Chronic spontaneous urticaria (CSU) is an autoimmune disease where patients suffer from hives (urticaria) – swollen bumps that appear on the skin without an external reason. CSU can also present as painful and puffy swellings under the skin (angioedema). A diagnosis of CSU means the recurrence of one or both symptoms for 6 weeks or longer – meaning that the symptoms keep coming back.
The underlying mechanism for CSU involves the production of “autoantibodies”, which are antibodies that target the patient’s own proteins instead of something foreign. Many patients with “type I autoimmune CSU” present with IgE autoantibodies. Other patients with “type IIb autoimmune CSU” present with IgG autoantibodies.
In CSU, the activity of IgE and IgG autoantibodies activate immune cells (mast cells and basophils) via the cross-linking of FcεRI receptors. Next in the signaling cascade, the cross-linked FcεRI receptors activate Bruton’s tyrosine kinase (BTK). If FcεRI signaling is impaired, as when the BTK gene (and protein) is absent in BTK-null mice and BTK-deficient humans, then there is a reduction in the levels of histamine and inflammatory cytokine released by mast cells and basophils.
Fenebrutinib is an experimental drug that blocks BTK. In lab experiments, fenebrutinib blocked IgE-mediated histamine release from mast cells. Treating healthy volunteers with fenebrutinib blocked IgE-mediated basophil activation. Apart from mast cells and basophils, BTK is critical in B cells, and blocking BTK with fenebrutinib has shown promise in B cell-related diseases, including rheumatoid arthritis. As B cells give rise to antibodies, it may be that blocking BTK could disrupt the production of FcεRI-activating autoantibodies seen in CSU.
We undertook a Phase 2 study to assess blocking BTK with fenebrutinib in adult patients who had CSU for more than 6 months and who did not respond to treatment with antihistamines (H1-antihistamines up to 4-fold of the approved dose). Forty-one patients were enrolled in a pilot study; 93 patients were enrolled later in an expanded study and we report results for this group.
Between May 2018 and October 2019, patients were on study at centers in Germany, Canada, and the USA. Treatments - patients were randomly allocated to placebo (23 patients) or fenebrutinib (low dose: 50 mg daily, 23 patients; middle dose: 150 mg daily, 24 patients; high dose: 200 mg twice daily, 23 patients). During the 8-week treatment period, patients continued to receive H1-antihistamines (same dose throughout study).
The focus of the study (primary endpoint) was a measure of the change in disease score at Week 8 in comparison to baseline – using the Urticaria Activity Score over 7 days (UAS7). The study also measured (secondary endpoints) – the change in UAS7 at Week 4 versus baseline, the proportion of patients whose disease was well controlled (UAS7 ≤6) at Week 8, efficacy in patients with type IIb autoimmunity, and effects on IgG-anti-FcεRI levels.
BTK inhibition demonstrates activity in CSU: Compared to placebo, patients who were treated with middle and high doses of fenebrutinib had greater average drops in UAS7 scores at Week 8 from baseline – the primary endpoint. BTK inhibition (versus placebo) resulted in patients having well-controlled disease, with more patients demonstrating this response as the drug dose was increased. The proportion of patients who had a complete response (no disease) at Week 8 also showed a dose-dependent trend.
BTK inhibition results in rapid improvement of CSU: The highest level of improvement seen in patient UAS7 scores was achieved early in the treatment. That means, UAS7 scores at Week 8 were similar to those at Week 4. Even within the first week of treatment, BTK inhibition led to marked increases in the proportion of patients with well-controlled disease.
Patients with and without type IIb autoimmunity: Patients with type IIb autoimmunity have disease that is harder to treat with currently available treatments. Blood samples were used to identify patients with and without type IIb autoimmunity at the start of the study. At the highest dose of fenebrutinib, the percentage of patients who showed a reduction in disease was similar, regardless of presence/absence of type IIb autoimmunity.
BTK inhibition decreases IgG-anti-FcεRI autoantibodies: Among patients with IgG-anti-FcεRI autoantibodies, treatment with fenebrutinib substantially reduced these autoantibodies at Week 8 at all dose levels compared to placebo, without reducing the broad entire subclass of antibodies. Greater reductions in IgG-anti-FcεRI were associated with greater decreases in UAS7 scores at Week 8.
Fenebrutinib is well-tolerated: The most common side effects were hives (urticaria), common cold (nasopharyngitis), and headache. There were no serious side effects or deaths. Four patients on active treatment had elevated levels of liver enzymes (transaminase elevations) not associated with any physiological symptoms, which resolved within 10-30 days after stopping treatment.
Summary: Targeting BTK with inhibitor drugs may be useful in CSU. CSU type IIb disease is harder to treat with currently available treatments but these patients responded to fenebrutinib across all dose levels, while those with CSU type I had smaller responses at the lower drug doses. The rapid onset of efficacy (effectiveness) suggests that the major mechanism of action in CSU is the blocking of FcεRI signaling via BTK inhibition in mast cells and basophils.