Dexpramipexole reduces eosinophils, improves lung function in moderate to severe asthma

In patients with moderate to severe eosinophilic asthma, treatment with dexpramipexole depleted blood and tissue eosinophils, which correlated with improvement in lung function, according to results of the phase 2 EXHALE trial.

“Dexpramipexole is a drug that was originally developed in amyotrophic lateral sclerosis. In the pivotal phase 2 and 3 trial of amyotrophic lateral sclerosis, the drug didn’t meet its primary endpoint but was noted to profoundly lower blood eosinophil counts with the degree of peripheral blood eosinophilia,” Salman Siddiqui, MD, clinical professor of airway disease at the University of Leicester, U.K., said during a presentation at the virtual European Respiratory Society International Congress. “The development of the drug then pivoted to development in eosinophil-mediated immune diseases.”

EXHALE is a multicenter, parallel-group, randomized, double-blind phase 2 trial that included 100 participants from 28 U.S. sites (mean age, 45 years). All participants had a baseline blood eosinophil count of at least 300 cells/µL, a pre-bronchodilator FEV₁ of less than 80% predicted or at least 40% predicted and impaired asthma control defined by an Asthma Control Questionnaire-6 score of at least 1.5. Participants were randomly assigned to daily dexpramipexole (Knopp Biosciences) at 300 mg (n = 28), 150 mg (n = 26), 75 mg (n = 22) or placebo (n = 27) after a 2-week open-label run-in phase. Two-thirds of participants were on moderate- or high-dose inhaled corticosteroid and long-acting beta agonist therapy and 20% to 30% met criteria for severe asthma.

The primary outcome was change in blood eosinophil count from baseline to 12 weeks.

At 12 weeks, researchers observed dose-dependent blood eosinophil attenuation among participants assigned dexpramipexole. This reaction was equivalent to an 80% reduction in eosinophil count with the 300 mg dexpramipexole dose compared with placebo (P < .0001), Siddiqui said.

“The drug lowers eosinophils over an 8- to 12-week period, supporting its impact on the bone marrow and eosinophil maturation across all three tracing strata and subsequent recovery on drug withdrawal over a further 12 weeks,” Siddiqui said.

The researchers also looked at the effect of dexpramipexole on nasal eosinophil peroxidase levels. In a prespecified analysis, nasal eosinophil peroxidase was reduced at week 12 by 89% with 300 mg per day (P = .021 vs. placebo), 82.6% with 150 mg per day (P = .021) and 35.5% with 75 mg per day (P = .54) compared with 16.7% in the placebo group. These results reinforce previous reports that showed effective tissue eosinophil lowering with dexpramipexole in patients with chronic rhinosinusitis with nasal polyps and hypereosinophilic syndrome, according to a press release issued by Knopp Biosciences.

Regarding secondary endpoints, the researchers reported a trend toward improvement in lung function relative to placebo with the 300 mg dexpramipexole dose, but this trend was not significant (P = .1). However, at week 8 and during the eosinophil recovery period at weeks 16 and 18, this trend reached statistical significance, Siddiqui said.

There was no statistically significant or clinically important impact on exhaled nitric oxide or Asthma Control Questionnaire-6 scores with any dexpramipexole doses compared with placebo.

Dexpramipexole was well tolerated and there were no adverse events leading to discontinuation, according to the release.

“Our study supports the notion that dexpramipexole is a potent oral anti-eosinophilic agent in moderate to severe eosinophilic asthma,” Siddiqui said. “These data support further development of dexpramipexole in moderate to severe eosinophilic asthma.”

Reference:

• Knopp Biosciences presents new phase 2 data at ERS 2021 demonstrating that reduction in eosinophil count by dexpramipexole significantly correlates with improvement in lung function. https://www.biospace.com/article/releases/knopp-biosciences-presents-new-phase-2-data-at-ers-2021-demonstrating-that-reduction-in-eosinophil-count-by-dexpramipexole-significantly-correlates-with-improvement-in-lung-function/. Posted Sept. 7, 2021. Accessed Sept. 7, 2021.