Promising treatment options for chronic hives on the horizon

Dupilumab, barzolvolimab, and remibrutinib appear to help reduce disease activity in patients with chronic spontaneous urticaria (CSU), according to the results of three studies presented at AAAAI 2023.

In the phase III LIBERTY-CSU CUPID Study A, the interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist dupilumab was superior to placebo, with significantly greater reductions in Urticaria Activity Score over 7 days (UAS7) and in Dermatology Life Quality Index (DLQI), which is a measure of quality of life.

Meanwhile, data from the phase IIb study of the novel oral Bruton's Tyrosine Kinase (BTK) inhibitor remibrutinib showed that significantly more patients who received remibrutinib achieved complete response (UAS7=0) or well-controlled urticaria (UAS7≤6) compared with those who received placebo. This was true for subgroups of patients with and without prior exposure to anti-IgE treatment.

Finally, initial results from an ongoing phase I study suggested that barzolvolimab may have therapeutic effects, with dose-dependent reductions in UAS7 and no cases of adverse event (AE)-related treatment discontinuation.

Targeted therapies have been studied to extend the treatment toolbox for chronic spontaneous urticaria (CSU) since the approval of the monoclonal anti-IgE antibody, omalizumab, in 2014. [J Clin Med 2022;11:4453; https://tinyurl.com/yccpor3f]

The findings from these three studies look encouraging and provide hope for expanding the treatment options for CSU.

Helping improve quality of life

LIBERTY-CSU CUPID Study A included 138 CSU patients at least 6 years of age who remained symptomatic despite treatment with H1-antihistamines. They were randomly assigned to receive add-on dupilumab at 300 mg (adults/adolescents ≥60 kg) or 200 mg (adolescents <60 kg/children ≥30 kg; n=70) or matching placebo (n=68) subcutaneously every 2 weeks.

Mean UAS7 (range, 0–42) at baseline was 31.9 in the dupilumab group and 30.8 in the placebo group. At week 24, the scores decreased by 20.5 and 12.0 points, respectively, with the between-group difference of 8.5 points achieving significance (p=0.0003). [AAAAI 2023, abstract 308]

Mean DLQI (range 0–30, with higher scores indicating lower quality of life) at baseline was 13.5 in the dupilumab group and 15.3 in the placebo group. Treatment with dupilumab produced significantly greater reductions in DLQI scores at week 24 (–10.8 vs –7.6; difference, –3.2; p=0.0026.

“CSU is a chronic inflammatory disease that causes itchy wheals and/or angioedema that recur for [about] 6 weeks. CSU adversely impacts health-related quality of life, and many patients continue to experience substantial disease burden despite treatment with H1-antihistamines,” said Dr Marcus Maurer, lead author of the LIBERTY-CSU CUPID Study A, of the Charité – Universitätsmedizin Berlin in Berlin, Germany.

Dupilumab showed that it has the potential to improve disease activity and, in turn, the quality of life of patients with CSU.

Efficacious regardless of previous anti-IgE treatment 

In the phase IIb study, a total of 311 CSU patients were randomly assigned to the following treatment groups: remibrutinib 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo. Treatment was given for 12 weeks.

Of the patients, 84 (27 percent) had a history of anti-IgE treatment. There was no consistent difference seen in UAS7 at week 12 between the subgroups of patients with and without previous anti-IgE treatment: 10 mg once daily: −21.1 and −20.6; 35 mg once daily: −25.2 and −19.0; 100 mg once daily: −7.7 and −18.8; 10 mg twice daily: −14.8 and −20.5; 25 mg twice daily: −25.8 and −18.7; 100 mg twice daily: −26.2 and −18.1; and placebo: −2.8 and −9.7. [AAAAI 2023, abstract 404]

“Similarly, no different trends were observed in subgroups with and without previous anti-IgE treatment in terms of proportion of patients achieving UAS7=0 and UAS7≤6, across remibrutinib doses and placebo, at week 12,” noted principal investigator Dr Alexander Greiner from the University of California at San Diego, US.

“Larger studies are required to confirm the findings of this phase IIb study,” Greiner added.

Promising therapeutic candidate

The phase I double-blind trial included 45 CSU patients who were assigned to one the following treatment groups: barzolvolimab 0.5 mg/kg every 4 weeks, 1.5 mg/kg every 4 weeks, 3 mg/kg every 8 weeks, 4.5 mg/kg every 8 weeks, and placebo. Treatment was given intravenously and for 12 weeks, with a 12-week follow up.

Safety results showed that urinary tract infections, headache, neutropenia, and back pain were the most common AEs (≥10 percent of barzolvolimab-treated patients). None of these AEs led to treatment discontinuation. Declines noted in haematology parameters were similar to prior single-dose barzolvolimab studies.

In terms of efficacy, barzolvolimab induced dose-dependent improvements in urticaria control test, tryptase suppression, and UAS7. These improvements occurred as early as week 1. At week 8, UAS7 decreased by –15.8, –19.6, and –22.7 in the three lower-dose groups, and by –12.4 in the placebo group. Patients who received prior omalizumab responded similarly.

“Mast cells are key effector cells in CSU. Barzolvolimab, a monoclonal anti-KIT antibody, has been demonstrated to deplete skin mast cells in chronic inducible urticaria and reduce disease activity,” according to Maurer, the study’s lead author.

“This multi-dose study further supports development of barzolvolimab as a promising therapeutic candidate for CSU with a novel mast cell-targeted mechanism,” he added.