Izokibep: Preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis

Abstract

Psoriasis, an immune-mediated inflammatory disease, affects nearly 125 million people globally. The interleukin (IL)-17A homodimer is a key driver of psoriasis and other autoimmune diseases, including psoriatic arthritis, axial spondyloarthritis, hidradenitis suppurativa, and uveitis. Treatment with monoclonal antibodies (mAbs) against IL-17A provides an improvement in the Psoriasis Area and Severity Index compared to conventional systemic agents. In this study, the Affibody^Ⓡ technology was used to identify and optimize a novel, small, biological molecule comprising three triple helical affinity domains, izokibep (previously ABY-035), for the inhibition of IL-17A signaling. Preclinical studies show that izokibep, a small 18.6 kDa IL-17 ligand trap comprising two IL-17A-specific Affibody domains and one albumin-binding domain, selectively inhibits human IL-17A in vitro and in vivo with superior potency and efficacy relative to anti-IL-17A mAbs. A Phase 1 first-in-human study was conducted to establish the safety, pharmacokinetics, and preliminary efficacy of izokibep, when administered intravenously and subcutaneously as single doses to healthy subjects, and as single intravenous and multiple subcutaneous doses to patients with psoriasis (NCT02690142; EudraCT No: 2015-004531-13). Izokibep was well tolerated with no meaningful safety concerns identified in healthy volunteers and patients with psoriasis. Rapid efficacy was seen in all psoriasis patients after one dose which further improved in patients receiving multiple doses. A therapeutic decrease in joint pain was also observed in a single patient with concurrent psoriatic arthritis. The study suggests that izokibep has the potential to safely treat IL17A-associated diseases such as psoriasis, psoriatic arthritis, axial spondyloarthritis, hidradenitis suppurativa, and uveitis.

Keywords: ABY-035; IL-17A inhibition; first-in-human; izokibep; psoriasis.

Figure 1.

Izokibep structure and binding curves. The ligand trap format of izokibep increased the inhibitory capacity of the molecule compared to the monomeric format and with greater inhibition than secukinumab and ixekizumab, where izokibep blocked IL-17A binding to IL-17 R. (A) the proposed binding mode of izokibep involves simultaneous binding of two IL-17A Affibody affinity domains (blue) on each side of the homodimeric IL-17A target protein (gray), thus improving the potency. The albumin binding domain (yellow) enables high-affinity binding to albumin, extending the plasma half-life. (B) Formatting of the IL-17A-binding ligand trap of izokibep, illustrated by an izokibep precursor (dark blue), resulted in a superior inhibitory profile over the unformatted monomer (light blue) as well as secukinumab (red) in an NHDF cell assay. (C) Binding of IL-17A to IL-17 R in the presence of izokibep (dark blue), secukinumab (red), and ixekizumab (gray), as determined by SPR. Human recombinant IL-17 R was immobilized on a chip and human recombinant IL-17A was injected at a concentration of 50 nM in the presence of izokibep (K_D 0.3 pM), secukinumab (K_D 60 pM), or ixekizumab (K_D 2 pM) at a 1:1 ratio,(a concentration much higher than the reported K_D values).

Figure 2.

Izokibep – superior potency in in vitro cell-based assays and in vivo murine model relative to secukinumab and ixekizumab. (a) Potency of izokibep, secukinumab, and ixekizumab in an NHDF cell assay, stimulated with 64 pM IL-17A and 10 fM IL-1beta. All compounds inhibit the IL17Ainduced IL-6 production in a dose-dependent manner. IC50 values generated were 0.4, 3.5, and 41 ng/mL for izokibep, ixekizumab, and secukinumab, respectively. (B) Izokibep prevents the KC secretion in response to stimulation by IL-17A in vivo. KC concentrations were determined by ELISA using a KC-quantification kit. Doses indicated on the x-axis are given in mg/kg and the response on the y-axis in % inhibition ± SD. n = 6 animals per compound and dose level.

Figure 3.

Design of the first-in-human study with izokibep and exposure. ^amoderate-to-severe psoriasis (PASI≥12). ^ball severities, moderate-to-severe and mild-to-moderate psoriasis (PASI≥12 and PASI<12).

Figure 4.

Pharmacokinetic profile of izokibep. Mean plasma concentration-time profiles of izokibep following (A) single IV doses in healthy subjects, (B) single SC or IV 40 mg dose in healthy subjects, and (C) repeated 40-mg SC administration in patients, with dosing once every other week on seven occasions (arrows). LLOQ: <0.020 µg/mL. IV, intravenous; LLOQ, lower limit of quantification; SC, subcutaneous.

Figure 5.

Clinical response to treatment with izokibep. (a)mean (SD) PASI score by week for patients with moderate-to-severe psoriasis (PASI≥12 at baseline). Patients received a single dose of 2 or 40 mg izokibep IV in part C2 and C1, respectively. In part D, patients received multiple doses izokibep SC Q2W 3 × 40 mg (last dose in week 4) or 7 × 40 mg (last dose in week 12). The on- and off-treatment effects are presented until week 12. (b) Psoriatic plaque lesion of selected individual patient prior to (left) and 14 days after (right) a single 40 mg IV dose of izokibep.

Figure 6.

Individual absolute PASI scores in patients receiving multiple 40 mg doses of izokibep SC Q2W (indicated by arrows). Blue line indicates PASI 1.5.