Discussion
neuropathic pain, inflammation, autoimmune diseases, infections, pain, pruritus, bacterial infections, AD
INFLAMMATION, DISEASE, AUTOIMMUNE DISEASES, INFECTIONS, SKIN LESIONS, SKIN LESION INFLAMMATION, BACTERIAL INFECTIONS, DISEASES, INFLAMMATORY DISEASE
IRAK4 is a promising target for the treatment of TLR/IL-1R–driven skin, gastrointestinal and rheumatic autoimmune diseases, but the potential of interrupting this pathway has yet to be realized. We developed a potent, selective, orally administered heterobifunctional IRAK4 degrader, KT-474 (SAR444656), which demonstrated consistent effects on target expression, biomarkers of inflammation and clinical endpoints in a phase 1 placebo-controlled trial in HVs with an open-label cohort of patients with HS and patients with AD. To our knowledge, this is the first published clinical trial using a heterobifunctional degrader.Single doses of KT-474 led to rapid, profound degradation of IRAK4 that persisted for days in PBMCs, consistent with its catalytic mechanism of action and potency. This persistent degradation enabled substantially lower doses of KT-474 to achieve more than 90% IRAK4 degradation with daily dosing; a steady-state plasma CIRAK4 knockdown in blood and skin was generally well tolerated in HVs and patients. There were no drug-related infections during the 14–28 d of dosing when IRAK4 was maximally suppressed or during the subsequent 2 weeks of follow-up when IRAK4 levels were returning toward baseline. This was consistent with the phenotype of IRAK4 null humans, who, in infancy and early childhood, have a susceptibility to select bacterial infections that resolve once they reach adulthoodWe have demonstrated that IRAK4 degradation functionally inhibits the TLR/IL-1R pathway in patients treated with KT-474. In HVs, we used ex vivo stimulation of whole blood with TLR4 and TLR7/8 agonists and showed broad inhibition of disease-relevant proinflammatory cytokine and chemokine production associated with doses of KT-474 achieving more than 90% IRAK4 knockdown in PBMCs. The HS and AD patient cohort demonstrated that IRAK4 degradation by KT-474 in blood and skin had a systemic anti-inflammatory effect. Although HS and AD are inflammatory diseases of the skin, plasma levels of proinflammatory cytokines and acute phase reactants involved in innate immunity, as well as Th1 and Th2 responses, have been shown to be elevated in these diseasesAs clinical trials with active biologics in HS (for example, anti-TNF-α and anti-IL-17 antibodies and JAK inhibitors) and AD (for example, cytokine-targeting antibodies and JAK inhibitors) have shown improvement in skin lesions and symptoms as early as 4 weeks into treatmentIn HS, the two patients with very severe disease, both of whom had progressed on prior biologics, did not show clinical response. It is possible that these patients with very severe, biologic-refractory disease either required a longer duration of KT-474 therapy to see response or had a greater disease burden that was less responsive to IRAK4 targeting. In AD, KT-474, on average, had a modest effect on EASI score at 4 weeks. However, there was a robust reduction of pruritus, suggesting that improvement in skin lesions may lag behind the effect on pruritus, and, therefore, a greater impact on EASI score may be achieved with longer duration of KT-474 dosing. The marked improvement in pain and/or pruritus that we observed in patients with HS and patients with AD treated with KT-474 for a relatively short period of time also raises the possibility that IRAK4 degradation could be modifying those symptoms via a neuro-immune mechanism in conjunction with its impact on skin lesion inflammation. The activation of TLRs and IL-1Rs on sensory nerves in skin and dorsal root ganglia has been implicated in both neuropathic pain and pruritusClinical proof of concept for heterobifunctional degraders has been limited to a small number of oncology programs where compounds targeting estrogen receptor (ARV-471) (refs. The limitations of the patient cohort portion of the study include the small sample size, the absence of a placebo control group and the relatively short duration of therapy. The small sample size and lack of placebo control could have impacted the assessment of clinical efficacy for diseases such as HS and AD where the clinical course can wax and wane over time in some patients. Dosing with KT-474 for 28 d likely provided only a truncated view of the drug’s clinical activity, because it takes approximately 1 week to reach steady-state IRAK4 degradation in blood and at least 2 weeks to reach steady-state degradation in skin. The safety and efficacy of continuous long-term dosing with KT-474, which is anticipated for patients with HS and AD, was also not addressable in this trial.Our study shows that an oral IRAK4 degrader in development for TLR/IL-1R–driven autoimmune diseases has robust in vivo activity against the target and pathway in HVs and patients, with a favorable safety and tolerability profile. The preliminary clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD is encouraging and supports moving forward with confirmatory, placebo-controlled phase 2 trials.