A Phase I Study Evaluating the Safety, Pharmacokinetics, and Clinical Response of a Human IL-12 p40 Antibody in Subjects with Plaque Psoriasis

Abstract

The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

“…Understanding the complex, pleiotropic action of IL-23R and the specific variants that give rise to each of these autoimmune traits will undoubtedly increase progress in our understanding of the molecular pathophysiology underlying these chronic autoinflammatory conditions. Moreover, coupled with the recent advances in autoinflammatory biology, the IL23R variants described herein may lead to a deeper understanding of molecular action of targeted therapeutics such as the efficacious IL-12/IL-23 monoclonal antibodies [44][45][46] and prove useful in autoinflammatory pharmacogenetics.…”

“…In sum, these studies demonstrate several key aspects of IL-23/T H -17 pathobiology related to psoriasis: (1) Both IL-12p40 and IL-23p19 mRNA expression levels are significantly elevated in both nonlesional psoriatic skin versus normal skin as well as lesional psoriatic skin versus non-lesional psoriatic skin. 37,38 (2) (5) clinical studies have shown dramatic efficacy of IL-12p40 antibodies in reducing symptoms in a high percentage of psoriatic subjects 44,45 and those with active Crohn's disease. 46 These diverse studies have conspired to highlight the central function of the IL-23/T H -17 axis in mediating chronic inflammatory disease pathogenesis, downplaying the role of IL-12.…”

The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

“…(3,4). Consistent with this hypothesis, an Ab anti-blocking the p40 subunit of IL-12, a cytokine essential for Th1 development, has demonstrated early clinical efficacy in the treatment of psoriasis (5). However, p40 is a common subunit for two cytokines, IL-12 and IL-23.…”

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

“…Details of the study design as well as the safety, pharmacokinetic, and clinical response results are reported elsewhere (45). Each patient was assigned to one of four dose groups and received a single i.v.…”

“…This first-in-human study of the administration of anti-IL-12p40 in patients with moderate-to-severe psoriasis vulgaris, showed remarkable clinical responses (45). Safety results showed that anti-IL-12p40 was well tolerated, and only transient variable decreases in CD4 ϩ T cells and CD16 ϩ CD56 ϩ NK cells were noted in some patients (45).…”