Therapy Analysis - Epilepsy
Future therapy options
So what else is on the horizon for sufferers who remain refractory to therapy? According to Pharmaprojects' data, a pipeline breakdown shows 12, 3, 10 and 4 NCEs currently in preclinical, Phase I, Phase II and Phase III development, respectively (Graph 2). In terms of molecular mechanisms, these developmental compounds appear to fall predominantly into the same groups as the previously-launched drugs. One notable addition however, is the development of potassium channel openers. The most advanced of these is Valeant's retigabine, which is in Phase III trials. Retigabine's main mechanism of action is through the modulation of the M-current, which is the counterbalance mechanism neurones use to help return the cell membrane to its normal state, effectively acting as a 'brake' on the electrical activity propagating nerve impulses. The M-current is therefore present in many neuronal cell types and has a strong role in controlling membrane excitability. Retigabine activates the KCNQ2 and KCNQ3 potassium channels responsible for conducting the M-current and thereby reduces membrane excitability.
After successfully completing Phase I trials in healthy volunteers, retigabine proved effective in a controlled Phase II study in epilepsy patients. In a randomized, double-blind, 8 week dose-escalation and 8 week maintenance period Phase IIb study in 396 adults with treatment- refractory partial-onset seizures, retigabine 600, 900 and 1200mg/day significantly reduced median monthly seizure frequency from baseline by 23, 29 and 35%, respectively, versus 13% on placebo. The drug proved equally effective in two pivotal Phase III studies, RESTORE-1 and -2, investigating the efficacy and safety of 600-1200mg/day as an adjunctive to 1-3 antiepileptic drugs in patients with refractory partial onset seizures. Results from RESTORE-1 in 306 patients gave a median reduction in total partial seizure frequency at 28 days of 44.3% in patients on at least 1 dose of retigabine, and 54.5% during the maintenance phase. No serious sideeffects or adverse events were observed. RESTORE-2 met the primary efficacy endpoints with doses of 600 and 900mg, however, there were a large number of dose-related discontinuations due to adverse events. These positive Phase III results have validated potassium channels as a target in epilepsy treatment and led to expectations of EU and US registration filings for retigabine later this year. In a market which currently shows a slight lack of Phase III compounds, retigabine could provide a welcome addition to the treatment options for epileptics.
Another novel late-stage epilepsy candidate is Eisai's perampanel, a selective, non-competitive AMPA glutamate receptor antagonist. The rationale behind this mechanism of action is to inhibit the neuronal excitability and sensitisation caused by glutamate. Two doubleblind, placebo-controlled Phase II studies in 153 patients with refractory partial seizures have been completed. Data show the drug was well tolerated in both studies. Preliminary efficacy data indicated the drug had an antiepileptic response in 40% of patients, compared to 20% on placebo. There was also a median reduction in seizure frequency of 40% on perampanel, compared to an increase of 2% on placebo. Phase III trials are currently underway in patients with refractory partial seizures, to assess perampanel as add-on therapy.
Moving further back the pipeline, there are a few entirely novel approaches to epilepsy therapies which could have a significant impact on managing this disease. One such company working in this field is NsGene, which is developing a method to improve the targeting of a traditional antiepilepsy therapy. Its ECPEP implant contains genetically-modified human cells delivering an undisclosed active compound directly to the brain. It is currently in animal model studies to evaluate its ability to suppress seizures.
Taking a step further away from NCE-based drugs is Neurologix, which is developing NLX-E201, a gene therapy designed to deliver neuropeptide Y to areas where seizures occur, to restore the chemical balance and dampen excessive electrical activity. A US IND for an open-label Phase I trial in temporal lobe epilepsy patients has been approved, and is awaiting initiation, pending the resolution of IP issues. Preclinical results from rodents and primates found neuropeptide Y gene transfer reduced spontaneous seizures and positively influenced the biological processes which contribute to a chronic epileptic state.
Another interesting avenue under exploration is peptide antagonists of connexins and pannexins, under development by NeuroSolutions for neurological disorders, including epilepsy. StemCells, a company that specialises in developing human neural stem cells for the repair and replacement of neural tissue, is also in the early stages of evaluating a stem cell-based therapy for epilepsy.
