[Translation] A randomized, double-blind, placebo-controlled Phase I clinical study to evaluate the safety and tolerability of KPG-818 capsules after multiple oral administration in healthy Chinese subjects, as well as the pharmacokinetic characteristics and food effect test

评估KPG-818胶囊在中国健康受试者中多次口服给药后KPG-818及代谢物KPG-818H的药代动力学特征。评估KPG-818胶囊在中国健康受试者中多次口服给药后的安全性和耐受性。评估食物对KPG-818胶囊在中国健康受试者中单次口服给药后PK的影响。

[Translation]

To evaluate the pharmacokinetic characteristics of KPG-818 and its metabolite KPG-818H after multiple oral administration of KPG-818 capsules in healthy Chinese subjects. To evaluate the safety and tolerability of KPG-818 capsules after multiple oral administration in healthy Chinese subjects. To evaluate the effect of food on the PK of KPG-818 capsules after a single oral administration in healthy Chinese subjects.

Start Date11 Apr 2024

Sponsor / Collaborator

Kangpu Biopharmaceuticals Ltd.

CTR20233129 / RecruitingPhase 1

一项评价SM17在中国健康受试者和中重度特应性皮炎患者中的随机双盲、安慰剂对照的I期临床研究

[Translation] A randomized, double-blind, placebo-controlled Phase I clinical study evaluating SM17 in healthy subjects and patients with moderate to severe atopic dermatitis in China

第一部分：Ia期健康受试者研究主要目的：评估SM17在中国健康成人受试者中单次及多次给药的安全性和耐受性。次要目的：评估SM17在中国健康受试者中单次及多次给药后的药代动力学（PK）特征。评估SM17在中国健康受试者中的免疫原性。第二部分：Ib期成年中重度特应性皮炎患者研究主要目的：评估SM17在成年中重度特应性皮炎患者中多次给药的安全性与耐受性。次要目的：评估SM17在成年中重度特应性皮炎患者中多次给药的PK特征。评估SM17在成年中重度特应性皮炎患者中的免疫原性。评估SM17治疗成年中重度特应性皮炎患者的初步有效性。探索性目的：探索SM17在成年中重度特应性皮炎患者中多次给药后的药效学（PD）特征。探索SM17多次给药后的PK/PD相关性。探索PD标志物与特应性皮炎有效性评估指标之间的相关性。

[Translation]

Part I: Phase Ia healthy subject study Primary objective: To evaluate the safety and tolerability of SM17 after single and multiple administrations in healthy Chinese adult subjects. Secondary objective: To evaluate the pharmacokinetic (PK) characteristics of SM17 after single and multiple administrations in healthy Chinese subjects. To evaluate the immunogenicity of SM17 in healthy Chinese subjects. Part II: Phase Ib study in adult patients with moderate to severe atopic dermatitis Primary objective: To evaluate the safety and tolerability of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. Secondary objective: To evaluate the PK characteristics of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. To evaluate the immunogenicity of SM17 in adult patients with moderate to severe atopic dermatitis. To evaluate the preliminary efficacy of SM17 in the treatment of adult patients with moderate to severe atopic dermatitis. Exploratory objective: To explore the pharmacodynamic (PD) characteristics of SM17 after multiple administrations in adult patients with moderate to severe atopic dermatitis. To explore the PK/PD correlation of SM17 after multiple administrations. To explore the correlation between PD markers and effectiveness evaluation indicators for atopic dermatitis.

Start Date21 Nov 2023

Sponsor / Collaborator

Sinolink Pharma (Suzhou) Limited

NCT05332834 / CompletedPhase 1

A Phase 1, First-in-Human, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SM17 When Administered Intravenously as a Single Ascending Dose in Healthy Subjects (Part A) and as Multiple Ascending Doses in Healthy Subjects (Part B)

This trial is a phase 1, first-in-human, randomized, double-blind, placebo-controlled dose escalation trial following single and multiple doses intravenous administration of SM17.
It aims to evaluate the safety, tolerability, pharmacokinetic characteristics, pharmacodynamic effect and immunogenicity of single and multiple doses of SM17 injection in healthy subjects.

Start Date14 Jun 2022

Sponsor / Collaborator

Sinomab Bioscience Ltd.

100 Clinical Results associated with IL17RB

100 Translational Medicine associated with IL17RB

0 Patents (Medical) associated with IL17RB

421

Literatures (Medical) associated with IL17RB

16 Oct 2024·mBio

A multistage Plasmodium CRL4 ^WIG1 ubiquitin ligase is critical for the formation of functional microtubule organization centers in microgametocytes

Article

Author: Artavanis-Tsakonas, Katerina ; Brochet, Mathieu ; Rashpa, Ravish ; Smith, Cameron

ABSTRACT Malaria is a mosquito-borne infectious disease caused by unicellular eukaryotic parasites of the Plasmodium genus. Protein ubiquitination by E3 ligases is a critical post-translational modification required for various cellular processes during the lifecycle of Plasmodium parasites. However, little is known about the repertoire and function of these enzymes in Plasmodium . Here, we show that Plasmodium expresses a conserved cullin RING E3 ligase (CRL) complex that is functionally related to CRL4 in other eukaryotes. In P. falciparum asexual blood stages, a cullin-4 scaffold interacts with the RING protein RBX1, the adaptor protein DDB1, and a set of putative receptor proteins that may determine substrate specificity for ubiquitination. These receptor proteins contain WD40-repeat domains and include W D-repeat protein i mportant for g ametogenesis 1 (WIG1). This CRL4-related complex is also expressed in P. berghei gametocytes, with WIG1 being the only putative receptor detected in both the schizont and gametocyte stages. WIG1 disruption leads to a complete block in microgamete formation. Proteomic analyses indicate that WIG1 disruption alters proteostasis of ciliary proteins and components of the DNA replication machinery during gametocytogenesis. Further analysis by ultrastructure expansion microscopy (U-ExM) indicates that WIG1-dependent depletion of ciliary proteins is associated with impaired the formation of the microtubule organization centers that coordinate mitosis with axoneme formation and altered DNA replication during microgametogenesis. This work identifies a CRL4-related ubiquitin ligase in Plasmodium that is critical for the formation of microgametes by regulating proteostasis of ciliary and DNA replication proteins. IMPORTANCEPlasmodium parasites undergo fascinating lifecycles with multiple developmental steps, converting into morphologically distinct forms in both their mammalian and mosquito hosts. Protein ubiquitination by ubiquitin ligases emerges as an important post-translational modification required to control multiple developmental stages in Plasmodium . Here, we identify a cullin RING E3 ubiquitin ligase (CRL) complex expressed in the replicating asexual blood stages and in the gametocyte stages that mediate transmission to the mosquito. WIG1, a putative substrate recognition protein of this ligase complex, is essential for the maturation of microgametocytes into microgametes upon ingestion by a mosquito. More specifically, WIG1 is required for proteostasis of ciliary proteins and components of the DNA replication machinery during gametocytogenesis. This requirement is linked to DNA replication and microtubule organization center formation, both critical to the development of flagellated microgametes.

03 Oct 2024·Brain

Cul-4 inhibition rescues spastin levels and reduces defects in hereditary spastic paraplegia models

Article

Author: Carsetti, Claudia ; Rinaldo, Cinzia ; Sardina, Francesca ; Giorgini, Ludovica ; Fattorini, Gaia ; Cestra, Gianluca

AbstractHereditary spastic paraplegias (HSPs) are degenerative motor neuron diseases characterized by progressive spasticity and weakness in the lower limbs. The most common form of HSP is due to SPG4 gene haploinsufficiency. SPG4 encodes the microtubule severing enzyme spastin. Although, there is no cure for SPG4-HSP, strategies to induce a spastin recovery are emerging as promising therapeutic approaches. Spastin protein levels are regulated by poly-ubiquitination and proteasomal-mediated degradation, in a neddylation-dependent manner. However, the molecular players involved in this regulation are unknown.Here, we show that the Cullin-4-RING E3 ubiquitin ligase complex (CRL4) regulates spastin stability. Inhibition of CRL4 increases spastin levels by preventing its poly-ubiquitination and subsequent degradation in spastin-proficient and in patient derived SPG4 haploinsufficient cells. To evaluate the role of CRL4 complex in spastin regulation in vivo, we developed a Drosophila melanogaster model of SPG4 haploinsufficiency which show alterations of synapse morphology and locomotor activity, recapitulating phenotypical defects observed in patients. Downregulation of the CRL4 complex, highly conserved in Drosophila, rescues spastin levels and the phenotypical defects observed in flies. As a proof of concept of possible pharmacological treatments, we demonstrate a recovery of spastin levels and amelioration of the SPG4-HSP-associated defects both in the fly model and in patient-derived cells by chemical inactivation of the CRL4 complex with NSC1892.Taken together, these findings show that CRL4 contributes to spastin stability regulation and that it is possible to induce spastin recovery and rescue of SPG4-HSP defects by blocking the CRL4-mediated spastin degradation.

01 Oct 2024·JAMA Oncology

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Article

Author: Jerzak, Katarzyna J. ; Ingle, James N. ; O’Regan, Ruth M. ; Müller, Bettina ; Viale, Giuseppe ; Bellet, Meritxell ; van Mackelenbergh, Marion T. ; Dell’Orto, Patrizia ; Kammler, Roswitha ; Colleoni, Marco ; Schnabel, Catherine A. ; Fleming, Gini F. ; Loi, Sherene ; Karlsson, Per ; Geyer, Charles E. ; Ciruelos, Eva M. ; Coleman, Robert E. ; Treuner, Kai ; Regan, Meredith M. ; Zaman, Khalil ; Bernardo, Antonio ; Bonnefoi, Herve R. ; Zhang, Yi ; Tondini, Carlo ; Neven, Patrick ; Martino, Silvana ; Davidson, Nancy E. ; Lang, Istvan ; Villa, Federica ; Francis, Prudence A. ; Jochum, Wolfram

ImportanceAdjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor–positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.ObjectiveTo assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.Design, Setting, and ParticipantsThis prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])–high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.Main Outcomes and MeasuresPrimary end points were breast cancer–free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.ResultsTumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, −1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.Conclusions and RelevanceIn this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

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