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Andrew E. Greenstein1; Pamela N. Munster2; Jasgit C. Sachdev3; Gini

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Andrew E. Greenstein1; Pamela N. Munster2; Jasgit C. Sachdev3; Gini 155 Impact of Relacorilant, a Selective Glucocorticoid Receptor Antagonist, on the Immunosuppressive Effects of Endogenous Cortisol 1 2 3 4 1 5 Copies of this poster obtained Andrew E. Greenstein ; Pamela N. Munster ; Jasgit C. Sachdev ; Gini F. Fleming ; Andreas Grauer ; Stacie Peacock Shepherd through Quick Response (QR) Code are for personal use only and may not be reproduced 1 2 3 without permission from ASCO® Corcept Therapeutics, Menlo Park, CA, USA; University of California, San Francisco School of Medicine, San Francisco, CA, USA; HonorHealth Research Institute/TGen, Scottsdale, AZ, USA; and the author of this poster. 4The University of Chicago Medicine, Chicago, IL, USA; 5formerly Corcept Therapeutics, Menlo Park, CA, USA Contact: [email protected] RESULTS RELACORILANT PROMOTES CHECKPOINT INHIBITOR RESPONSE IN TRANSCRIPTIONAL AND HEMATOLOGICAL EFFECTS OF Immune Activation and Antagonism of GC Activity by Relacorilant in a Figure 11. Plasma and Whole Blood Trends in Patients with Durable Benefit. BACKGROUND o In melanomas: SYNGENEIC MOUSE MODEL RELACORILANT SUGGEST IMPROVED IMMUNE ACTIVITY IN PHASE Patient with Complete Response GR EXPRESSION IS ASSOCIATED WITH TUMOR INFILTRATION OF The combination of a PD-1 antagonist antibody (αPD1, an ICI) and relacorilant was assessed in 1/2 STUDY IN PATIENTS WITH ADVANCED SOLID TUMORS In the Phase 1/2 solid tumor study, complete response per RECIST 1.1 was observed in CORTISOL EFFECTOR AND REGULATORY IMMUNE CELLS – Positive correlations between GR and CD8+ cytotoxic T-cells (R=0.24, Neutrophil-to-Lymphocyte P<0.001), T (R=0.29, P<0.001), and T-helper type 2 (Th2) cells (R=0.2, the EG7 tumor model. RNA profiling was conducted in whole blood from patients with advanced solid tumors one patient with ovarian cancer during treatment with relacorilant + nab-paclitaxel. Ratio Tregs CD3+ regs 10 0.12 Cortisol, a glucocorticoid (GC), regulates a wide range of processes, s 1.0 Tumor GR expression was assessed via IHC in 10 TNBC and 2 melanoma cases. P<0.001) were observed (Figure 3B–D). (predominantly pancreatic and ovarian cancer) treated with relacorilant + nab-paclitaxel Ovarian ll including the suppression of T-cell activation, pro-inflammatory While relacorilant or αPD1 alone had no significant effect in this model, their combination o The patient’s NLR declined from 5.5 (elevated) to 2.5 (normal) during the 7-day e Other 0.10 C (n = 46). Fold change and P value were calculated by comparing RNA counts between r o In both tumor types, T-cell infiltration, marked by the expression of CD3, potently suppressed tumor growth (P= 0.0 07, Figure 5A). 8 0.8 cytokine secretion, and immune cell trafficking, by binding to the – Negative correlations between GR and T-helper type 1 (Th1) cells were relacorilant lead-in preceding the first treatment cycle Figure( 10A). Pancreatic ea Figure 8 l baseline and cycle 1 day 15 (C1D15) ( ). + positively correlated with tumor GR expression (Figure 1 and Figure 2A). 3 0.08 c glucocorticoid receptor (GR). observed (R=-0.36, P<0.001) (Figure 3E). 4 o By day 14, 80% (8/10) of mice in the αPD1 arm had tumors larger than 1800 mm compared o The NLR improvement was accompanied by a reduction in GR-controlled transcripts 6 0.6 R CD o Relacorilant + nab-paclitaxel suppressed the expression of canonical GR-controlled L o Tumor GR expression was also positively correlated with FOXP3+ (a marker to 20% (2/10) in the αPD1 + relacorilant group. f 0.06 ononu N o GR is expressed in most human cells and is particularly abundant ptgs2 and dusp1 on day 15. The abundance of these transcripts increased o genes (ptgs2, P<0.001), confirming on-target antagonism of GR. M of regulatory T-cells [Tregs] that suppress cytotoxic T-cell function), PD1+ (a 4 0.4 % in immune cells. RATIONALE #1 FOR COMBINING ICI'S WITH RELACORILANT The αPD1 + relacorilant group also showed significantly improved tumor control and survival above baseline as the disease later progressed, treatment with relacorilant was 0.04 + common ICI target that suppresses effector function), and CD57+ cells (a o Genes encoding candidate-immunomodulatory drug targets (including cxcl8, ptger4, Elevated GC activity has been implicated in the pathophysiology probability compared to αPD1 alone (Figure 5B and C). discontinued, and dexamethasone was eventually administered (Figure 10B). 2 D45 marker of natural killer cells) (Figure 2B-D). Immune infiltration and PD-L1 expression have been associated with improved ido1; P<0.001) were also suppressed. 0.02 C 0.2 f of multiple cancer types, including breast, ovarian, squamous cell, response to ICI [14]. o Plasma IFNγ slightly increased, while IL-10 decreased in this patient (Figure 10C). o o An assessment of individual tumor-volume trajectories confirmed better tumor control % and cervical, as well as lymphomas [1-5], and is associated with poor Analysis of transcriptomics data from TCGA showed that GR expression also 0 0.00 0.0 correlated with markers of immunosuppressive cells. o Tumors with these features also show high expression of GR, the target of between days 10–20 in the αPD1 + relacorilant group compared to αPD1 alone (Figure 6). Figure 8. Suppression of GR-Controlled and Candidate-Immunomodulatory C1D1 C1D8 C1D15 treatment outcomes. o A decrease in Tregs and an increase in CD3+, CD4+, and CD8+ was observed early in C1D1 C1D8 C1D1 C1D8 relacorilant. Relacorilant alone significantly decreased circulating IL-10, an anti-inflammatory cytokine, Drug Target Genes in a Phase 1/2 Solid Tumor Study of Relacorilant + Nab- Figure 10D o Patients administered synthetic GC prior to immune checkpoint o A positive correlation of GR and programmed death-ligand 1 (PD-L1) treatment ( ). expression was observed (R=0.25, P<0.001), with particularly strong Suppression of tumor-infiltrating CD3+ T-cells may be reversed with compared to vehicle (P=0.002, Figure 7). Paclitaxel. inhibitor (ICI) therapy experienced worse outcomes across multiple Ptgs2 IFNα IL-10 relacorilant. oncology indications [6-8]. correlations in adrenal (R=0.48, P<0.001), bladder (R=.45, P<0.001), and Figure 10. Biomarkers in a Patient with Ovarian Cancer with Complete 400 100 6 60 4 ) pancreatic cancers (R=0.46, P<0.001) (Figure 3A). Baseline vs Day 15 ) L -20 Response on Relacorilant + Nab-Paclitaxel Therapy. 20 L 2 10 m m o Similarly, patients with adrenocortical cancer (ACC) and excess / 300 6 / 1.5 cxcl8 g pg systemic GC less frequently benefitted from pembrolizumab than RATIONALE #3 FOR COMBINING ICI'S WITH RELACORILANT p ( ( Figure 1. Immunohistochemical Staining of a TNBC Tumor Sample. Figure 3. Correlation Between GR Expression, PD-L1 Expression, t n n (A) NLR Reduction During Relacorilant (B) Reduction in n o o ACC patients with normal GC levels [9, 10]. i Relacorilant + αPD1 was more effective than αPD1 alone in a syngeneic mouse model. i t t Quantification of GR is shown in the top panel (green, yellow, and red indicating and Immune Cell Infiltrate.Analysis is based on data accessed via TCGA. ou 200 a 4 -15 Single-Agent Lead-In GR-Controlled Transcripts a 1.0 r r C t 10 t n The degree of immune suppression by endogenous GC and the increasing intensity), while CD3-expressing cells (T-cells) are highlighted on the (A) Correlation of GR and PD-L1 expression, with correlations within adrenal, Relacorilant alone decreased circulating IL-10, an anti-inflammatory cytokine, in mice. 500 n e ptger4 e c c n resulting consequences for anti-tumor immune response are not fully bladder, and pancreatic cancers highlighted on the right. (B-E) Correlations of ido1 n bottom (positive cells marked in green). o 100 2 o 0.5 e 6 ptgs2 C C u understood. GR expression with infiltration of CD8+, Treg, Th1, and Th2 cells in cutaneous l 400 e a 10-10 n V i melanoma. l o Normal morning serum cortisol ranges are high enough (276-552 0 0 e 0.0 P 300 4 s ptgs2 R Baseline C1D15 C7D1 EOT nM) that GR activation is expected, which is critical for normal Figure 5. Efficacy of αPD1 + Relacorilant in Syngeneic Mouse Model. Tumor control L C1D1 C1D15 C1D1 C1D15 Ba N 3 f physiology. -5 200 was defined as tumor volume <1800 mm . 10 o 10.0 R=0.48, <0.001 P=0.001 dusp1 o However, GR activation at physiological levels also suppresses 2 % 7.5 100 T-cell function, including the IFNγ and TNFα pathways, and alters 5.0 the cellular composition of blood, depleting lymphocytes and 2.5 (A) (B) (C) 100 R=0.25, <0.001 GR Expression 0.0 Tumor Volume Tumor Control Survival Probability 0 0 -4 -2 0 2 4 increasing myeloid cell abundance. -5 0 5 100 D-7 D-1 Baseline C1D15 C4D1 EOT PD-L1 Expression 100 75 ) Vehicle 3 2000 α PD1 + Log2-fold Change From Baseline αPD CONCLUSIONS 75 Relacorilant RELACORILANT: A SELECTIVE GR ANTAGONIST 10.0 Relacorilant R=0.45, <0.001 1500 Changes in Pro- and GR is abundantly expressed in human tumors and immune cells, and high GR Relacorilant (CORT125134, Corcept Therapeutics) is a selective cortisol 50 7.5 αPD1 + Relacorilant 50 50 Vehicle (C) Anti-Inflammatory Cytokines (D) Effect on T-Cells and Tregs expression is associated with high immune infiltrate and PD-L1 expression. 5.0 1000 P=0.002 Relacorilant Normalizes Elevated Neutrophil-to-Lymphocyte Ratio (NLR) modulator that: 2.5 αPD1 P=0.002 6 0.6 P=0.006 ) Physiological concentrations of cortisol broadly suppress human PBMC GR Expression 0.0 500 25 Relacorilant L GR Expression 25 P=0.007 α PD1 in Patients with Solid Tumors Probability of Survival o binds GR (K<1 nM), i Tumor Volume (mm -5 0 5 IFN CD4+ P=0.007 αPD1 + Relacorilant m activation in vitro.
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