A multicenter, randomized, double-blind, placebocontrolled Phase 2b dose-finding study to investigate the efficacy, safety and tolerability of LOU064 in adult chronic spontaneous urticaria patients inadequately controlled by H1-antihistamines

Chronic Spontaneous Urticaria (CSU) is defined as the spontaneous occurrence of
itchy wheals (hives), angioedema or both lasting for at least 6 weeks CSU can
be debilitating and is associated with intense itching and has a major impact
on patient*s well-being.

Second generation H1-antihistamines are recommended as first line treatment for
subjects with CSU but less than 40% of these subjects respond adequately..
While uptitration of second generation antihistamines is recommended by most
CSU treatment guidelines as second line therapy (Zuberbier et al 2018), the
efficacy of uptitrated H1-antihistamines in CSU has not been studied in larger
clinical studies and hence uptitration is considered off-label. Omalizumab is a
highly effective third line therapy for CSU subjects. However, less than 50% of
subjects treated with Omalizumab reach a complete control of signs and symptoms
of CSU (Kaplan et al 2016). Therefore, there is a high medical need for new
treatment options for CSU subjects.
Bruton*s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and member of
the TEC kinase family. BTK is expressed in selected cells of the adaptive and
innate immune system including B cells, macrophages, mast cells/basophils and
thrombocytes.
Recently, it has been demonstrated that inhibition of BTK leads to inhibition
of mast cell and basophil activation/degranulation in vitro and to reduced
wheal sizes in skin prick tests with patients suffering from IgE-mediated
allergies (Smiljkovic et al 2017; Regan et al 2017; Dispenza et al 2018). Thus,
BTK inhibition is a promising therapeutic concept for the treatment of chronic
urticaria.

The primary objective of this study is to characterize the dose-response
relationship of LOU064 administered once or twice daily in subjects with CSU
with respect to change from baseline in UAS7 at Week 4.

This is a global Phase 2b multicenter, randomized, double-blind,
placebo-controlled study. Study duration is 18 weeks (2 weeks screening period;
12 weeks treatment period; 4 weeks follow-up period). The study comprises the 7
following treatment arms:
10 mg LOU064 once daily
35 mg LOU064 once daily
100 mg LOU064 once daily
10 mg LOU064 twice a day
25 mg LOU064 twice a day
100 mg LOU064 twice a day
Placebo
Eligible subjects will be randomly assigned to the treatment arms in a
1:1:1:1:1:1:1 ratio.

LOU064 capsules (dose strengths: 10 mg; 25 mg; 50 mg)
Placebo capsules

Based on a thorough review of safety information currently available in the
literature together with an assessment of safety data obtained from both
clinical and preclinical experience with LOU064, the following safety topics
are considered as potential risks for LOU064 and require close monitoring in
the proposed study: infections, impaired platelet function, myomodulation, risk
of cardiovascular origin, drug-drug interactions and reproductive toxicity. For
details see section 4.3 of the protocol.

Patients should visit the hospital 7 times, visits take longer than usual (up
to 4 hours).Additional procedures are blood draws, completion of diary, ECG,
completoin of questionnaires, urinalysis, PK sampling. See for details protocol
table 8.1 (assesment schedule).

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