Dichlorphenamide Shows Clear Benefit in Periodic Paralysis

Megan Brooks

April 22, 2016

VANCOUVER — For patients with hypokalemic periodic paralysis (PP), dichlorphenamide (Keveyis, Taro Pharmaceutical Industries Ltd) significantly reduces the rate and severity of muscle weakness attacks and improves quality of life, according to pivotal phase 3 data.

The same appears to be true for patients with hyperkalemic PP, but because of a smaller number of patients, the trial couldn't demonstrate significance for hyperkalemic PP.

James Burge, MD, from the MRC Center for Neuromuscular Diseases, London, United Kingdom, presented the data here at a plenary session at the American Academy of Neurology (AAN) 2016 Annual Meeting.

Dr James Burge

PP is a muscle channelopathy causing episodic weakness and eventually patients over time can develop fixed weakness. It's a very rare disease, affecting an estimated 1 in 100,000 individuals.

In August 2015, the US Food and Drug Administration approved dichlorphenamide for primary hypokalemic PP, primary hyperkalemic PP, and related variants.

Significant Treatment Effect

Dr Burge reported data from the multinational phase 3 randomized, double-blind, parallel-group, placebo-controlled trial that led to approval.

The trial was designed initially to compare dichlorphenamide against acetazolamide against placebo, he told conference attendees, "but we ran into serious problems with recruitment, mainly because patients who had previously been taking dichlorphenamide know that it's very effective, so essentially this trial is a comparison of dichlorphenamide against placebo."

The trial was run as two parallel 9-week trials with the same design — one for patients with hypokalemic PP (n = 44) and one for patients with hyperkalemic PP (n = 21) — each with a 1-year open-label extension period in which all patients received dichlorphenamide. The primary outcome was the average number of weekly attacks over the final 8 weeks of the double-blind phase, measured by patient self-report.

In the hypokalemic PP group, there was a "significant treatment effect" of dichlorphenamide for the primary outcome. There was a similar treatment effect in the patients with hyperkalemic PP, but because the numbers are small it was underpowered and didn't reach statistical significance for the primary outcome measure, Dr Burge noted.

Table: Median Attack Rate per Week in Double-Blind Phase

Group Dichlorphenamide Placebo P Value
Hypokalemic PP 0.3 2.4 .02
Hyperkalemic PP 0.9 4.8 .08


Dichlorphenamide also had a significant treatment effect on several secondary endpoints, including attack duration and severity and quality of life, Dr Burge said.

The severity-weighted attack rate was lower with dichlorphenamide relative to placebo treatment (hypokalemic: 0.6 vs 5.7 [P = .02]; hyperkalemic, 1.0 vs 5.8 [P = .03]).

In addition, the physical component summary score of the Short Form-36 assessment was improved in patients with hypokalemic PP treated with dichlorphenamide compared with their peers treated with placebo (treatment effect, 7.29; 95% confidence interval, 2.26 - 12.32; P = .006).

Dichlorphenamide had no significant effect on inter-attack muscle strength during the double-blind phase.

The benefit of dichlorphenamide on attack rates was maintained in the open-label extension period, Dr Burge reported, and patients who switched from placebo to dichlorphenamide also saw a marked reduction in the frequency and severity of attacks.

"There are adverse effects [with dichlorphenamide], and this is important," Dr Burge said. The most common is paraesthesia (47%), he noted, but several patients also reported cognitive problems, mental slowness, difficulty with clarity of thinking and arithmetic, and fuzzy-headedness. However, "the majority of patients tolerated the side effects very well," he said.

"Real Win" for Rare Disease Research

Commenting on the study for Medscape Medical News, Nicholas Johnson, MD, assistant professor of neurology, University of Utah, Salt Lake City, and principal investigator, Utah Program for Inherited Neuromuscular Research, said, "The investigators have to be commended because it's a very rare condition and they were able to get a number of people to participate in the trial."

"As opposed to other compounds that are currently on the market, at least in the results they presented, it appears that [dichlorphenamide] may be among the most successful in reducing the number of attacks," Dr Johnson added.

"In periodic paralysis," he explained, "the issue is that people will have this episodic weakness that can last for several minutes or several hours and during this period they can often be debilitated. They can't move, they can't walk, they can't work. These attacks may occur once a day or several times a day out to about once a month or two."

"One of the goals is to prevent these episodic attacks because it's thought that if you do that then you may have some benefit in reducing the progression to fixed weakness. Any drug that is able to successfully treat or prevent these attacks I think is very good, and their data is quite impressive in terms of the frequency of attacks that they were able to prevent," Dr Johnson said.

He also thinks this trial is a "real win" for rare disease research. "They were able to overcome several obstacles. They had a compound that had good proof of concepts, but they had to establish successful multinational consortium and they were able to find an industry partner who was able to help them along. So it's certainly significant for periodic paralysis but also I think may serve as a model to bring orphan drugs to market for more orphan diseases."

The trial was funded by Taro Pharmaceutical Industries Ltd. Dr Burge has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2016 Annual Meeting. PL02.001. Presented April 20, 2016.


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