A non-clinical comparative study of IL-23 antibodies in psoriasis.

Four antibodies that inhibit interleukin (IL)-23 are approved for the treatment of moderate-to-severe plaque psoriasis. Here, we present non-clinical data comparing ustekinumab, guselkumab, tildrakizumab and risankizumab with regard to thermostability, IL-23 binding affinity, inhibitory-binding mode, in vitro potency and in vivo efficacy. Risankizumab and guselkumab exhibited 5-fold higher affinity for IL-23 and showed more potent inhibition of IL-23 signaling than ustekinumab and tildrakizumab. Risankizumab and guselkumab completely blocked the binding of IL-23 to IL-23Rα as expected, whereas tildrakizumab did not. In vitro, risankizumab and guselkumab blocked the terminal differentiation of TH17 cells in a similar manner, while tildrakizumab had minimal impact on TH17 differentiation. In a human IL-23-induced ear-swelling mouse model, risankizumab and guselkumab were more effective than ustekinumab and tildrakizumab at reducing IL-17, IL-22, and keratinocyte gene expression. Our results indicate that the four clinically approved antibodies targeting IL-23 differ in affinity and binding epitope. These attributes contribute to differences in in vitro potency, receptor interaction inhibition mode and in vivo efficacy in preclinical studies as described in this report, and similarly may affect the clinical performance of these drugs.

Facilitating Longitudinal Exposure-Response Modeling of a Composite Endpoint Using the Joint Modeling of Sparsely and Frequently Collected Subcomponents.

Longitudinal exposure-response modeling plays an important role in optimizing dose and dosing regimens in clinical drug development. Certain clinical trials contain induction and maintenance phases where the maintenance treatment depends on the subjects' achieving the main endpoint outcome in the induction phase. Due to logistic difficulties and cost considerations, the main endpoint is usually collected more sparsely than a subcomponent (or other related endpoints). The sparse collection of the main endpoint hampers its longitudinal modeling. In principle, the frequent collection of a subcomponent allows its longitudinal modeling. However, the model evaluation via the visual predictive check (VPC) in the maintenance phase is difficult due to the requirement of the main-endpoint model to identify the treatment subgroups. This manuscript proposes a solution to this dilemma via the joint modeling of the main endpoint and the subcomponent. The challenges are illustrated by analyzing the data collected up to 60 weeks from a phase III trial of ustekinumab in patients with moderate-to-severe ulcerative colitis (UC). The main endpoint Mayo score, a commonly used composite endpoint to measure the severity of UC, was collected only at baseline, the end of the induction phase, and the end of the maintenance phase. The partial Mayo score, which is a major subset of the Mayo score, was collected at nearly every 4 weeks. A longitudinal joint exposure-response model, developed under a latent-variable Indirect Response modeling framework, described the Mayo score time course and facilitated the VPC model evaluation under a response-adaptive trial design.

Ustekinumab en un paciente con pioderma gangrenoso y enfermedad de Crohn refractaria / Ustekinumab in a patient with pyoderma gangrenosum and refractory Crohn's disease

No disponible

Ustekinumab en el tratamiento de la enfermedad de Crohn / Ustekinumab to treat Crohn's disease

Ustekinumab es un anticuerpo monoclonal dirigido frente a la subunidad p40, que forma parte de las interleucinas IL-12 y IL-23. En los ensayos clínicos fase3, ustekinumab ha demostrado su eficacia frente a placebo, en términos de respuesta clínica y remisión de la inducción. Cuando se ha empleado como terapia de mantenimiento por vía subcutánea, ustekinumab ha confirmado su beneficio terapéutico (sobre placebo) tanto en la respuesta clínica como en la remisión, en pacientes que habían respondido clínicamente a la terapia de inducción. Adicionalmente, ustekinumab ha demostrado una mejoría de los parámetros de curación mucosa. El perfil de seguridad del fármaco ha sido bueno, con tasas de infecciones infrecuentes (sin reactivación de tuberculosis) y ausencia de descripción de tumores. El desarrollo de inmunogenicidad frente al fármaco parece ser infrecuente. En resumen, ustekinumab representa una prometedora opción de tratamiento en pacientes con enfermedad de Crohn, como alternativa a los fármacos anti-TNFα (AU)

Ustekinumab is a monoclonal antibody directed against the p40 subunit, which is part of interleukins IL-12 and IL-23. The efficacy of ustekinumab versus placebo in terms of clinical response and remission of induction has been shown in phase3 clinical trials. When used as subcutaneous maintenance therapy, the therapeutic benefit of ustekinumab over placebo has been confirmed in both clinical response and remission in patients who have responded clinically to induction therapy. In addition, ustekinumab has demonstrated an improvement in mucosal healing parameters. The safety profile of the drug has been good, with low infection rates (without reactivation of tuberculosis) and absence of tumour reporting. The development of drug immunogenicity appears to be rare. In summary, ustekinumab is a promising treatment option in patients with Crohn's disease, as an alternative to anti-TNFα drugs (AU)