exicorilant (CORT125281) / Corcept Therap - LARVOL DELTA

Glucocorticoids Selectively Inhibit Hippocampal CA1 Pyramidal Neurons Activity Through HCN Channels. (PubMed, Int J Mol Sci) - "The corticosterone-induced inhibition in CA1 was blocked by the glucocorticoid receptor antagonist CORT125281, but remained unaffected by the mineralocorticoid receptor antagonist spironolactone. Notably, membrane-impermeable bovine serum albumin-conjugated dexamethasone mimicked corticosterone's effects on CA1 neurons, which exhibited prominent hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents...Corticosterone enhanced HCN channel activity in CA1 neurons via glucocorticoid receptors, and the HCN channel inhibitor ZD7288 abolished corticosterone's suppressive effects on action potentials. These findings suggest that glucocorticoids selectively inhibit CA1 pyramidal neuron activity through HCN channels, providing new insight into the mechanisms of glucocorticoid action in hippocampal circuits."

Journal • CA3

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells. (PubMed, Cells) - "GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression...The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR-LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NR3C1 • PSIP1

Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC (clinicaltrials.gov) - P1/2 | N=39 | Completed | Sponsor: Corcept Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

The glucocorticoid receptor-LEDGFp75 interaction in prostate cancer therapy cross-resistance (AACR 2023) - "Glucocorticoid receptor, a transcription factor, has been implicated in resistance to ARSI (via the GR bypass), and docetaxel (DTX) therapies...The effects of Exicorilant and Relacorilant (Corcept Therapeutics) were evaluated on LEDGFp75 protein expression levels...Interestingly, upregulation of GR in enzalutamide resistant LNCaP cells correlated with LEDGFp75 upregulation, and GR silencing in these cells decreased this upregulation...In addition, RNAseq studies have been initiated to determine the degree of transcriptional overlap between GR and LEDGFp75 in chemoresistant PCa cells. Our goal is to link mechanistically the GR-LEDGFp75 transcriptional network to ARSI/taxane cross-resistance in PCa and target this network to attenuate therapy resistance."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PSIP1

Phase 1 efficacy and pharmacodynamic results of exicorilant + enzalutamide in patients with metastatic castration-resistant prostate cancer. (ASCO-GU 2023) - P1/2 | "This study did not include an ENZA-alone arm and was thus not designed to assess the contribution of EXI to the efficacy of the EXI + ENZA combination. In heavily pretreated pts with prior ENZA exposure, 1 PSA response and no radiographic responses were observed. PD analysis confirmed systemic GR modulation."

Clinical • Metastases • P1 data • PK/PD data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN1C • NR3C1

Cortisol/glucocorticoid receptor: a critical mediator of the ovulatory process and luteinization in human periovulatory follicles. (PubMed, Hum Reprod) - "Successful ovulation and luteinization are essential for female fertility. Women with dysregulated cortisol levels often suffer from anovulatory infertility. Deciphering the functional role of glucocorticoid receptor signaling in human periovulatory follicles enhances our knowledge of basic ovarian physiology and may provide therapeutic insights into treating infertility in women."

Journal • Infertility • Oncology • Sexual Disorders • FKBP5 • PGR

Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC (clinicaltrials.gov) - P1/2 | N=39 | Active, not recruiting | Sponsor: Corcept Therapeutics | Recruiting ➔ Active, not recruiting | N=80 ➔ 39 | Trial completion date: Dec 2024 ➔ Jan 2023

Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase I results of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer (ESMO 2022) - P1/2 | "Conclusions A maximum-tolerated dose of EXI in combination with ENZA was identified with fatigue and pain as the most common AEs. No clinically relevant changes were observed in ENZA exposure when given with EXI relative to ENZA alone."

Clinical • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Corcept Therapeutics Announces Fourth Quarter and Full-Year 2021 Audited Financial Results and Provides Corporate Update (GlobeNewswire) - "Solid Tumors: (i) Updated overall survival data from Phase 2 trial in patients with recurrent platinum-resistant ovarian cancer expected in first quarter 2022; Phase 3 trial planned to start second quarter 2022; (ii) Selection of the optimum dose of exicorilant or relacorilant plus enzalutamide in patients with castration-resistant prostate cancer (CRPC) expected in second quarter 2022."

New P3 trial • P2 data • Trial status • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Urothelial Cancer

In Vivo Profiling with F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions. (PubMed, Mol Pharm) - "Profiling target engagement in vivo showed that the GR antagonists RU486 (mifepristone) and CORT125281 engaged GR in fewer normal tissues compared to ORIC-101 or the agonist dexamethasone. Furthermore, F-YJH08 detected GR in human prostate cancer tumor models and measured receptor binding by RU486. In summary, these data show for the first time that antagonist/GR interactions can be measured in vivo with F-YJH08, a finding with clinical relevance as GR antagonists and C-YJH08 are currently in clinical trials."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Corcept Therapeutics Announces Third Quarter Financial Results And Provides Corporate Update (GlobeNewswire) - "Solid Tumors:...Updated overall survival data from the Phase 2 trial expected in the first quarter of 2022. Selection of the optimum dose of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer (CRPC) expected later this year...'We and our investigators are excited to advance relacorilant for the potential treatment of ovarian cancer and plan to meet with the FDA in the coming months to arrive at the best path forward'."

FDA event • P2 data • Trial status • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Ovulatory upregulation of angiotensin-converting enzyme 2, a receptor for SARS-CoV-2, in dominant follicles of the human ovary. (PubMed, Fertil Steril) - "The hormone-regulated expression of ACE2 in granulosa cells suggests a potential role of ACE2 in the ovulatory process. These data also imply the possible impact of COVID-19 on a vital cyclic event of ovarian function and thus on women's overall reproductive health. However, SAR-CoV-2 infection in ovarian cells in vivo or in vitro has yet to be determined."

Journal • Gynecology • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • PCR • PGR

Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC (clinicaltrials.gov) - P1/2; N=80; Recruiting; Sponsor: Corcept Therapeutics; Trial completion date: Jul 2021 ➔ Dec 2024; Trial primary completion date: Mar 2021 ➔ Apr 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Corcept Therapeutics Announces Fourth Quarter, Full-Year 2020 Preliminary Selected Financial Results and 2021 Revenue Guidance; Provides Corporate Update (BioSpace) - “Preliminary results in 178-patient, controlled, Phase 2 trial of relacorilant plus nab-paclitaxel in patients with metastatic ovarian cancer expected in first half 2021; Preliminary results in first 40 patients enrolled in open-label Phase 3 RELIANT trial of relacorilant plus nab-paclitaxel in patients with metastatic pancreatic cancer expected in first half 2021; Selection of optimum dose of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer ('CRPC') expected by third quarter 2021; Patient selection underway in 20-patient, open-label, Phase 1b trial of relacorilant plus PD-1 checkpoint inhibitor pembrolizumab in patients with adrenal cancer with cortisol excess.”

Enrollment status • P2 data • P3 data • Adrenal Cortex Carcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer

Corcept Therapeutics Announces Third Quarter 2020 Financial Results and Provides Corporate Update (GlobeNewswire) - "Enrollment complete in 178-patient, controlled, Phase 2 trial of relacorilant plus nab-paclitaxel in patients with metastatic ovarian cancer; results expected in first half 2021; Enrollment continues in 80-patient, open-label Phase 3 RELIANT trial of relacorilant plus nab-paclitaxel in patients with metastatic pancreatic cancer; results in first 40 patients expected in first half 2021; Selection of optimum dose of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer expected in first quarter 2021."

Clinical protocol • Enrollment status • P2 data • P3 data • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer

Corcept Therapeutics Announces Second Quarter 2020 Financial Results and Provides Corporate Update (GlobeNewswire) - "Phase 2 trial of relacorilant plus nab-paclitaxel in patients with metastatic ovarian cancer; results expected in first half 2021....Selection of optimum dose of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer expected by year-end, Phase 1b trial of relacorilant plus PD-1 checkpoint inhibitor pembrolizumab in patients with metastatic or unresectable adrenal cancer expected to start in third quarter 2020."

Clinical protocol • Enrollment status • P2 data • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer

The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity. (PubMed, J Endocrinol) - "In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity."

Journal

Corcept Therapeutics announces first quarter 2020 financial results and provides corporate update (GlobeNewswire) - "Controlled, Phase 2 trial of relacorilant plus nab-paclitaxel (Abraxane®) to treat metastatic ovarian cancer enrolling patients at sites in the United States and Europe; results expected in first half 2021. Phase 3 trial of relacorilant plus nab-paclitaxel in metastatic pancreatic cancer (RELIANT) to start in second quarter 2020 Selection of optimum dose of exicorilant plus enzalutamide in castration-resistant prostate cancer expected by year-end, Phase 1b trial of relacorilant plus PD-1 checkpoint inhibitor pembrolizumab (Keytruda®) to treat patients with metastatic or unresectable adrenal cancer to start in third quarter 2020."

Enrollment status • P2 data • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Urothelial Cancer

Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC (clinicaltrials.gov) - P1/2; N=80; Recruiting; Sponsor: Corcept Therapeutics; Active, not recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • KLK3

Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC (clinicaltrials.gov) - P1/2; N=80; Active, not recruiting; Sponsor: Corcept Therapeutics; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

Mass Balance Recovery and Metabolite Profile of CORT125281 in Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Corcept Therapeutics

Clinical • New P1 trial