Chronic Spontaneous Urticaria Responds Quickly to BTK Inhibitor

BOSTON — A form of chronic hives improved quickly and significantly in response to treatment with a novel Bruton’s tyrosine kinase (BTK) inhibitor, a multicohort dose-finding study showed.

As many as a fourth of patients with chronic spontaneous urticaria (CSU) had complete responses within the first week of starting remibrutinib, increasing to 41.9% by week 12. Across all dose groups, 40-54% of patients had significant improvement from week 2 through week 12.

Adverse events were generally mild or moderate and not dose-dependent, reported Marcus Maurer, MD, of Charité University Medicine in Berlin, during the American Academy of Dermatology (AAD) meeting here.

“In this phase 2b dose-finding study, patients treated with remibrutinib showed a well-controlled disease status as early as week 1,” he said.

Median time to complete response and well-controlled disease (Urticaria Activity Score Over Seven Days of 0 and ≤6, respectively) was shortest with remibrutinib 25 mg BID. The percentage of patients achieving these responses were higher at week 2, week 4, and week 12 with remibrutinib arms compared with placebo.

CSU causes persistent (≥6 weeks) itchy wheals and/or angioedema, which substantially affect quality of life. The condition arises from mast-cell activation associated with type 1 and type IIb autoimmunity. In some studies, more than half of patients obtain inadequate disease control with second-generation H₁-antihistamines.

BTK inhibitors offer potential activity against type I and type IIb CSU by inhibiting autoantibody production in B cells and mediating degranulation in mast cells, said Maurer. Investigators in the phase IIb trial randomized 311 patients to six remibrutinib dosage groups or placebo for 12 weeks. The primary endpoints were time to first complete response, time to well-controlled disease, and disease control up to 12 weeks, as determined by by the Urticaria Activity Scale.

All of the remibrutinib arms outperformed placebo, but the 25 mg BID dose led to the best results, including well-controlled disease status in 27.9% of patients within 1 week, increasing to 55.8% at weeks 4 and 12, and complete response in 32.8% of patients by week 2, increasing to 41.9% at weeks 4 and 12.

Gut-Centered Therapy Passes Early Psoriasis Test

An investigational therapy that interacts with immune-system receptors in the small intestine showed preliminary activity in patients with mild or moderate psoriasis.

Across three different dosage cohorts of novel agent EDP1815, 25-31.9% of patients achieved at least a 50% reduction in the Psoriasis Severity and Area Index (PASI50) after 16 weeks. Placebo-treated patients had a PASI50 response rate of 12.1%, as reported at the AAD meeting by Douglas Maslin, MD, of Evelo Biosciences.

Follow-up for 24 weeks after treatment ended showed both durability and deepening of responses with EDP1815, an encapsulated non-living strain of Prevotella histicola derived from human duodenal biopsy. Among 30 patients with PASI50 responses at 16 weeks, 18 (60%) had PASI ≥50 responses at the end of the post-treatment follow-up period.

In a subgroup of 20 patients with PASI50-74 responses at week 16, nine (45%) had PASI ≥75 responses after an additional 24 weeks of follow-up. Several patients had further improvement to PASI100 (complete clearance) at week 24 post-treatment follow-up.

“The feedback we’ve gotten from patients indicates that they like the idea of being treated with a natural type of therapy,” said Maslin. “The safety profile we’ve seen is not different from placebo in more than 500 patients who have been dosed so far (including 249 in the phase II trial) … These data demonstrate the potential of EDP1815 as a foundational psoriasis treatment for all stages of disease.”

The results were “incredible” in suggesting potential for maintaining disease control after frontline therapy without need for continuous therapy, said abstract-session moderator Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland.

“We have great treatments for psoriasis that knock down the disease, but we know the disease comes back, and we need something that [controls] the immune system,” he said at the session. “The primary results [with EVP1815] are not that impressive. Do you see this as an adjunct, where we knock down the disease and then perhaps use this to keep the disease away?”

Maslin agreed with that assessment but said researchers have learned a lot about the drug and think the primary efficacy can be improved.

EVP1815 evolved from the company’s small intestinal axis, or SINTAX, platform whereby medicines interact with the small intestine to send inflammation-resolving signals throughout the body. Treatment does not act locally on the small intestine or disrupt the microbiome.

Early Success of Pyoderma Gangrenosum

More than three fourths of patients with pyoderma gangrenosum (PG) responded to a novel therapy targeting neutrophil activation, more than half of whom had complete wound closure, in a small proof-of-concept study.

Fifteen of 19 patients (78%) met response criteria and nine had complete responses to vilobelimab. Six of seven patients treated with the highest dose of the anti-C5a antibody achieved complete response. Clinical activity correlated with sustained suppression of C5a.

“Vilobelimab every 2 weeks showed safety and tolerability,” said Afsaneh Alavi, MD, of the Mayo Clinic in Rochester, Minnesota, in presenting the findings at the AAD session.

“We observed no dose-dependent adverse events, and the adverse event profile was in line with the underlying disease and patient condition,” he continued. “The 2,400-mg dose results in a high rate of target ulcer closure and represents the dose for phase III exploration. Ulcers remain closed 2 months after treatment completion in a majority of patients.”

A rare inflammatory dermatosis that causes painful skin ulcers, PG has no approved treatment. Neutrophil activation driven by complement C5a is thought to be a key mechanism of pathophysiology in PG, providing a rationale for targeting the molecule.

Alavi reported findings from a phase II, open-label, dose-escalation trial involving 19 patients treated with one of three vilobelimab dosing schedules (three doses during the first week followed by three maintenance doses over 5 weeks, then individualized titration for nine more doses). The primary outcome was measured with the 6-point Physician’s Global Assessment (PGA), with response defined as PGA ≤3, whereas PGA ≤1 was considered clinical remission and closure of a target ulcer.

The 19 patients had a mean PG duration of 3.6 years and mean target ulcer area of 36 cm². The mean time to target ulcer response was 69 days and mean time to target ulcer closure was 104 days.