Executive Director, Clinical Biomarker Strategy & Development Ultragenyx Novato
This 30-minute presentation is one of the four presentations in a two-hour symposium, which is proposed by Drs. Yow-Ming Wang and Xiaofei Wang. The title of the two-hour symposium is Biomarker Strategies in Therapeutics Development for Rare Diseases.
Drug development for rare diseases has to deal with unique challenges due to insufficient knowledge of the disease, scarcity of data and limited number of available patients. Netherton Syndrome (NS) is a rare genetically defined disease caused by the loss of function mutation encoding LEKTI (lympho-epithelial Kazal-type-related inhibitor), expressed in skin epidermis. LEKTI regulates activity of kallikrein-related peptidase 5 (KLK5) enzyme essential for skin homeostasis, its absence or deficient function causes severe skin barrier disruptions, skin inflammation, and excessive desquamation. Currently there is no effective therapy for NS disease.
In this work a semi-mechanistic PK-PD model for novel KLK5 inhibitor, DS-2325, will be presented. DS-2325 is intended to replace deficient LEKTI enzyme in NS patients. The model captures primary NS disease pathophysiology, predicts drug distribution in blood and skin, describes drug’s mechanisms of action. It is aimed to test various hypotheses covering existing knowledge gaps in order to better inform current and future clinical development. Implemented for mice and human species the model describes the dynamics of LEKTI, KLK5 and DS-2325 in skin epidermis over time. Using the model the available preclinical in-vitro and in-vivo data were translated into predictions in human, allowing us to evaluate the degree of KLK5 modulation in different treatment scenarios. Model helped to analyze and optimize dosing regimen as well as identify parameters having the greatest impact on the study design.
Learning Objectives:
Upon completion, participants will learn by example why mechanistic model can be a useful tool in drug development for rare diseases.
During presentation the audience will become familiar with Netherton syndrome disease and unique challenges it presents for patient treatment.
Upon completion, participants will learn how mechanistic model can integrate a range of in-vitro/in-vivo and clinical data making the model an effective instrument to inform and optimize clinical study design
Upon completion the audience will learn how to anticipate and address the unique challenes of rare disesae drug development and where biomarker strategy can help to overcome these.
