Selective sodium channel blocking shows promise in trigeminal neuralgia
medwireNews: Phase II study findings provide a basis for further investigation of a Nav1.7 selective sodium channel blocker in trigeminal neuralgia.
Among 15 patients randomly assigned to receive the drug, BIIB074 150 mg three times per day, five (33%) were classified as treatment failures over a 28-day double-blind phase, compared with nine of (64%) of 14 patients assigned to receive placebo.
Treatment failure was defined as discontinuing treatment due to lack of efficacy or treatment-related adverse effects, experiencing more than three paroxysms in 7 days and a 50% increase or more in the frequency or severity of paroxysms, or a Patient Global Impression of Change (PGIC) rating of much worse or very much worse.
While this difference in treatment failure rates was not significant, Joanna Zakrzewska (University College London Hospitals NHS Foundation Trust, UK) and colleagues note that there were significant differences favoring BIIB074 in the secondary endpoints.
The median time to treatment failure was 14 days for patients given placebo, whereas it was not reached among those given BIIB074. And the researchers estimated a significant 45% placebo-adjusted reduction in the number of paroxysms for patients taking BIIB074 and a significant 50% reduction in the average daily pain score. There were also significant differences between the two groups in those reporting improvement on the PGIC and the Clinical Global Impression of Change.
Prior to randomization, the patients had completed a 7-day run-in phase and an open-label phase during which they received BIIB074 150 mg three times per day for 21 days, without the use of other sodium channel blockers or medications that might interfere with the reversible monoamine oxidase-B inhibitor.
Forty-four of 67 patients completed this open-label phase, and the 29 who responded, achieving at least a 30% reduction in the number or severity of paroxysms of pain over the past 7 days versus the run-in phase, or a PGIC rating of much improved or very much approved, were eligible for the double-blind, randomized phase.
The researchers comment in The Lancet Neurology that this randomized withdrawal study design is crucial in relation to trigeminal neuralgia because it exposes patients with severe pain to placebo for the minimum time possible.
But in a related comment, Troels Staehelin Jensen (University of Aarhus, Denmark) points out that this also presents limitations, such as the risk of carryover effects when going from BIIB074 to placebo and the preselection of only patients who responded.
Zakrewska and team also note that 18 of the 41 patients who withdrew during the open-label phase did so because of an absence of efficacy, with many doing so in the first few days of treatment.
Speculating that this may have been partly related to anxiety over discontinuing previous medications, they aim to address this in their planned phase III trial by allowing the concomitant use of ongoing medications for the first 2 weeks of BIIB074 treatment.
BIIB074 was otherwise well tolerated, they report. A total of 13 treatment-emergent adverse events were experienced by four (27%) of 15 patients taking BIIB074, of which seven were deemed treatment related. This compared with 17 adverse events reported for five (36%) patients given placebo, of which five were deemed treatment-related.
The most common adverse events with BIIB074 were headache, pyrexia, nasopharyngitis, sleep disorder, and tremor, each occurring in one patient. There were no serious adverse events reported during the double-blind phase.
The researchers note that “by contrast with findings for carbamazepine and oxcarbazepine, treatment with BIIB074 was associated with low rates of cognitive impairment, and could be administered at therapeutic dose without the need for titration.”
They add that “given its good tolerability, it might also be possible to increase the dose of BIIB074 to determine if efficacy could be improved.”
By Lucy Piper
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