在 ccRCC 的高峰期HIF2α 药物研发不断发展——Casdatifan 启动 3 期临床试验.pdf

1、At the PEAK of ccRCC,HIF-2 Drug Development eVOLVEs Casdatifan Initiates Phase 3 TrialsJonathan Yingling,Chief Scientific Officer,Arcus BiosciencesHIF-2 Is a Key Driver in the Development and Progression of ccRCC1 Hypoxic response EPO/red blood cell generationCell Growth/CycleAngiogenesis&Oxygen Sup

2、plyEpithelial-MesenchymalTransitionMetastasisMetabolism Cholesterol uptake Fatty acids Lipoproteins Migration/invasion Extracellular matrix/cell-cell interaction Cytoskeleton organization Stemness Proliferation DNA repair Ribosome biogenesis E2F/MYC targetsHIF-2HIF-1HundredsofGenesUpregulatedCasdati

3、fan1.Culliver O.Transl Androl Urol.2017;6:1313.2.Choi WSW,et al.J Kidney Cancer VHL.2021;8:17.3.Choueiri TK,et al.Nat Med.2020;26:151930.ARC-20 is a Phase 1 Dose-Escalation and Dose-Expansion Study of CasdatifanTwo Datasets from Ongoing ARC-20 Cohorts Demonstrate Casdatifan Activity in ccRCCCasdatif

4、an Clinical Biomarker StrategyLongitudinal serum/plasma and pre-post biopsyEXCLUSIO ZONEHIF-1 and HIF-2 ImmunohistochemistryGenomic alterations(VHL and others)by WESTranscriptomic analysis by RNAseqHIF-2 HIF-1 PAXgeneDNAIHCWES and RNAseq*p20 x On-TxArchival baseline samplesOn-treatment samples 14-20

5、 days after initiation of cas therapy85%maximal decrease in sEPO in both patientsAdditional HIF-2 target genes decreased On-TxMagnitude and Duration of Peripheral EPO Reduction is Associated with ORRPatients segregated into 2 groups based on median best EPO reduction(-85%)from baselineEPO Reduction

6、Deeper(n=64)EPO Reduction Less Deep(n=63)%(95%CI)n%(95%CI)ncORR37.5%(25.7,50.5)2417.5%(9.1,29.1)11PD7.8%(2.6,17.3)523.8%(13,36.2)15PD(n=20)SD(n=72)CR+PR(n=35)-100-80-60-40-200%Best EPO change*p0.05*p0.001Deeper EPOLess Deep EPO1471013161922252831-100-80-60-40-200Study Week1471013161922252831-100-80-