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

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.

Modeling of age-dependent amyloid accumulation and γ-secretase inhibition of soluble and insoluble Aß in a transgenic mouse model of amyloid deposition.

According to the "amyloid hypothesis," accumulation of amyloid beta (Aß) peptides in the brain is linked to the development of Alzheimer's disease. The aims of this investigation were to develop a model for the age-dependent amyloid accumulation and to quantify the age- and treatment-duration-dependent efficacy of the γ-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble Aß40 and Aß42 brain concentrations were compiled from multiple naïve, vehicle, and MRK-560-treated animals. The age of Tg2576 mice in the studies ranged between 3.5 and 26 months. Single doses of MRK-560 inhibited soluble Aß40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble Aß40 levels in animals older than 13 months. Absolute levels of Aß variants increased exponentially over age and reached a plateau at ∼20 months. In the final model, it was assumed that MRK-560 inhibited the Aß production rate with an Aß level-dependent IC50.The age-dependent increase in Aß levels was best described by a logistic model that stimulated the production rate of soluble Aß. The increase in insoluble Aß was defined as a function of soluble Aß by using a scaling factor and a different turnover rate. The turnover half-life for insoluble Aß was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble Aß. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice.