乌鸦传媒

VANCOUVER -- Trial results for dichlorphenamide, recently approved for treatment of periodic paralysis with the brand name Keveyis, were featured prominently here at a plenary session of the American Academy of Neurology.

Details of one of two clinical trials that supported the approval -- which had not been presented in detail nor published when the FDA approved the drug in August 2015 -- confirmed that the drug reduced both duration and frequency of attacks by 80%-90% in this rare genetic condition, which afflicts roughly one person per 100,000 population.

Presented by, of the MRC Centre for Neuromuscular Diseases in London, the trial showed clearly significant efficacy in the hypokalemic form of periodic paralysis and strong trends toward benefit in the hyperkalemic form. Trial results were published last week in .

But he noted that the trial also confirmed that dichlorphenamide can induce paresthesia and negatively affect cognition, and recommended that patients for whom mental sharpness is critical should consider alternative therapy.

, of Massachusetts General Hospital in Boston, who co-moderated the plenary session, told 乌鸦传媒 that it was "hugely important" to have an FDA-approved drug for periodic paralysis.

Periodic paralysis is a skeletal muscle ion channelopathy, mostly involving mutations in calcium or sodium channel proteins. The former account for about 60% of cases whereas dysfunctional sodium channels account for some 20%, Burge explained. In terms of biomarkers, the condition manifests with either abnormally high or abnormally low blood levels of potassium.

Clinically, periodic paralysis presents as attacks of muscle weakness that occur at varying intervals and durations. These typically begin in patients' teens or 20s.

Dichlorphenamide has been known to be effective for many years. It was formerly approved as a treatment for glaucoma, but the proliferation of glaucoma therapies eventually led to its withdrawal from the market for commercial reasons. That left periodic paralysis patients with only one other treatment, acetazolamide, which is less effective. Seeing an opportunity, the Israeli firm Taro Pharmaceuticals began pursuing regulatory approvals for dichlorphenamide.

Burge discussed the severe difficulties he and his colleagues had in recruiting patients for the trial, which was one reason the hyperkalemic side ended up underpowered.

The rarity of periodic paralysis was the biggest but not the only problem, Burge explained. As originally designed, the study was to include acetazolamide as an active comparator in addition to placebo control, but this appeared to discourage many patients from participating.

Many periodic paralysis patients have had experience with dichlorphenamide and believe it to be superior to acetazolamide, according to Burge, and so were not enthusiastic about the two-thirds probability of receiving an inactive or inferior drug. Consequently, the acetazolamide arm was dropped. Meanwhile, bureaucratic obstacles in Europe limited enrollment there.

The upshot was that the investigators were able to randomize 44 hypokalemic and 21 hyperkalemic patients into the 9-week trial, which had attack frequency in the final 8 weeks as the primary endpoint. The randomized phase was followed by a 1-year open-label extension.

Among hypokalemic patients, the placebo group showed a median frequency of 2.4 attacks per week versus 0.3 per week with dichlorphenamide (P=0.02). In the hyperkalemic patients, the corresponding median frequencies were 4.8 versus 0.9 (P=0.08).

A similar pattern was seen for median attack duration, with about a 10-fold reduction with the active drug versus placebo in hypokalemic patients and a somewhat smaller and statistically nonsignificant improvement in the hyperkalemic group.

Across both types of patients, Burge reported, acute worsening was seen in seven patients on placebo versus none of those receiving dichlorphenamide.

The drug was also associated with better quality of life scores on the SF-36 instrument, primarily driven by improvements in the physical components.

In the extension phase, patients originally assigned to placebo who switched to the active drug had marked reductions in attack frequency and duration. Among those initially assigned to dichlorphenamide, the effects were generally maintained with open-label treatment.

Safety results indicated that about 20% of patients of both disease subtypes experienced cognitive disorders with dichlorphenamide, and paresthesia was seen in 38% of hypokalemic and 67% of hyperkalemic patients.

The states that there is a risk of falls, and recommends dosage reduction or withdrawal in patients who experience falls.