Next Rosa IMpact Webinar

A mechanistic systems pharmacology model for prediction of LDL cholesterol lowering by anti-PCSK9 in human dyslipidemia Kapil Gadkar, Scientist at Genentech Wednesday, May 14, 2014 1:00 to 2:00 pm EDT Abstract: Proprotein convertase subtilisn-like kexin type 9 (PCSK9) is emerging as a promising target for treatment of hyperlipidemia and cardiovascular disease. A phase 1 clinical study with RG7652 (anti-PCSK9) demonstrates a dose dependent reduction in low-density lipoprotein cholesterol (LDLc) in subjects, as a monotherapy and in combination with statins. However, clinical data on PCSK9-targeted therapies are still limited, and critical questions, including the impact of statin background therapy, the responsiveness of different patient subtypes, and the relationship of response to baseline biomarkers, have not yet been characterized in clinical populations. In order to investigate these issues and make forward predictions for Phase II/III clinical trials for RG7652, we have developed a Quantitative Systems Pharmacology (QSP) model of the mechanistic interaction and cross-regulation of LDL, LDL receptor, and PCSK9 in health and dyslipidemic disease, including statin and anti-PCSK9 mechanisms of action and effects. The QSP approach leverages preclinical and mechanistic data as well as available clinical data. The QSP model predicted a slightly better effect of anti-PCSK9, in terms of % LDLc reduction, when added in combination with statin compared to anti-PCSK9 monotherapy. This is primarily due to the neutralization of the statin-induced upregulation of PCSK9 and its detrimental effect on LDL. However, higher PCSK9 in statin-treated patients is also predicted to lead to greater target-mediated clearance of anti-PCSK9 and faster rebound of LDLc. The model was used to compare predicted responses in dyslipidemics vs. familial hypercholesterolemia (FH) patients. Results suggested that the reduced LDLR activity, which less than 10% of normal, observed in homozygous FH patients is predicted to reduce the efficacy of anti-PCSK9, due to the greater relative importance of LDLR-independent LDL uptake mechanisms. Further, the model predicted minimal impact of baseline LDLc and PCSK9 on anti-PCSK9 driven LDLc % lowering. The application of the QSP model has led to novel predictions and understanding of the effects of anti-PCSK9 treatment on different patient subtypes and has enabled anticipation and planning for clinical scenarios for which data are currently unavailable. Register for this free webinar at www.rosaandco.com/webinar.html. After registering you will receive a confirmation email containing information about joining the webinar. More information about the webinar series, an archive of past webinars, and a list of future webinar speakers may be found at http://www.rosaandco.com/webinar.html. Toufigh Gordi, PhD President, PK/PD and Clinical Pharmacology Services Direct: 408-480-7314 Corp: 408-370-9800 Fax: 408-370-9810 [email protected]