LOUISVILLE, Ky. — Treatment with add-on dupilumab (Dupixent) was linked with clinically meaningful improvements in hives and itch severity in patients with chronic spontaneous urticaria (CSU), according to the LIBERTY-CSU CUPID Study A trial.
In patients as young as 6 years with itch and hives that were not adequately controlled on antihistamine treatment alone, dupilumab plus H1 antihistamines significantly reduced itch, hives, and urticaria activity in the phase III, 24-week trial in both patients with low baseline serum total IgE (<100 IU/mL) and high baseline IgE (≥100 IU/mL), reported Thomas Casale, MD, of the University of South Florida in Tampa, at the American College of Allergy, Asthma & Immunology (ACAAI) annual meeting.
The trial was one of several ACAAI presentations on CSU treatment, which also included findings from a study of longer treatment or updosing with omalizumab (Xolair), and results from a phase IIb study of an oral Bruton’s tyrosine kinase (BTK) inhibitor.
ACAAI session moderator Jay Lieberman, MD, of the University of Tennessee Health Science Center in Memphis, told MedPage Today that new therapies are very much needed for the large number of CSU patients who fail to get relief with antihistamines alone.
“This is a condition that really impacts quality of life, with patients suffering itch and hives all over their bodies,” he said. “We now have omalizumab for these [antihistamine-refractory] patients, but we need other options. That’s why it is so exciting to start seeing data on these other therapies.”
CSU is defined as hives (wheals), swelling, or both continuously or intermittently occurring for at least 6 weeks. Unlike acute urticaria, CSU often has no readily identifiable cause. Casale noted that roughly 50% of CSU patients don’t respond to typical H1 antihistamines even at four times the licensed doses typically prescribed to patients with the condition.
Omalizumab was approved in 2014 for the treatment of CSU in patients age 12 and older who do not achieve adequate symptom relief with antihistamines. As for other options, “We know that other drugs do work in these patients, but we haven’t had good data on them,” Casale said.
The trial randomized patients to treatment with add-on dupilumab (n=70) or placebo (n=68) every 2 weeks for 24 weeks.
Adults and adolescents weighing at least 60 kg (about 132 lbs) in the active treatment arm received a 600-mg loading dose followed by 300 mg every 2 weeks. Adolescents and children weighing 30 kg to under 60 kg received a 400-mg loading dose followed by 200 mg doses every 2 weeks. Children weighing 15 kg to under 30 kg were treated with a 600-mg loading dose followed by 300 mg every 4 weeks.
Antihistamine therapy was allowed to be continued during the trial at up to four times the licensed dose. The primary endpoint was change from baseline at week 24 in the Itch Severity Score over 7 days (ISS7). Secondary endpoints were change in Urticaria Activity Score over 7 days (UAS7) and Hive Severity Score over 7 days (HSS7).
Baseline median serum total IgE was 101.0 IU/mL (overall population). Dupilumab significantly reduced ISS7, HSS7, and UAS7 at week 24 regardless of baseline serum total IgE (<100 or ≥100 IU/ mL), according to the researchers.
At week 24, the least squares (LS) mean change from baseline in ISS7 (range 0-21) was -10.2 with dupilumab and -6.0 with placebo (P=0.0005). For UAS7 (range 0-42), the LS mean change was -20.5 and -12.0, respectively (P=0.0003).
Treatment-emergent adverse events (TEAEs) occurred in 50% of dupilumab patients and 58.8% of the placebo group, with injection-site reactions occurring in 11.4% and 13.2%, respectively. Conjunctivitis occurred in one patient in the placebo group (1.5%). Serious TEAEs occurred in two dupilumab-treated patients and five placebo patients.
Patients with CSU with a poor response to 12 weeks of omalizumab seemed to benefit from longer treatment with omalizumab, or with updosing if they had low IgE and/or high body mass index (BMI) at the start of treatment.
Giselle Mosnaim, MD, of NorthShore University Health System in Glenview, Illinois, said the recommended treatment course for CSU patients who fail to respond to H1 antihistamine therapy is an initial dose of 300 mg omalizumab every 4 weeks. That dose can be increased to 600 mg every 2 weeks for a total of 6 months.
But she noted that in clinical practice, the decision to discontinue omalizumab is often made at around 3 months, if the therapy does not appear to be working.
“However, studies suggest that there are early and late responders to omalizumab, and many patients require multiple doses to achieve a response,” she said, citing findings from a 2015 study in which around half of patients who were non-responders at week 12 showed responses to omalizumab at week 24.
Mosnaim and colleagues sought to identify characteristics associated with late omalizumab response in CSU patients by analyzing data from the phase IV XTEND-CIU trial.
They identified low baseline IgE and high BMI as characteristics that predicted updosing benefit, suggesting that these patients may benefit most from longer treatment and/or updosing.
Treatment with remibrutinib, an investigational BTK inhibitor, improved CSU symptoms in patients irrespective of baseline CU-index positivity, reported Warner Carr, MD, of the University of California Irvine School of Medicine.
In the phase IIa study, the agent was given at various doses and treatment schedules, and the largest improvements were reported in patients who were CU-index positive before beginning the therapy. However, CU-index negative patients also saw improvements in UAS7, Carr said.
Of the 311 patients in the study, serious AEs occurred in five remibrutinib-treated patients versus none in the placebo-treated patients.
Carr said findings from the study are being further evaluated in an ongoing phase III trial in CSU patients.
Casale disclosed relationships with, and/or support from, multiple entities including Sanofi, Regeneron, Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, Aquestive, Celltrion, Escient Pharmaceuticals, and MedImmune.
Mosnaim disclosed relationships with AstraZeneca, Genentech, GlaxoSmithKline (GSK), Novartis, Regeneron, Sanofi, and Teva, as well as serving as president of the American Academy of Allergy, Asthma & Immunology.
Carr disclosed relationships with AstraZeneca, Teva, Boehringer Ingelheim, Regeneron, Sanofi, Circassia, CSL Behring, Genentech, GSK, Horizon Pharma, Kaleo, Mylan, Pfizer, Shire, Meda, Baxalta, Novartis, Greer Laboratories, Alcon Laboratories, Valeant Pharmaceuticals, Grifols, Optinose, and Aerocrine.