Corcept Therapeutics
Overview
Corcept Therapeutics (CORT) is engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of the hormone cortisol. Elevated levels and abnormal release patterns of cortisol are implicated in a broad range of diseases. The company's first approved product, Korlym®, treats patients with Cushing’s syndrome, a rare disease that is caused by excess cortisol activity. The active ingredient in Korlym is mifepristone, a compound that modulates cortisol activity by acting as a competitive antagonist at the glucocorticoid receptor (“GR”), one of the body’s two cortisol receptors. The company first made Korlym available to patients commercially in April 2012.
Corcept Therapeutics has discovered three structurally distinct series of proprietary, selective cortisol modulators, all of which share mifepristone’s affinity for GR but, unlike mifepristone, do not bind to the progesterone receptor (“PR”) and so do not cause effects associated with antagonism of progesterone activity, such as termination of pregnancy, endometrial thickening and vaginal bleeding. Development of compounds from these series is in progress.1
Corcept Therapeutics is conducting clinical trials of three compounds from its portfolio of proprietary selective cortisol modulators, including: 
a Phase 2 trial of relacorilant to treat patients with Cushing’s syndrome; (ii) a Phase 1/2 trial of relacorilant combined with Celgene Corporation’s drug Abraxane® (nab-paclitaxel) to treat patients with a variety of solid tumors; (iii) a Phase 1/2 trial of CORT125281 combined with Pfizer Inc.’s androgen receptor antagonist Xtandi® (enzalutamide) to treat patients with castration-resistant prostate cancer (“CRPC”); and (iv) a Phase 1 trial in healthy subjects to assess the safety and tolerability of CORT118335, which the company plan to develop for the treatment of non-alcoholic steatohepatitis (“NASH”) and antipsychotic-induced weight gain.
Cushing’s Syndrome
Korlym to Treat Patients with Cushing’s Syndrome. Cushing’s syndrome is the clinical manifestation of hypercortisolism. It most often affects adults aged 20 to 50. An estimated 10 to 15 of every one million people are newly diagnosed with this syndrome each year, resulting in approximately 3,000 new patients and about 20,000 patients with Cushing’s syndrome in the United States, approximately half of whom are cured by surgery.
The United States Food and Drug Administration (“FDA”) has approved Korlym as a once-daily oral medication for the treatment of hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. The FDA has designated Korlym an “orphan drug” for the treatment of this indication. Orphan drugs receive seven years of marketing exclusivity for the approved indication from the date of drug approval, as well as tax credits for clinical trial costs, marketing application filing fee waivers and assistance from the FDA in the drug development process.
The company's orphan drug marketing exclusivity for Korlym to treat patients with Cushing’s syndrome expires in February 2019. Corcept Therapeutics has three patents listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (known as the “Orange Book”), with terms extending to 2028, 2033 and 2038, respectively, that the company believe would be infringed by a generic competitor for Korlym.
The company sell Korlym exclusively in the United States, using experienced sales representatives targeting the endocrinologists and other specialists caring for patients with Cushing’s syndrome. The company also reach patients directly through web-based initiatives and interactions with patient groups. Because many people who suffer from Cushing’s syndrome are undiagnosed or inadequately treated, Corcept Therapeutics has developed and continue to refine and expand programs to educate physicians and patients about diagnosis of this syndrome and the role cortisol modulators can play in treating the disease. In addition, Corcept Therapeutics has a field-based force of medical science liaisons.
The company use one specialty pharmacy and one specialty distributor to distribute Korlym and provide logistical support to physicians and patients. The company's policy is that no patient with Cushing’s syndrome will be denied access to Korlym for financial reasons. To help it achieve that goal, the company fund its own patient support programs and donate money to independent charitable foundations that help patients cover the cost of all aspects of their Cushing’s syndrome care, whether or not their care includes taking Korlym.
Relacorilant to Treat Patients with Cushing’s Syndrome. Corcept Therapeutics has completed enrollment in a 30 patient, Phase 2 trial of its proprietary, selective cortisol modulator, relacorilant, to treat patients with Cushing’s syndrome. Relacorilant shares Korlym’s affinity for GR. Unlike Korlym, it has no affinity for PR and so does not cause the effects associated with PR affinity, including endometrial thickening and vaginal bleeding.
The trial is open label and is being conducted at sites in the United States and Europe. The first seventeen patients to enroll in the trial were assigned to a “low-dose” cohort. Results from this cohort were positive, including statistically significant improvements in glucose tolerance and serum osteocalcin (a marker of bone growth that is suppressed in Cushing’s syndrome). Forty-five percent of the patients with uncontrolled hypertension exhibited a five millimeter or greater reduction in systolic or diastolic blood pressure. As expected, patients experienced no progesterone-related side effects. There were no discontinuations due to drug-related adverse events and no serious adverse events.
The trial is fully enrolled. The company plan to start a Phase 3 trial later this year.
FKBP5 Gene Expression Assay. The blood tests available to physicians to diagnosis patients with hypercortisolism and optimize their treatment are imprecise and often fail to identify patients with less severe manifestations of the disease. Corcept Therapeutics has developed an assay to measure expression of the gene FKBP5, which is stimulated by cortisol activity, and conducted analytical validation pursuant to the Clinical Laboratory Improvement Amendments (“CLIA”). The company believe this assay will enable physicians to more easily identify new patients with hypercortisolism and better treat those already in their care.
Oncology
Many types of solid tumors express GR and are potential targets for cortisol modulation therapy, among them triple-negative breast, ovarian, castration-resistant prostate, cervical, and pancreatic cancers, as well as sarcoma and melanoma.
Relacorilant to Treat Patients with Solid-Tumors. Corcept Therapeutics is conducting a Phase 1/2 open label trial of Abraxane in combination with relacorilant to treat solid tumors. As the company identify indications of clinical activity in a particular tumor-type, the company will further test the combination’s efficacy and safety in expansion cohorts of approximately 20 patients. In December 2017, the company opened a cohort to treat patients with metastatic pancreatic cancer. The company continue to explore opening cohorts in patients with other solid tumors, including metastatic triple-negative breast and ovarian cancer. The company may also initiate trials that evaluate relacorilant with other cancer therapies as a treatment for solid tumors, including immunotherapy.
Korlym to Treat Patients with Triple-Negative Breast Cancer (“TNBC”). In December 2016, the company announced the results of its Phase 1/2 trial of Korlym in combination with eribulin (Eisai Inc.’s drug, Halaven®) to treat patients with metastatic TNBC. The trial studied 21 patients with GR-positive tumors, one with GR-negative tumors and one with tumors whose GR status was not known. As determined using the Response Evaluation Criteria in Solid Tumors (“RECIST”), efficacy results were as follows: four patients exhibited a partial response, defined as a 30 percent or greater reduction in tumor size; eight had stable disease; and 11 had progressive disease. Six patients achieved progression-free survival (“PFS”) longer than the upper bound of the 95% confidence interval for PFS (15 weeks) in patients receiving Halaven® monotherapy in a comparable population (Aogi et al., Annals of Oncology 23: 1441-1448, 2012). Median PFS in the trial was 11.1 weeks – compared to 7.2 weeks in the Halaven monotherapy study reported by Aogi.
The company believe the addition of Korlym to chemotherapy warrants further study. University of Chicago investigators are leading a 64-patient double-blind, placebo-controlled, multi-center, Phase 2 trial of Korlym combined with Abraxane to treat patients with TNBC. Celgene is funding the trial. University of Chicago investigators are also conducting a 74-patient, open label trial of Korlym combined with Merck’s drug Keytruda® (pembrolizumab) in patients with advanced HER2-negative and triple-negative breast cancer. Merck is funding the trial. Corcept Therapeutics is providing Korlym to both trials.
Cortisol Modulators to Treat Patients with Castration-Resistant Prostate Cancer (“CRPC”). Because androgens stimulate prostate tumor growth, androgen deprivation is a common treatment for metastatic prostate cancer. Tumors eventually escape androgen deprivation therapy through the proliferation of cells for which cortisol’s stimulation of GR is the primary growth factor. Combining a cortisol modulator with an androgen modulator such as Xtandi may block this escape route.
Corcept Therapeutics has begun dosing patients at sites in the United States and Europe in an open label Phase 1/2 trial of its proprietary, selective cortisol modulator CORT125281 combined with Xtandi in patients with metastatic CRPC.
University of Chicago investigators are leading an 84-patient, controlled, multicenter Phase 2 trial of Korlym combined with Xtandi to treat patients with metastatic CRPC. The Department of Defense and the Prostate Cancer Foundation are funding the trial. Pfizer is providing Xtandi. Corcept Therapeutics is providing Korlym.
Corcept Therapeutics has exclusively licensed patents from the University of Chicago covering the use of cortisol modulators combined with anticancer agents to treat TNBC and with androgen deprivation agents to treat CRPC.
Antipsychotic-Induced Weight Gain and NASH. In animal models, its proprietary selective cortisol modulator CORT118335 potently prevents and reverses the weight gain caused by Eli Lilly and Company’s antipsychotic medication Zyprexa® (olanzapine). These findings replicate data from placebo-controlled clinical trials the company conducted, in which mifepristone (the active ingredient in Korlym) significantly reduced the weight gain and other adverse metabolic effects in healthy subjects administered Zyprexa® or Johnson & Johnson’s antipsychotic medication Risperdal® (risperidone). The company published the results of these trials in the journals Advances in Therapy, Gross et al (2009) and Obesity, Gross et al (2010).
CORT118335 also prevents and reverses non-alcoholic fatty liver disease and liver fibrosis in animal models. The company conducted these pre-clinical studies in response to reports suggesting that cortisol modulation with Korlym may have played a role in reversing fatty liver disease in patients with Cushing’s syndrome. Fatty liver disease is a precursor to NASH.
Corcept Therapeutics is conducting a Phase 1 trial of the safety, tolerability and pharmacokinetics of CORT118335. The company plan to advance the compound to Phase 2 as a potential treatment for antipsychotic-induced weight gain and NASH.
Other Selective Cortisol Modulators
The company's portfolio of proprietary selective cortisol modulators, which includes relacorilant, CORT125281 and CORT118335, consists of more than 500 compounds in three structurally distinct families. All of these compounds potently block GR but not the progesterone, estrogen or androgen receptors. Many of these compounds have demonstrated positive results in animal or in vitro models of cortisol modulation. The company plan to continue identifying new compounds and advancing the most promising of them towards the clinic.
The United States Patent & Trademark Office (“USPTO”) has issued it nine composition of matter patents covering its selective cortisol modulators and 25 method of use patents covering the use of cortisol modulators to treat a wide range of serious disorders, including Cushing’s syndrome. Corcept Therapeutics has exclusively licensed three U.S. method of use patents from Stanford University and five method of use patents from the University of Chicago. The company also own an extensive portfolio of patents in countries around the world. Corcept Therapeutics has applied, and will continue to apply, for U.S. and foreign patents covering the composition and method of use of its product candidates.
Liquidity and Capital Resources
At March 31, 2018, the company had an accumulated deficit of $175.7 million. Since 2012, Corcept Therapeutics has relied on revenues from the sale of Korlym and proceeds from the sale of common stock and the now repaid Financing Agreement with Biopharma to fund its operations.
Based on its current plans, which include fully funding its Cushing’s syndrome commercial operations, conducting Phase 2 and Phase 3 trials of relacorilant in both Cushing’s syndrome and solid tumors, the development of CORT125281 to treat patients with CRPC and CORT118335 to treat patients with antipsychotic-induced weight gain and NASH, the company expect to fund its operations without needing to raise additional funds, although the company may choose to raise additional funds to finance its strategic priorities. If the company were to raise funds, equity financing could be dilutive to stockholders. Debt financing, if available, could involve restrictive covenants. Funds raised through collaborations with other companies may require it to relinquish certain rights in its product candidates.
At March 31, 2018, the company had cash, cash equivalents and marketable securities of $140.4 million, consisting of cash and cash equivalents of $33.1 million and marketable securities of $107.3 million, compared to cash and cash equivalents of $31.1 million and marketable securities of $73.0 million at December 31, 2017. Net cash provided by operating activities for the three months ended March 31, 2018 was $34.4 million, compared to $9.6 million for the three months ended March 31, 2017 primarily due to higher sales volumes and receipt of $12.9 million from its former specialty pharmacy. Net cash used in investing activities for the three months ended March 31, 2018 was $34.3 million, primarily due to purchases of marketable securities, compared to $19.4 million for the three months ended March 31, 2017. Stock option exercises provided $1.9 million for the three months ended March 31, 2018, compared to $1.1 million for the comparable period of 2017. The company made no payments under the Financing Agreement during the three months ended March 31, 2018, compared to $4.8 million during the three months ended March 31, 2017. The company extinguished its obligations under the Financing Agreement in July 2017. No further payments are due.
The cash in its bank accounts and its marketable securities could be affected if the financial institution holding them were to fail or be subject to adverse conditions in the financial markets. Corcept Therapeutics has never experienced a loss or lack of access to cash.
Contractual Obligations and Commercial Commitments
The company's contractual payment obligations and purchase commitments as of December 31, 2017 are disclosed in its Annual Report on Form 10-K for the year ended December 31, 2017, and have not changed materially during the three months ended March 31, 2018.
