Disease Analysis: Epilepsy

Disease Overview

Epilepsy is characterized by recurrent, unprovoked seizures, and is one of the most common chronic neurological disorders globally. A seizure is a transient manifestation of signs and/or symptoms, including a disturbance of consciousness, emotion, behavior, or motor function, which occurs because of abnormal excessive or synchronous neuronal activity in the brain.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 55.8 million prevalent cases of active epilepsy worldwide, and forecasts that number to increase to 59.0 million prevalent cases by 2027.
• The traditional antiepileptic drug (AED) market is highly genericized and there are limited branded AEDs left without generic equivalents. Additionally, though these newer branded AEDs differentiate themselves from older ones, there are still unmet needs in this market to be addressed, including refractory epilepsy and rare specific epilepsies.
• The partial-onset seizure (POS) market represents the largest market in the epilepsy disease space; however, it is highly saturated with an extensive repertoire of anticonvulsants available for prescription. Primary drugs in this patient segment are the broad-label leaders Keppra/Keppra XR, Lamictal/Lamictal XR, and Vimpat, as they are simple to use and safe. GSK has managed to slow the ensuing generic erosion of Lamictal/Lamictal XR, but UCB has not been so successful with Keppra/Keppra XR, and now only sees significant sales in Japan.
• Keppra/Keppra XR and Lamictal/Lamictal XR sales will fall as increasing numbers of generic levetiracetam and lamotrigine drugs threaten their respective market shares. UCB’s high-performing Vimpat is also now facing generic erosion, with the first US generics released in April 2022. Brand and company reputation will help to offset the decrease in sales, particularly with Lamictal/Lamictal XR, but attention will turn to the follow-on brands (Fycompa and Xcopri) to preserve market share from ensuing generics. UCB will continue to encourage physicians to opt for its newer branded products Briviact or Vimpat in order to maintain its market-leading position in the epilepsy space.
• The breadth of each drug’s label is highly pertinent to its competitive edge and provides impetus for the ongoing uptake of branded antiepileptics. Even in the saturated POS market, numerous label expansions broadening POS drug usage to monotherapy use and the treatment of pediatric patients are likely to bolster uptake. Further expansion to generalized and secondary generalized seizures, specific subpopulations such as refractory epilepsy patients, and rare pediatric epilepsy patients may also help to maximize commercial potential.
• Despite the rare niche epilepsy syndromes encompassing much smaller patient populations, companies which successfully achieve approval in these indications should be able to gain higher returns for their therapies. This is because there are so few drugs, or none in some circumstances, that have been specifically approved for indications such as Lennox-Gastaut syndrome (LGS), Dravet syndrome, PCDH19 epilepsy, and CDKL5 epilepsy. The lack of competition in comparison to the larger generalized and POS market segments combined with the large unmet need will mean these drugs are likely to be priced at a premium. Epidiolex, for example – the first plant-derived prescription cannabinoid approved in the US for Dravet syndrome – faces little competition and therefore can justify a higher price.
• Potential competitors are catching up, however, with more drugs in this segment being approved or nearing submission. As more drugs enter the rare epilepsy syndromes market, there will be a greater demand for higher rates of seizure reduction and improved tolerability. Fintepla, for example, has shown unparalleled efficacy in trials in Dravet syndrome, but is hindered by its safety/tolerability profile. As new and distinguished compounds become available in this patient segment, market share will be absorbed from former leaders in the space.
• The most pressing unmet needs in the epilepsy area have remained consistent over the past several years. Primary unmet needs include additional treatment options for refractory epilepsy patients, effective medicines for specific epilepsy syndromes such as PCDH19 epilepsy and CDKL5 syndrome, and better ways to manage common co-morbidities afflicting epilepsy patients.
• Key recent events in this space include a supplemental US approval and positive CHMP opinion for UCB’s Fintepla for the treatment of LGS, while the drug also launched for Dravet syndrome in Japan in September 2022. Additionally, the US launch of Marinus’s Ztalmy for the treatment of CDKL5 deficiency disorder occurred in July 2022. The launch of Ztalmy is significant as it is the first treatment indicated for use in CDKL5 deficiency disorder, and the drug therefore faces minimal competition. A corresponding EU filing for Ztalmy was submitted in October 2021, with a CHMP opinion expected in early 2023. Sun Pharmaceutical’s Sezaby for the treatment of neonatal seizures in full-term and preterm infants was approved in November 2022, as was Azurity’s Zonisade for POS in July 2022. Finally, positive long-term safety and efficacy data were recently released for Xenon’s pipeline asset XEN1101 in POS.
• SK Biopharmaceuticals’ Xcopri was approved by the FDA for the treatment of POS epilepsy in adults in November 2019, and by the EMA in March 2021. The drug exhibited cases of drug reaction with eosinophilia and systemic symptoms (DRESS) in Phase II clinical trials. However, results from a large Phase III open-label extension study of Xcopri as an adjunctive treatment in POS epilepsy patients have shown that a slower titration rate than that utilized in earlier studies mitigates the risk of DRESS syndrome occurring. These results permitted the omission of a black box warning for DRESS syndrome on Xcopri’s prescribing information. Xcopri’s efficacy trial data are extremely encouraging in refractory epilepsy patients and in achieving seizure freedom, setting the drug up well for garnering POS market share.
• Pipeline drugs in development include Takeda’s soticlestat, which is in Phase III trials for Dravet syndrome and LGS. Though the drug trails behind other assets in the rare epilepsy syndromes market, its unique mechanism, robust efficacy, and extremely attractive safety and tolerability profile maintain its potential to carve out a place in this market segment. Additionally, Xenon’s XEN1101, a next-generation Kv7 potassium channel regulator, has demonstrated significant efficacy in trials and a favorable tolerability profile. As a therapy with the potential to improve seizure frequency and depression, a significant co-morbidity seen in this patient population, XEN1101 has the capacity to capture significant market share within the space.
• Marinus’s Ztalmy (oral ganaxalone) is being evaluated beyond CDKL5 deficiency disorder for use in tuberous sclerosis complex. A second-generation oral suspension is also in early-stage development, with the aim of providing enhanced efficacy, an improved safety profile, reduced dosing frequency, and better absorption. An intravenous formulation of ganaxalone is being evaluated for patients with refractory status epilepticus, for which there is currently a paucity of treatment options.
• There are numerous high-impact upcoming events expected in the epilepsy space, including a European approval decision for Ztalmy in CDKL5 deficiency disorder, as well as Phase III data for the same drug in status epilepticus (RAISE trial).