with SCNA1-related DS, was set up in the United States in June 2020 and is the first trial of gene therapy to treat DS.15 If successful, it may lead to the development of the first gene-specific disease-modifying approach in epilepsy.

To date, preliminary safety and efficacy data have been promising.15 Fewer than 20% of the 22 patients studied experienced a treatment-related adverse event, none of which were severe. Reductions in baseline convulsive seizure frequency were seen in all patients aged 2-12 and several aged 13-18 years. A related open-label clinical trial, ADMIRAL (NCT04740476), has been set up in the UK to investigate the safety and pharmacokinetics of multiple ascending doses of STK-001 in children and adolescents with DS.

The evidence gathered to date indicates that gene therapy has the potential to be a highly effective, more targeted treatment option for epilepsy. Current ASMs are ineffective for many and do not tackle the underlying disease mechanisms. Therefore, gene therapy may be a beneficial alterative to pharmacotherapy in refractory settings.

Written by Juliet Lawrence
Edited by Marta Palhas

References

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