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 ƒ 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 ƒ In the Phase 1/2 solid tumor study, complete response per RECIST 1.1 was observed in CORTISOL – Positive correlations between GR and CD8+ cytotoxic T-cells (R=0.24, Neutrophil-to-Lymphocyte EFFECTOR AND REGULATORY IMMUNE CELLS the EG7 tumor model. Tregs P<0.001), Tregs (R=0.29, P<0.001), and T-helper type 2 (Th2) cells (R=0.2, ƒ 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 CD3+ ƒ Cortisol, a glucocorticoid (GC), regulates a wide range of processes, ƒ 10 0.12 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 s including the suppression of T-cell activation, pro-inflammatory ƒ 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 (n = 46). Fold change and P value were calculated by comparing RNA counts between Other 0.10 C 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 r Figure 8 l Figure 1 Figure 2A baseline and cycle 1 day 15 (C1D15) ( ). + glucocorticoid receptor (GR). positively correlated with tumor GR expression ( and ). observed (R=-0.36, P<0.001) (Figure 3E). 3 0.08 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

o Relacorilant + nab-paclitaxel suppressed the expression of canonical GR-controlled CD 4 o Tumor GR expression was also positively correlated with FOXP3+ (a marker L

to 20% (2/10) in the αPD1 + relacorilant group. f 0.06 ononu c o GR is expressed in most human cells and is particularly abundant N

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. ƒ above baseline as the disease later progressed, treatment with relacorilant was % 0.04 common ICI target that suppresses effector function), and CD57+ cells (a RATIONALE #1 FOR COMBINING ICI'S WITH RELACORILANT The αPD1 + relacorilant group also showed significantly improved tumor control and survival o Genes encoding candidate-immunomodulatory drug targets (including cxcl8, ptger4, ƒ 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). ƒ 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 An assessment of individual tumor-volume trajectories confirmed better tumor control o Plasma IFNγ slightly increased, while IL-10 decreased in this patient (Figure 10C). o

ƒ % 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. ƒ 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 ƒ 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 o Similarly, patients with adrenocortical cancer (ACC) and excess m 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 (A) NLR Reduction During Relacorilant (B) Reduction in n o ƒ 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 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. 200 t

a 4 -15 Single-Agent Lead-In GR-Controlled Transcripts a 1.0 r r C ou n t 10 t n ƒ 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, ƒ 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 0.0 P 4 300 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 s e 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 RELACORILANT: A SELECTIVE GR ANTAGONIST 75 Relacorilant 10.0 R=0.45, <0.001 1500 Relacorilant Changes in Pro- and ƒ GR is abundantly expressed in human tumors and immune cells, and high GR ƒ 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

) ƒ 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

o binds GR (K<1 nM), Probability of Survival

i Tumor Volume (mm -5 0 5 IFN CD4+ P=0.007 m activation in vitro. PD-L1 Expression αPD1 + Relacorilant 0 0 0 ƒ Lower NLR is associated with improved outcomes on ICI [15]. t o antagonizes GR in cells (EC = 7.2 nM), and % of Mice with Tumor Control 4

50 pg / n

 0 5 10 15 0 5 10 15 20 25 0 5 10 15 20 25 ( 0.4 o Relacorilant, a potent, selective cortisol modulator that antagonizes GR, e

0 Days r 10.0 R=0.46, <0.001 Days Days o NLR elevations in cancer patients have been reported, but the physiological drivers n a o does not bind to the androgen and progesterone receptors o reverses this suppression. i CD3+ P 7.5 t f -5 0 5 are unclear. a

(Ki>10 μM) [11]. r 2

5.0 o PD-L1 Expression 0.3 ƒ In the EG7 mouse model, relacorilant promotes αPD1 activity. 2.5 0.2 CD8+ % ƒ ƒ A higher mean baseline NLR was observed in patients with solid tumors compared with en t In a Phase 1/2 study in patients with solid tumors (CORT125134-550, GR Expression c IL-10 0.0 0.2 o Consistent with the effects observed in isolated human PBMCs, the -5 0 5 healthy subjects (Figure 9, left). n NCT02762981), relacorilant demonstrated clinical activity in o PD-L1 Expression C 0.1 ability of relacorilant to promote T-cell function and pro-inflammatory combination with nab-paclitaxel [12]. Figure 6. Individual Tumor Volumes in Syngeneic Mouse Model. ƒ Relacorilant + nab-paclitaxel significantly reduced the NLR in solid-tumor patients with Tregs 0.0 0.0 cytokine secretion was corroborated in this model. ƒ       elevated baseline NLR (>3) but not in patients with normal NLR at baseline (Figure 9, Phase 2 and 3 studies with relacorilant in combination with nab- Figure 2. Correlation Between Tumor GR Expression and Cell C1D1 C1D15 D-1 C1D8 ƒ Evidence of T-cell activation by relacorilant was also observed in solid-tumor paclitaxel in patients with solid tumors are underway.   middle and right). Infiltration. Analysis is based on 10 TNBC and 2 melanoma cases. H-scores αPD1 Group αPD1 + Relacorilant Group patients with sustained response in a Phase 1/2 solid tumor study.    4000 3000 ƒ These data suggest that elevated GC activity may contribute to high NLR, and  In this poster, we present in vitro, in vivo, and clinical studies that were used to quantify tumor GR expression in IHC. o In this study, relacorilant suppressed GR-inducible genes and reduced )  R=0.24, <0.001  R=0.29, <0.001 ) relacorilant can normalize the NLR in some cancer patients. Relacorilant Improves Immune Activity in Patients with Durable 3 3 m suggest that relacorilant can reverse the immunosuppressive effects of (A) 3000 m the NLR. (B) m m ( CD3+ FOXP3+   ( 2000 Response e e

endogenous GC, making it well-suited for combination with an ICI. ) ) ƒ m 400 8 m These findings support the hypothesis that relacorilant can reverse immune -2 -2 u u Figure 9. Effects of Relacorilant + Nab-Paclitaxel on NLR. Healthy volunteer l 2 2 2000 l

=0.50, P=0.01 Tumor: R =0.58, P=0.007 o Tumor: R Tumor o ƒ In a subset of patients (n = 11, Table 1), durable clinical response was observed. V 2 2 V suppression by endogenous GC in solid tumor cancers. (µm Stroma: R =0.46, P=0.015 (µm Stroma: R =0.38, P=0.051   r r data taken from the Phase 1 study, patient data from the Phase 1/2 solid tumor study. a a o o 1000 e 300 e 6 r r

Stroma m 1000 m o These durable responses are notable given prior treatment history with nab- u u A A ƒ Clinical studies with immune checkpoint inhibitors and relacorilant are GR Expression GR Expression Solid tumor patients with elevated NLR (>3) are shown in red; patients with normal NLR T t t T i i   n n U U paclitaxel and historic data in similar patients. 200 4 are shown in blue. planned (eg, CORT125134-551, NCT04373265). r r e e TNBC 0 0 p METHODS p   t t 0 5 10 15 20 25 0 5 10 15 20 25 ƒ Melanoma Evidence of an immune response to relacorilant + nab-paclitaxel in these patients is 2 ou n 100 ou n Days Days Elevated Baseline NLR C C         indicated by the following observations (Figure 11). l IN VITRO AND IN SILICO STUDIES l l l Cell Abundance Cell Abundance 15 e e C C 0 ƒ Immune cell markers and GR expression were assessed by 0 o Circulating blood counts: Increase in T-cell count (P=0.06), decrease in Tregs (P=0.06), 0 50 100 150 200 250 0 50 100 150 200 250 REFERENCES   e P=0.025 t

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Baseline i - -2 Mouse Model. All Participants o Whole blood RNA counts: Decreased expression of ptgs2 early in treatment (P=0.008).   15 1997. 70(2): p. 241-7. transcripts in data accessed from The Cancer Genome Atlas (TCGA, 15 op h r (µm (µm

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e 1.5 e r Tumor: R =0.33, P=0.049 r Tumor: R =0.58, P=0.004 3. Sharma, P., et al., Estimation of cortisol levels in patients with premalignant disorders and oral squamous www.cancer.gov/tcga). Cellular abundance was calculated using xCell [13].   N A 200 2 A 2 Table 1. Summary of Remarkable Responders. The patient with complete t

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N 10 p 7. Scott, S.C. and N.A. Pennell, Early Use of Systemic Corticosteroids in Patients with Advanced NSCLC 0 0 m treated with either vehicle or αPD1 (mouse surrogate RMP1-14) ip Q5D RELACORILANT RESTORES T-CELL ACTIVATION INHIBITED BY Figure 4. PBMC Activation Upon Stimulation With αCD3 + IL-12. 10 y Cholangiocarcinoma PR 59 No o i L t Healthy Solid Tumor Day 1 Day 8 - Treated with Nivolumab. J Thorac Oncol, 2018. 13(11): p. 1771-1775. a o t - R

CD8+/CD137+ TNFα IFNγ Subjects Patients l +/- relacorilant once daily for 25 days. Mice were not treated or handled in CORTISOL IN HUMAN PBMCS i PDAC PR 54 No 150 150 150 8. Fuca, G., et al., Modulation of peripheral blood immune cells by early use of steroids and its association op h l r

t 5 any way intended to alter normal GC. o r

ƒ Concentration(pg/mL)

To understand the molecular consequences of GC activity on T-cell activation, t P<0.001 P=0.05 u PDAC PR 50 Yes with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune n P=0.006 e o N the effects of cortisol and relacorilant were assessed in human PBMCs (Figure 4). C 100 100 100 checkpoint inhibitors. ESMO Open, 2019. 4(1): p. e000457. ƒ Cytokines were measured by Luminex in terminal sera. d e t Acinar pancreatic PR 32 Yes

a 0 l u 9. Habra, M.A., et al., Phase II clinical trial of pembrolizumab efficacy and safety in advanced o T-cells were stimulated by addition of CD3 + IL-12, and stimulation was m

α i t

S 50 50 50 Vehicle Relacorilant 0 Ovarian—Low-grade serous SD 39 No—Adjuvant f adrenocortical carcinoma. J Immunother Cancer, 2019. 7(1): p. 253. CLINICAL STUDIES assessed by profiling cell surface markers on CD4+ and CD8+ T-cells as well o Day 1 Day 8 ƒ as secreted pro-inflammatory cytokines. % Ovarian—Low-grade serous SD 38 Yes 10. Head, L., et al., Response to Immunotherapy in Combination With Mitotane in Patients With Metastatic A Phase 1/2, single-arm, non-randomized, open-label, multicenter trial in 0 0 0 Unstim.Control GC RELA GC + Unstim.Control GC RELA GC + Unstim.Control GC RELA GC + Adrenocortical Cancer. J Endocr Soc, 2019. 3(12): p. 2295-2304. RELA PDAC SD 37 Yes patients with solid tumors was performed to determine the preliminary ƒ Cortisol (400 nM) suppressed nearly all effects of stimulation by αCD3 + IL-12 RELA RELA Stimulated 11. Hunt, H.J., et al., Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol- efficacy of relacorilant + nab-paclitaxel (CORT125134-550, NCT02762981). while relacorilant (300 nM) restored nearly all effects of stimulation that were Stimulated Stimulated PDAC SD 33 Yes suppressed by cortisol. 4-yl)sulfonyl)-4,4a,5,6,7,8-hexah ydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) ƒ Healthy volunteer data from a Phase 1 study were analyzed for CR, complete response; PDAC, pancreatic ductal adenocarcinoma, PR, partial response; SD, stable disease. methano ne (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J Med Chem, 2017. comparison (CORT125134-120, NCT03508635). o Expression of CD137, a costimulatory immune checkpoint molecule, on CD8+ 60(8): p. 3405-3421. cells was induced by stimulation, suppressed by cortisol, and restored by 12. Munster, P.N., et al., Relacorilant (RELA) with nab-paclitaxel (NP): Safety and activity in patients with ƒ ® RATIONALE #2 FOR COMBINING ICI'S WITH RELACORILANT Whole blood was collected in PAXgene tubes and RNA was quantified relacorilant (P<0.001, Figure 4A). ACKNOWLEDGEMENTS DISCLOSURES RATIONALE #4 FOR COMBINING ICI'S WITH RELACORILANT pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA). J Clin Oncol, 2019. 37(15_suppl): ® ƒ Activated T-cells that secrete pro-inflammatory cytokines are primary using nCounter FLEX (NanoString). AEG: Employee, Corcept p. 4130-4130. – Similar effects were observed with PD-1, LAG3, CTLA-4, and TIGIT surface meditators of the anti-tumor immune response. The clinical studies (NCT02762981, NCT03508635, NCT04373265) are supported by Corcept Therapeutics. ƒ High GC activity may be the cause of elevated NLR in some cancer patients. PNM: Investigator/Researcher, Corcept 13. Aran, D., Z. Hu, and A.J. Butte, xCell: digitally portraying the tissue cellular heterogeneity landscape. ƒ Lymphocyte and neutrophil abundance were determined using standard expression on both CD4+ and CD8+ T-cells (data not shown). Editorial support was provided by Tina K. Schlafly of Corcept Therapeutics. Funding for editorial, design, and production ƒ T-cell activation and cytokine secretion are suppressed by physiological JCS: Consultant/Advisor: Puma, Novartis, TTC Oncology, Ipsen, Pfizer; Investigator/Researcher, Corcept ƒ This Phase 1/2 solid tumor study suggests that NLR, Tregs, IL-10, and transcription Genome Biol, 2017. 18(1): p. 220. differential complete blood-count tests and the neutrophil-to-lymphocyte o The cytokines TNFα and IFNγ were also induced by stimulation, suppressed concentrations of cortisol. support for this poster was provided by Corcept to MedVal Scientific Information Services, LLC, Princeton, NJ. Experiments of GR-target genes may be decreased, while IFNγ and T-cells may be increased by ratio (NLR) was calculated as the absolute neutrophil count divided by the by cortisol, and restored by relacorilant (P=0.006 and P=0.05, respectively, GFF: Consultant/Advisor: TTC Oncology; Investigator/Researcher: Corcept, Merck, Genentech, Abbvie, Syros, Leap 14. Nakamura, Y., Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse ƒ Relacorilant can reverse the effect of cortisol, restoring activation and cytokine were conducted at Ardigen SA, QualTek Molecular Laboratories, Precision for Medicine, NeoGenomics, Meso Scale Discovery Therapeutics, Compuge, Sanofi, Iovance; Speaker, Curio Science; Author Payment, UpToDate relacorilant + nab-paclitaxel. Events. Front Med (Lausanne), 2019. 6: p. 119. absolute lymphocyte count. Figure 4B and C). secretion. Services, Vivopharm, Ampersand Biosciences, Acepix Biosciences, Nanostring Technologies, and through clinical study AG: Employee, Corcept ƒ These immune effects have been associated with improved response to ICI. 15. Lalani, A.A., et al., Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint ƒ Cytokines were assessed by immunoassays in EDTA plasma. – Similar effects were observed for IL-1β, IL-6, and IL-2 (data not shown). NCT02762981.The authors developed and revised the poster and provided approval of the final version. SPS: Employee at time of abstract submission, Corcept blockade for metastatic renal cell carcinoma. J Immunother Cancer, 2018. 6(1): p. 5.

Supported by funding from Corcept Therapeutics Presented at the Virtual American Society of Clinical Oncology (ASCO) Annual Meeting, May 29 - June 2, 2020.