Corresponding author:
Sergio Sánchez-Fernández, MD
ssanchezf@unav.es
Mailing address:
Av. Pio XII, 36
Clínica Universidad de Navarra
Pamplona, Spain
Zip code: 31008
+34 948 25 54 00 (ext. 4462)
Chronic spontaneous urticaria (CSU) is defined by the presence of wheals
with or without angioedema for more than six weeks, where no
precipitating cause is identified.1 Its
physiopathology includes type I autoimmunity, with immunoglobulin E
(IgE) autoantibodies against self-antigens, as well as type IIb
autoimmunity, which involves the presence of IgG autoantibodies against
IgE or the high-affinity IgE receptor, FcεRI.2H1-antihistamines remain the first-line treatment of
CSU. However, only 39% of these patients achieve control with standard
doses.3 Among those who are non-respondent, up-dosing
H1-antihistamines proves effective in 63% of patients.
Omalizumab, a recombinant humanized monoclonal anti-IgE antibody, has
been widely used to treat antihistamine-refractory CSU. A 2018
meta-analysis of 67 real-life studies of patients with CSU treated with
omalizumab reported rates of complete and partial response of 72% and
18%, respectively.4 However, there is a proportion of
CSU patients who do not adequately respond to omalizumab, particularly
those with features of type IIb autoimmunity.5 This
has led to a continued search for other potential targets for the
treatment of CSU.
Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase
activated by phosphorylation. It is found in myeloid cells, especially
in B lymphocytes, and is essential to their development and
differentiation.6 In mast cells, BTK is involved in
signaling following high-affinity binding of FcεRI to the Fc of a
specific IgE. Phosphorylated BTK activates phospholipase Cγ1, resulting
in increased cytoplasmic calcium levels, further signaling by
Ras/Raf-1/MEK/ERK, and cytoskeletal actin
rearrangement.7 Fenebrutinib is an orally
administered, selective and reversible BTK inhibitor. Metz et al
recently published a double-blind, placebo-controlled, phase 2 trial
where fenebrutinib (50mg daily, 150mg daily or 200mg twice-daily) or
placebo were randomly administered to 93 adults with CSU refractory to
up-dosed H1-antihistamines during 8 weeks. Fenebrutinib
was more effective than placebo in reducing weekly Urticaria Activity
Score (UAS7) after 8 weeks, achieving rates of well-controlled disease
(UAS7≤6) of up to 57% (with a 200mg twice-daily
dose).8 Interestingly, this effect was similar at week
4 than at the 8-week endpoint (61% of well-controlled patients in the
200mg twice-daily group). In comparison, data from omalizumab clinical
trials show a proportion of well-controlled urticaria between 37% and
51% four weeks after a single 300mg dose.9 This early
effectiveness observed with fenebrutinib could prove beneficial, as it
would allow for more timely treatment reevaluations and decision-making.
Fenebrutinib was effective as early as during the first week of
treatment, with 39% of patients in the 200mg twice-daily group
achieving a well-controlled state at this point.8
Furthermore, fenebrutinib was equally effective in patients with and
without type IIb autoimmunity. Metz et al found that patients with a
positive basophil histamine release assay (BHRA+) or positive anti-FcεRI
IgG antibodies presented better improvement of UAS7 at lower doses
(fenebrutinib 50mg, 150mg daily) compared to those without these
features of autoimmunity.8 This addresses the
challenge of finding an effective therapeutic target in patients with
type IIb autoimmunity, which are less likely to respond to
omalizumab.5 The oral route of administration of
fenebrutinib also shows some advantages, such as the possibility of
taking the drug at home. In addition, preclinical studies in mammalian
blood found that fenebrutinib has high oral bioavailability as well as
decreased plasma clearance compared to its intravenous administration,
which may result in longer-lasting inhibition of BTK in the treatment of
CSU.10
Overall, the study by Metz et al portrays fenebrutinib as a new,
fast-acting and safe alternative in the treatment of CSU. Despite some
limitations, such as its sample size and limited follow-up, this study
opens the way to further investigation regarding fenebrutinib and other
potential BTK inhibitors in CSU, preferably by comparing them
side-by-side to omalizumab or other therapies. BTK shows promise as a
therapeutic target in CSU, particularly in patients with type IIb
autoimmnunity on which achieving control remains a challenge. It is time
to not only phenotype but to endotype CSU for a more individualized
treatment. This increased understanding will allow for the discovery of
new molecular pathways that may become novel targets for CSU.