Cortisol Modulator Shows Early Signs of Safety, Efficacy in Healthy Volunteers

The glucocorticoid receptor antagonist CORT125134 is safe and has shown preliminary signs of efficacy in healthy volunteers participating in a Phase 1 trial, say researchers in England.

Their study, “Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study,” appeared in the journal Clinical Pharmacology in Drug Development.”

Cortisol signaling is indirectly controlled by the glucocorticoid receptor (GR). When cortisol binds the GR, the receptor becomes activated and migrates to the nucleus, where it regulates the expression of many genes. This influences a myriad of processes, including inflammation, immune response and brain function.

CORT125134, also known as relacorilant, is being developed by Corcept Therapeutics of Menlo Park, California, for Cushing’s disease patients and others who may benefit from it. The drug is a GR antagonist, blocking the receptor’s activity.

In order to evaluate the safety and tolerability of CORT125134, and learn how it behaves in the body, Corcept researchers conduced a Phase 1 trial in healthy subjects.

The British study, conducted at the Quotient Clinical in Nottingham, included 81 adults who received a single ascending-dose of CORT125134 or placebo, and 48 subjects who received multiple-ascending doses of the drug versus placebo.

Single doses were tested in nine distinct groups. Six tested six different doses of CORT125134, one tested a 150 mg dose in subjects receiving a high-fat meal, and two groups included patients receiving prednisone (a well-known GR activator), prednisone plus Korlym (mifepristone), or prednisone plus CORT125134.

Korlym is a medicine approved for Cushing’s  patients with high blood sugar levels due to high cortisol in circulation. But the drug targets the progesterone receptor and is associated with side effects like pregnancy termination and irregular vaginal bleeding.

Multiple doses, given for up to 14 days, were tested in four additional cohorts. Researchers observed that CORT125134 was rapidly absorbed and eliminated, presenting a suitable profile for once-daily dosing.

Efficacy was determined by CORT125134’s ability to counteract the effects of prednisone. In addition, a single dose of 500 mg or multiple dosing with 250 mg had similar effects as those seen with 600 mg of Korlym — the therapeutic dose used for Cushing’s treatments.

Most common treatment-related adverse events reported in the single-ascending dose part of the study were nausea, vomiting and thirst; most were mild. In those given multiple-ascending doses, adverse events included mild musculoskeletal and connective tissue disorders, as well as gastrointestinal system disorders.

Multiple 500 mg doses exceeded the maximum tolerated dose, as it led to musculoskeletal symptoms that forced researchers to stop treatment.

“This first-in-human study has demonstrated that CORT125134 is well tolerated following single doses up to 500 mg and repeated doses up to 250 mg once daily for 14 days,” researchers wrote. “Pharmacological activity was confirmed following the administration of a single 500-mg dose and daily administration of 250 mg.”

Corcept is now enrolling participants into a Phase 2 open-label trial (NCT02804750) to evaluate CORT125134 in patients with Cushing’s syndrome. This trial is being conducted in the United States and Europe and will include 80 participants. Top-line results are expected in the first quarter of 2018.

From https://cushingsdiseasenews.com/2017/10/10/phase-1-data-demonstrates-efficacy-safety-of-cort125134-in-healthy-volunteers/

Cushing’s Testing at NIH

Rank Status Study
1 Recruiting Study to Evaluate CORT125134 in Patients With Cushing’s Syndrome

Condition: Cushing’s Syndrome
Intervention: Drug: CORT125134
2 Recruiting Cushing’s Disease Complications

Condition: Cushing’s Disease
Intervention: Other: Exams and questionnaires
3 Recruiting The Accuracy of Late Night Urinary Free Cortisol/Creatinine and Hair Cortisol in Cushing’s Syndrome Diagnosis

Condition: Cushing Syndrome
Intervention:
4 Recruiting Treatment for Endogenous Cushing’s Syndrome

Condition: Endogenous Cushing’s Syndrome
Intervention: Drug: COR-003
5 Recruiting Saliva Cortisol Measurement as a Screening Test for Suspicious Cushings Syndrome in Children.

Condition: Cushings Syndrome
Intervention: Other: Children refered to the obesity clinic
6 Recruiting Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing’s Disease

Condition: Cushing’s Disease
Intervention: Drug: LCI699
7 Recruiting Treatment of Cushing’s Disease With R-roscovitine

Condition: Cushings Disease
Intervention: Drug: R-roscovitine
8 Recruiting A Study of ATR-101 for the Treatment of Endogenous Cushing’s Syndrome

Condition: Cushing Syndrome
Interventions: Drug: ATR-101;   Drug: Placebos
9 Recruiting Evaluation of 68Ga-DOTATATE PET/CT, Octreotide and F-DOPA PET Imaging in Patients With Ectopic Cushing Syndrome

Condition: Cushing Syndrome
Interventions: Drug: F-DOPA PET Scan;   Drug: Mifepristone;   Drug: Ga-DOTATATE;   Drug: Octreoscan;   Other: CT, MRI
10 Not yet recruiting Endocrine Cardiomyopathy in Cushing Syndrome: Response to Cyclic GMP PDE5 inhibitOrs

Condition: Cushing’s Syndrome Cardiomyopathy
Intervention: Drug: Tadalafil
11 Recruiting Long-term Beneficial Metabolic Effects of Adrenalectomy in Subclinical Cushing’s Syndrome of Adrenal Incidentaloma

Condition: Cushing Syndrome
Intervention: Procedure: surgery
12 Recruiting Long Term Safety and Efficacy of Pasireotide s.c. in Patients With Cushing’s Disease

Condition: Cushings Disease
Intervention: Drug: SOM230
13 Recruiting New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome

Condition: Cushing Syndrome
Interventions: Drug: Pentetreotide;   Drug: 18-F-fluorodeoxyglucose;   Drug: (18F)-L-3,4-dihydroxyophenylalanine (18F-DOPA)
14 Not yet recruiting Targeting Iatrogenic Cushing’s Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition

Condition: Iatrogenic Cushing’s Disease
Interventions: Drug: AZD4017 and prednisolone;   Drug: Placebo Oral Tablet and prednisolone
15 Not yet recruiting Assessment of Persistent Cognitive Impairment After Cure of Cushing’s Disease

Condition: Cushing’s Disease
Intervention: Device: Virtual radial task in 3D
16 Recruiting Biomarker Expression in Patients With ACTH-Dependent Cushing’s Syndrome Before and After Surgery

Condition: Cushing’s Syndrome
Intervention:
17 Recruiting Efficacy and Safety Evaluation of Osilodrostat in Cushing’s Disease

Condition: Cushing’s Disease
Interventions: Drug: osilodrostat;   Drug: osilodrostat Placebo
18 Recruiting Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome

Condition: Cushing’s Syndrome
Intervention: Drug: metyrapone
19 Recruiting Adrenal Venous Sampling in Patients With Overt or Subclinical Cushings Syndrome, and Bilateral Adrenal Tumors

Condition: Cushing Syndrome
Intervention: Radiation: Adrenal venous sampling
20 Recruiting Glycemic Fluctuations in Newly Diagnosed Growth Hormone-Secreting Pituitary Adenoma and Cushing Syndrome Subjects

Condition: Pituitary Adenoma
Intervention: Device: continuous glucose monitoring
Rank Status Study
21 Recruiting Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing’s Disease

Conditions: Cushing’s Disease;   Corticotrophin Adenoma
Intervention: Drug: Gefitinib
22 Recruiting Cardiac Steatosis in Cushing’s Syndrome

Conditions: Endocrine System Disease;   Cardiovascular Imaging
Intervention: Other: 1H magnetic resonance spectroscopy and CMRI
23 Recruiting Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing’s Disease or Acromegaly

Conditions: Cushing’s Disease;   Acromegaly
Interventions: Drug: Pasireotide s.c.;   Drug: Sitagliptin;   Drug: Liraglutide;   Drug: Insulin;   Drug: Pasireotide LAR;   Drug: Metformin
24 Recruiting Study of Efficacy and Safety of Osilodrostat in Cushing’s Syndrome

Conditions: Cushing’s Syndrome;   Ectopic Corticotropin Syndrome;   Adrenal Adenoma;   Adrenal Carcinoma;   AIMAH;   PPNAD
Intervention: Drug: Osilodrostat
25 Recruiting Effects of Hormone Stimulation on Brain Scans for Cushing s Disease

Condition: Pituitary Neoplasm
Intervention: Drug: Acthrel
26 Recruiting Does Serum-DXM Increase Diagnostic Accuracy of the Overnight DXM Suppression Test in the Work-up of Cushing’s Syndrome?

Conditions: Cushing’s Syndrome;   Adrenal Incidentalomas;   Alcoholism;   Obesity
Intervention:
27 Recruiting Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome

Condition: Adrenal Tumour With Mild Hypercortisolism
Intervention: Procedure: Adrenalectomy
28 Recruiting Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism

Conditions: Hypercortisolism;   Cushing Syndrome
Interventions: Procedure: Adrenalectomy;   Other: Observation
29 Not yet recruiting Dynamic Hormone Diagnostics in Endocrine Disease

Conditions: Adrenal Insufficiency;   Congenital Adrenal Hyperplasia;   Cushing Syndrome;   Growth Hormone Deficiency;   Acromegaly;   Primary Hyperaldosteronism
Intervention: Other: 27 hour subcutaneous fluid sampling
30 Recruiting An Investigation of Pituitary Tumors and Related Hypothalmic Disorders

Conditions: Abnormalities;   Craniopharyngioma;   Cushing’s Syndrome;   Endocrine Disease;   Pituitary Neoplasm
Intervention:
31 Recruiting Ga-68-DOTATOC -PET in the Management of Pituitary Tumours

Condition: Pituitary Tumours
Intervention: Procedure: Gallium-68 DOTATOC PET
32 Recruiting Efficacy of Mifepristone in Males With Type 2 Diabetes Mellitus

Conditions: Type 2 Diabetes Mellitus;   Insulin Resistance
Interventions: Drug: Mifepristone 600 mg daily;   Drug: Placebo
33 Recruiting Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy

Conditions: Pituitary Adenomas;   Prolactinomas
Intervention: Drug: Lapatinib
34 Recruiting Mutations of Glucocorticoid Receptor in Bilateral Adrenal Hyperplasia

Condition: General Glucocorticoid Resistance
Intervention: Genetic: blood collection for mutation characterization
35 Recruiting Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex

Conditions: Cushing’s Syndrome;   Hereditary Neoplastic Syndrome;   Lentigo;   Neoplasm;   Testicular Neoplasm
Intervention:
36 Not yet recruiting Reduction by Pasireotide of the Effluent Volume in High-output Enterostomy in Patients Refractory to Usual Medical Treatment

Condition: Enterostomy
Interventions: Drug: Pasireotide;   Drug: Placebo
37 Recruiting Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B.

Condition: Breast Cancer
Intervention: Drug: Mifepristone
38 Recruiting SOM230 Ectopic ACTH-producing Tumors

Condition: Ectopic ACTH Syndrome
Intervention: Drug: Pasireotide
39 Recruiting Decreasing Rates of Intraurethral Catheterization Postoperatively in Spine Surgery

Condition: Post-operative Urinary Retention
Interventions: Drug: Tamsulosin;   Drug: Placebo
40 Recruiting Adrenal Tumors – Pathogenesis and Therapy

Conditions: Adrenal Tumors;   Adrenocortical Carcinoma;   Cushing Syndrome;   Conn Syndrome;   Pheochromocytoma
Intervention:

Promising Pre-Clinical and Phase 1 Data Support Advance of Selective Cortisol Modulator CORT125134 as Potential Treatment for Cushing’s Syndrome and Solid-Tumor Cancers

MENLO PARK, CA–(Marketwired – Apr 28, 2016) –  Corcept Therapeutics Incorporated (NASDAQ: CORT), a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol, today released data supporting the clinical advancement of its proprietary, selective cortisol modulator, CORT125134. The company has begun recruiting patients for a Phase 1/2 trial of the compound to treat patients with solid-tumor cancers. It also expects to begin recruiting patients for a Phase 2 study of CORT125134 to treat patients with Cushing’s syndrome this quarter.

“Advancing CORT125134 is an important step in protecting and extending our growing Cushing’s syndrome franchise and in developing cortisol modulation for a wide range of other serious diseases,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “This selective cortisol modulator has shown great promise. We are optimistic that, for some patients with Cushing’s syndrome, CORT125134 may be even better than our approved product, Korlym® — just as effective, but without the side effects associated with Korlym’s affinity for the progesterone receptor. Equally important, we look forward to investigating its potential as a treatment for solid-tumor cancers.”

CORT125134 is the lead compound in Corcept’s proprietary portfolio of selective cortisol modulators. It is a non-steroidal competitive antagonist of the glucocorticoid receptor (GR) that does not bind to the body’s other hormone receptors, including the progesterone receptor (PR). Korlym’s interaction with PR results in termination of pregnancy and can cause endometrial thickening and irregular vaginal bleeding in some women. CORT125134 is proprietary to Corcept and is protected by composition of matter and method of use patents extending to 2033.

Advancement to Phase 2 Trials Supported by Positive Pre-Clinical and Phase 1 Data
“The data generated so far make this compound a promising candidate to treat both Cushing’s syndrome and, potentially, a number of solid-tumor cancers,” said Hazel Hunt, Ph.D., Corcept’s Vice President of Research. “Its Phase 1 data showed that it shares Korlym’s potent affinity for GR, one of the receptors to which cortisol binds. Our clinical testing showed that it can prevent the effects of the steroid prednisone, a commonly-used synthetic GR agonist. Preventing the effects of prednisone is a very important finding, as it mirrors the essential quality of an effective medical treatment for patients with Cushing’s syndrome.”

Corcept’s Phase 1 trial of CORT125134 enrolled 124 healthy volunteers. GR antagonism was tested by measuring CORT125134’s ability to modulate prednisone’s effects on serum osteocalcin, white blood cell counts, glucose metabolism and expression of the FKBP5 gene — a marker of GR activation. With respect to all parameters, CORT125134 was as potent a modulator of prednisone’s activity as Korlym (see Figure 1; p value < 0.0003).

Pharmacokinetic data indicate that CORT125134 is suitable for once-daily dosing.

“Positive Phase 1 data, together with encouraging pre-clinical results, prompted us to advance CORT125134 as a treatment for Cushing’s syndrome as well as a treatment for cancer,” continued Dr. Hunt. “Substantial pre-clinical and clinical research suggests that cortisol modulation increases the effectiveness of chemotherapy in some solid-tumor cancers. Pre-clinical data suggest that CORT125134 may be even more potent than Korlym in treating some tumor types.”

Corcept and investigators at the University of Chicago have studied the effectiveness of CORT125134 in transgenic mouse models of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer. Mice implanted with TNBC tumor cells were treated with a combination of paclitaxel and CORT125134. Mifepristone (the active ingredient in Korlym) in combination with paclitaxel served as a positive control. As expected, the combination of mifepristone and paclitaxel significantly slowed tumor progression. However, the combination of CORT125134 and paclitaxel slowed it even more (see Figure 2; p value = 0.0004). In a similar experiment, castrated mice seeded with prostate cancer tumor cells were treated with either mifepristone or CORT125134. The outcome was comparable to the TNBC study: When combined with castration (which in humans would be achieved pharmacologically by the administration of an androgen receptor antagonist such as enzalutamide), mifepristone retarded tumor progression, but CORT125134 had an even more pronounced effect (see Figure 3; p value = 0.037).

CORT125134 may also enhance the efficacy of immune-modulation therapy. In an animal model of colon cancer, the addition of CORT125134 to PD-1 monotherapy significantly slowed tumor progression (see Figure 4; p value = 0.013):

Oncology Trial Design
This trial’s initial phase will investigate nab-paclitaxel in combination with CORT125134 to treat any solid-tumor cancer susceptible to treatment with nab-paclitaxel. (“Nab-paclitaxel” is the generic name for Celgene’s drug, Abraxane®.) Once a maximum tolerated dose is identified, Corcept plans to open one or more expansion cohorts, each containing 20 patients, to test the combination’s efficacy in one or more of the solid-tumor cancers studied in the dose-finding phase. Possible target indications include TNBC, castration-resistant prostate cancer, ovarian cancer, pancreatic cancer and sarcoma. Other dose-finding cohorts may be enrolled to study CORT125134 in combination with different companion therapeutic agents, including PD-1 inhibitors.

The trial is open-label and will be conducted at sites in the United States, the first of which is open and has begun screening patients.

“That we are advancing the same selective cortisol modulator as a treatment for both a metabolic disease and one or more oncologic indications is a testament to the broad therapeutic potential of cortisol modulation,” said Robert S. Fishman, MD, Corcept’s Chief Medical Officer. “We are excited to start these trials.”

Cushing’s Syndrome Trial Design
This Phase 2 trial of CORT125134 will enroll 30 patients with endogenous Cushing’s syndrome. Patients will be assigned to a low- or high-dose group and will receive CORT125134 for 12 weeks, with up-titration possible in each group at weeks four and eight. The trial will be open label. Study centers will be located in both the European Union and the United States.

About Korlym®
Korlym modulates the effect of cortisol at GR, one of the two receptors to which cortisol binds, thereby inhibiting the effects of excess cortisol in patients with Cushing’s syndrome. Since 2012, Corcept has made Korlym available as a once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.

About Cushing’s Syndrome
Endogenous Cushing’s syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing’s syndrome is an orphan indication that most commonly affects adults aged 20-50. An estimated 10-15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients annually in the United States. An estimated 20,000 patients in the United States have Cushing’s syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Triple-Negative Breast Cancer
Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth — estrogen, progesterone and the HER-2/neu gene — are not present. Because the tumor cells lack the necessary receptors, treatments that target estrogen, progesterone and HER-2 receptors are ineffective. In 2013, approximately 40,000 women were diagnosed with TNBC. It is estimated that more than 75 percent of these women’s tumor cells expressed the GR receptor to which cortisol binds. There is no FDA-approved treatment and neither a targeted treatment nor an approved standard chemotherapy regimen for relapsed TNBC patients exists.

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol. Korlym, a first-generation cortisol modulator, is the company’s first FDA-approved medication. The company is conducting a Phase 1/2 trial of mifepristone for the treatment of TNBC, a Phase 1/2 trial of CORT125134 to treat a variety of solid-tumor cancers and has a proprietary portfolio of other selective GR antagonists that modulate the effects of cortisol but not progesterone. Corcept owns extensive intellectual property covering the use of cortisol modulators, including mifepristone and CORT125134, in the treatment of a wide variety of metabolic, oncologic and psychiatric disorders. It also holds composition of matter patents for CORT125134 and its other selective cortisol modulators.

Forward-Looking Statements
Statements made in this news release, other than statements of historical fact, are forward-looking statements. These forward-looking statements, including statements regarding the initiation and advancement of clinical trials and the development of Corcept’s pre-clinical and clinical pipeline, are subject to known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements, including the pace of enrollment in or the outcome of the company’s Phase 1/2 study of CORT125134 to treat solid-tumor cancers and planned Phase 2 trial of CORT125134 to treat patients with Cushing’s syndrome, the effects of rapid technological change and competition, the protections afforded by Corcept’s intellectual property rights, or the cost, pace and success of Corcept’s other product development efforts. These and other risks are set forth in the company’s SEC filings, all of which are available from the company’s website (www.corcept.com) or from the SEC’s website (www.sec.gov). Corcept disclaims any intention or duty to update any forward-looking statement made in this news release.

Abraxane® is a registered trademark of Celgene Corporation.

From http://www.marketwired.com/press-release/promising-pre-clinical-phase-1-data-support-advance-selective-cortisol-modulator-cort125134-nasdaq-cort-2119635.htm

 

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