Autoimmune diseases, in which B and T lymphocytes drive responses to self-antigens [1], span about 100 clinical indications affecting 3–5 % of the population, and their prevalence is increasing [2]. One such disease is rheumatoid arthritis, which affects about 1 % of the global population; this chronic, systemic disorder involves cartilage destruction, pannus formation and synovial proliferation in joints [3]. The disease is driven in part by autoantibodies that destroy bone and drive chronic inflammation that damages joints [4], [5], [6], [7], [8]. Rheumatoid arthritis is currently treated using non-steroidal anti-inflammatory drugs, immunosuppressive glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) [9]. While these drugs are effective in many affected individuals, their use remains limited due to low safety, cost, and efficacy [10]. Another autoimmune disease is chronic spontaneous urticaria (CSU), in which rashes (“hives”) appear on the skin intermittently for periods lasting at least six weeks, and the rashes often burn or itch [11]. CSU appears to involve degranulation of skin mast cells, which release histamine and other factors into the blood that induce (a) vasodilation, causing skin redness; (b) vascular permeabilization, causing swelling; and (c) stimulation of sensory nerves, causing itching [12]. The current first-line treatment against CSU is second-generation antihistamines (sgAHs) [13], but these drugs can induce drowsiness and are ineffective in up to 60 % of affected individuals [14]. These autoimmune diseases, including systemic lupus erythematosus (SLE), pemphigus, hidradenitis suppurativa (HS), atopic dermatitis and others are organ damage caused by dysregulation of the body's immune cell dynamics [2].

A potential target in both rheumatoid arthritis and CSU is Bruton's tyrosine kinase, a non-receptor tyrosine kinase in B cells, bone marrow cells and platelets [15] that drives IgE-induced mast cell degranulation as well as the release of histamine and inflammatory factors [11]. The kinase also participates in several immune signaling pathways, causing cell proliferation and differentiation, antibody and cytokine production, and expression of costimulatory molecules [16]. BTK inhibitors inhibit autoantibody production in B cells and BTK-mediated degranulation in mast cells [1], and thus have the potential to be efficacious in autoimmune diseases. Results from a phase I clinical study of a BTK inhibitor Remibrutinib (LOU064) showed that covalent modification of BTK by treatment with Remibrutinib in healthy individuals resulted in near-complete covalent inhibition of B-cell receptor activation in basophils [17]. Several irreversible inhibitors of Bruton’s tyrosine kinase have entered phase II trials as treatments against rheumatoid arthritis [18], [19], [20], [21], [22], [23]. Some reversible inhibitors, which may show lower specificity or long-term efficacy than irreversible inhibitors [24], are in early stages of clinical development [25], [26].

In contrast to the irreversible inhibitors already in trials, HWH486 forms an irreversible covalent bond with cysteine 481 in Bruton’s tyrosine kinase, permanently inactivating the enzyme and inhibiting proliferation of B lymphocytes. HWH486 can strongly inhibit Bruton’s tyrosine kinase in vitro (unpublished data).

As an initial step in the clinical assessment of HWH486, we examined its tolerability, safety, pharmacodynamics and pharmacokinetics in healthy adults in this single-center, randomized, double-blind, placebo-controlled, phase I dose-escalation study.