Discussion
This study demonstrated that benralizumab resulted in significant
clinical improvement in subjective and objective measures in 78% (7/9)
of CSU patients unresponsive to H1-antihistamines who completed the
study, which was sustained for two months after the last treatment dose.
Furthermore, an overall difference of UAS7 greater than the MDC value of
14.7 between baseline and end of study post-benralizumab treatment
implies that this finding is also clinically meaningful (Table
1) . These results are consistent with the intent-to-treat primary
endpoint analysis recently reported24. Comparison of
benralizumab responders (n=7) to non-responders (n=2) revealed that the
average baseline UAS7 among treatment responders was less than
non-responders, although this difference was not statistically
significant (27 vs. 37.5, p=0.5). This suggests that clinical
improvement among responders was independent of baseline disease
severity. These observations support the use of benralizumab for
treatment of SGAH unresponsive CSU and provide evidence for a pathogenic
role for infiltrating eosinophils. Although significant differences were
observed between responders and non-responders at baseline for relative
blood eosinophil (2.2% vs. 7.9%, p=0.001) and basophil counts (0.3%
vs, 1.5%, p=0.01), these differences were minimal and no longer
apparent post-treatment (eos%: 0.0 vs. 0.0, p=0.99; basophil%: 0.4 vs.
0.2, p=0.88). Thus, non-responsiveness to benralizumab as measured by
changes in UAS7 are likely due to other mechanistic factors unrelated to
the presence of eosinophils which are eliminated by blocking IL-5R.
Further investigation is required to determine the relationship between
baseline peripheral blood eosinophil levels and benralizumab’s response
in CSU.
Not surprisingly, as seen in previous asthma studies, the effect of
benralizumab on eos% was observed immediately after the first dose and
was sustained for 8-weeks after the last dose.34 The
more prolonged effect of benralizumab in the complete responders after
discontinuation, compared to what has been reported after
discontinuation of omalizumab in controlled CSU patients, may be
explained by modification of biologic pathways important for promoting
persistent cutaneous inflammation associated with CSU. Additional
objective evidence to support this conclusion is the observed effect of
benralizumab in decreasing the numbers of lymphocytes observed in
non-lesional skin of complete responders compared to baseline lesional
biopsies. Eosinophils were also significantly reduced in the lesional
skin of non-responder and partial responder CSU subjects (n=4) 4-weeks
after the last dose of benralizumab compared to baseline lesional skin
biopsies, as would be expected given benralizumab’s primary mechanism of
action (Figure 3 D-E ).
A decrease in UAS7 should reflect an improved CSU-related QoL since both
outcomes measure wheals and pruritus, the two main clinical features of
CSU. As expected, the CU-QoL and UAS7 post-treatment values were
significantly correlated (r2=0.9, p<0.0001),
which support the internal consistency of our data. Besides the pruritus
and wheal component, the most significant improvement in CU-QoL were
reported for urticarial interference with physical activities, sleep and
spare time (S-Table 6) .
Improvements in UAS7 and CU-QoL for this pilot study are comparable to
the efficacy of omalizumab in CSU, as determined in a previous pilot
study (S-Table 7 ), with nearly the same percentage of complete
responders to benralizumab as omalizumab.35 It is
important to note, that when the larger Phase 3 omalizumab study
(ASTERIA I trial) for the treatment of CSU was conducted based on the
results of the earlier feasibility study, the number of patients with
50% reduction in mean UAS7 from baseline revealed a 35.8% complete
response and a 51.9% partial response.36 This
demonstrates that the omalizumab pilot study was a good indicator of
expected outcomes in the larger multicenter clinical trial.
Given benralizumab’s mechanism of action as an IL-5R antagonist, its
effect in the treatment of CSU is not outwardly apparent. However, DEGs
in blood before and after benralizumab has provided greater insight into
some biologic pathways that may explain its efficacy in the treatment of
CSU (S-Table 4 and 5 ). Urticarial wheals are clinical
manifestations of altered vasoactive and cellular infiltration kinetics
resulting from inappropriate activation of dermal mast cells in up to
50% of cases by IgG autoantibodies directly targeting the high affinity
IgE mast cell receptor ( FcER1-alpha subunit) or IgE affixed to these
receptors.37 The role of possible autoimmune
mechanisms in CSU, although not directly investigated in this study,
could be explained by our blood transcriptomic data which demonstrated
that benralizumab downregulated Indoleamine-2,3-Dioxygenase (IDO)
pathway expression. IDO is an interferon-γ-inducible enzyme that
catalyzes tryptophan degradation and drives Th2-mediated
inflammation.38 Elevated tryptophan degradation has
been shown to correlate with disease activity previously reported in
other autoimmune rheumatological conditions.39,40Thus, benralizumab-mediated inhibition of IDO activity may improve CSU
by restoring the basal tryptophan metabolic state from a hypercatabolic
state leading to immune homeostasis41 consistent with
what other studies have reported.42
A minimal persistent inflammation in CSU is maintained by infiltrating
inflammatory cells that release proinflammatory mediators,
cytokines/chemokines and adhesion molecules capable of recruiting and
activating other effector cell types.14 The sustained
clinical improvement by benralizumab in 5/9 CSU subjects until at least
4-weeks after the last dose, versus baseline, is reflected by a
significant reduction of peripheral blood inflammatory cell counts,
which was also seen in partial- and non-responders (n=4) (Figure
3 ). This is supported by benralizumab’s downregulation of DEGs in blood
transcriptomes that control cytokine/chemokine signaling pathways
(S-Table 4 ) and SIGLEC-8 gene expression. Since SIGLEC-8 is
expressed on human eosinophils and mast cells, this finding further
supports a role for IL5-receptor-mediated signaling of inflammatory
responses involving mast cells and eosinophils.43
The study helps to better understand potential alternative medications
in patients not responding to high dose SGAH. The number of complete
responders was remarkably high. The blood DEGs that were significantly
associated with response to benralizumab were IDO1, PTGDR2, ALOX15,
IL1RL1, and SLC29A1 all of which are regulated upstream by IL4. In this
context, it is worth mentioning that previous studies have reported
increased serum concentrations of IL4 during the appearance of
urticarial lesions in CSU patients. 44 Among those
DEGs, the expression of prostaglandin D2 receptor (PTGDR2) was most
evidently related to the response status (i.e., complete, partial or
no-response to benralizumab). Complete responders had under-expression
of PTGDR2, indicated by a negative z-score (z-score= -0.65); but,
partial or no-responders had persistent over-expression of PTGDR2,
indicated by positive z-scores, even after treatment with benralizumab.
The expression levels of this gene were correlated with UAS7, and also
with absolute and relative eosinophil or basophil scores. Previous
studies have reported increased prostaglandin D2 in venous blood
draining urticarial wheals.16 In this context,
over-expression of PTGDR2 might perpetuate or exaggerate the
inflammatory condition that may be unresponsive or less responsive to
monotherapy with an IL-5 antagonist alone. Fevipiprant (NVP-QAW039,
Novartis), a potent and selective PTGDR2 antagonist which has previously
been assessed for safety and tolerability in human studies45 could be studied in partial or non-responsive
benralizumab treated patients to confirm the relevance of this genetic
biomarker.