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Updated Clinical Milestones - Corcept Therapeutics (CORT)

07:29 EST 10 Nov 2017 | Biotech Watcher

Our Q3-2017 commentary on Corcept Therapeutics (CORT) utilized an older version of the milestones table. Updated milestones tables are provided here. It’s a gaudy portfolio, although our enthusiasm is tempered by the slow pace from the academic investigators.

Of special note, the University of Chicago investigators will launch its own clinical trial of mifepristone paired with pembrolizumab, an anti-PD1 checkpoint inhibitor, in December 2017. At least we hope that’s the case.

Corcept will pair CORT125134 (relacorilant) with a checkpoint inhibitor with its own in-house trial. Although it may launch after the University of Chicago’s study, we would not be surprised if its results are released first.

Background Information

For a brief refresher on how Corcept’s drugs may work with a checkpoint inhibitor, you can review our earlier articles.

Preclinical Studies (Sept. 20, 2017)

Milestones

Corcept Sponsored Trials

Metabolic Indications
While Cushing’s syndrome is a recognized indication, its successful treatment by Korlym should be viewed as “proof of concept” for working in other metabolic indications involving diabetes, obesity, and high blood pressure. This would be especially true with mild cases of Cushing’s syndrome involving small benign tumors on the adrenal gland (adrenal incidentilomas).
Cushing’s Syndrome
There are perhaps 7,000 to 10,000 patients in the USA that should benefit from this treatment. Nevertheless, the diagnostic category may greatly expand with middle-aged and older adults who are impacted byadrenal incidentilomas. This used to be called “subclinical Cushing’s Syndrome”. Korlym or a next-generation drug targets the metabolic consequences of the disease.

CORT 125134 (AKA recorilant) is a next generation, selective GR-antagonist. It is good at blocking the glucocorticoid receptor (GR), but unlike Korlym it does not block the progesterone receptors. It should lack some of Korlym’s side effects, especially its ability to terminate pregnancies. 
Phase IIa Top-Line Results (30 pts) - Recorilant
  Group 1: 100 mg/day for 4 weeks, then 150 mg/day for 4 weeks,
  then 200 mg/day for 4 weeks.
  Group 2: 250 mg/day for 4 weeks, then 300 mg/day for 4 weeks,
  then 350 mg/day for 4 weeks.
Q1-2018
Phase III Launch
  Relacorilant
Q3-2018
CORT118335
CEO Belanoff stated that CORT118335 produced promising results in animal models of fatty liver disease including a reduction of white fat in the liver and other organs. Additional work with metabolic syndrome is being conducted by independent investigators.

Cushing’s syndrome patients, especially those with mild disease, are “human models” for metabolic syndrome. Corcept’s patent for treating fatty liver disease is now published in the US and Europe.

Why CORT118335 rather than Korlym?

Cushing’s syndrome requires a drug that has wide dispersion through the body (Korlym). On the other hand, metabolic syndrome, especially involving NASH disease, requires a drug that is well absorbed by the liver (CORT118335). CORT118335’s targeting is inappropriate for Cushing’s syndrome. 

About two years ago, we also underscoredCORT118335’s potential use for treating alcohol withdrawal in animal models.
Metabolic Syndrome
In the Phase 1 trial, it is a 3-part, single center study of single and multiple ascending doses in healthy subjects.

Part 1 of the study is a double-blind, randomized, placebo-controlled assessment of single-ascending doses (SAD) of CORT118335. Subjects will be enrolled sequentially into 1 of up 7 cohorts (Cohorts A to G), each containing 8 subjects. Within each cohort, 6 subjects will be randomly assigned to receive a single dose of CORT118335 and 2 subjects will be randomly assigned to receive a single dose of matching placebo.

Part 2 Cohort A, food-effect, will be an open-label 2-way crossover study in one cohort of 12 subjects, randomized in a 1:1 ratio to receive a single dose of CORT118335 once after an overnight fast and once after a high-fat breakfast or the alternate sequence, over 2 study periods separated by a washout of at least 7 days/5 half-lives.

Part 2 Cohort B, PD cohort, will be a double-blind, randomized, placebo-controlled, 3-way cross-over study and will serve as proof of pharmacological effect (GR modulation) for CORT118335. Subjects will be randomized in a 1:1:1 ratio to receive placebo, and two dose levels of CORT118335 in one of three treatment sequences across 3 study periods separated by washouts of at least 7 days/5 half-lives. On each occasion, the ability of CORT118335 to ameliorate the pharmacological effects of a single dose of prednisone will be measured.

Part 3 is a double-blind, randomized, placebo-controlled assessment of multiple oral ascending doses of CORT118335. Subjects will be enrolled sequentially into 1 of up to 4 cohorts (Cohorts A to D), each containing 12 subjects. Within each cohort, 9 subjects will be randomly assigned to receive CORT118335 and 3 subjects to receive matching placebo daily for 14 days. There is an option for the last cohort (Cohort D) to undergo prednisone challenge before and after treatment with CORT118335 or placebo to study the effects of CORT118335 on the response to prednisone challenge.
  Phase 1 Results – 128 Healthy Patients – Dose Ranging, Double-Blind
  CORT118335 ± Prednisone, Glucose, Placebo
Q2-2018
  Phase 2 Launch – Metabolic Syndrome
  CORT118335
Q3-2018
Cancer Program
Solid Tumors
CORT125134 (recorilant) is in a Phase I/II trial to treat solid tumors including breast and ovarian cancer. In the Phase I part, CORT125134 is paired with Abraxane. Dose cohorts are employed to seek the maximum tolerated dose (MTD). There will likely be nothing interesting to report until most of the cohorts have been treated; the beginning dose levels are so low that efficacy is moot.

Recorilant has interesting promise. Besides lacking a couple side effects associated with Korlym, the animal models show potential superiority for treating solid tumors.

Recorilant appears to perform better than Korlym in mouse models of TNBC and castration-resistant prostate cancer. It also demonstrated good results with ovarian cancer cells in the lab. It is similar to Korlym but lacks some of its side effects.

If the trial progresses to Phase II, then recorilant will be paired with different agents, including a checkpoint inhibitor.
Phase I Results – Recorilant + Abraxane – (Up to 42 Pts)
  Maximum Tolerated Dose, Advanced Cancer
2H-2017*
  Phase II Launch – Expansion Cohorts – (~20 pts per Cohort, 84 total)
  Recorilant + Abraxane (ovarian & triple-negative breast cancer)
  Recorilant + Different Agents (inc. checkpoint inhibitors)
Q4-2017
Prostate Cancer
CEO Belanoff mentioned CORT 125281 stood out with treating rodent models of prostate cancer including castrated animals. There will be close attention from the cancer community on trials involving GR antagonists for treating prostate cancers that are resistant to enzalutamide and abiraterone.  

The Phase 1a trial involves separate single ascending dose (SAD) and then later a multiple ascending dose (MAD) cohorts. The MAD part of the study will be double-blind, randomized, placebo-controlled and parallel-group with respect to CORT125281.

If the Phase I goes well, Corcept plans to pair CORT125281 with Xtandi. 

The University of Chicago is also running a trial involving Korlym and the trial should be completed in December 2017 with results being released soon after completion. 
  Phase Ia Results – CORT125281 + Xtandi – 50 Healthy Patients
Mid-2018
  Phase 1b Launch – CORT125281 + Xtandi – Metastatic Prostate Cancer
Nov. 2017
   *Guesstimate

 
Independent Investigator Sponsored Trials
Cancer Program
GR+ Triple Negative Breast Cancer
Because of the experience with a recent trial (involving carboplatin and gemcitabine), investigators are reportedly limiting the number of patients with more than 2 previous chemotherapy regimens.
  Phase II Results (University of Chicago) (64 pts)
  Korlym + Abraxane
2H-2018
Advanced HER2-negative Breast Cancer & Checkpoint Inhibitor
The study will include a safety lead in of ten patients. Patients who are deemed eligible and have signed informed consent will be treated with pembrolizumab (Keytruda) at a fixed dose of 200 mg intravenously on day 1 of each 21-day cycle for each dose level. Mifepristone 300mg PO will be administered daily starting the week prior to pembrolizumab.

Pembrolizumab is an approved anti-PD-1 mAb, marketed by Merck.

The first cohort of 10 patients will be evaluated for safety (Phase 1). During dose expansion, the study will include triple-negative breast cancer patients. After successful Phase 1 safety is passes, then both cohorts will be subjected to dose expansion.

Cohort 1: Hormone receptor positive, treatment refractory breast cancer (25 to 34 pts)
Cohort 2: Triple Negative breast cancer (27 to 40 pts)
  Pembrolizumab + Mifepristone - (University of Chicago) (74 pts)
Dec. 2017
  Pembrolizumab + Mifepristone - (University of Chicago) (74 pts)
2H-2020*
Prostate Cancer
  Xtandi ± Mifepristone - (University of Chicago) - 108 pts
Q1-2018*
Advanced Non-Small Cell Lung Cancer
Corcept is listed as a collaborator in the study. It is an open-label design, in patients with metastatic NSCLC who have failed 2+ prior chemotherapies. It is hoped that mifepristone as a monotherapy will increase the median progression-free survival time to 15 weeks and overall survival time of 16 months. We are a bit queasy because we do not view Corcept’s drugs as monotherapies for treating cancer.
  Phase II Top-line Results(Cooper Institute) (40 Pts)
  300mg/day in 28-day cycles
2019*
Addiction Disorders
Recentcommentary implicates the use of glucocorticoid antagonists, including mifepristone, for treating general addiction problems.
Alcohol Withdrawal – Prior Phase IIa study reported positive results with untreated alcoholics. There is also an “observational” study in which cortisol levels predicted the drinking intensity in alcoholics.
  Phase II Results (Scripps – San Diego) (150 pts)
  Placebo, 600 mg, 1200 mg/day; 7 days
Q3-2020*
  Phase I/II Results (Brown University) (20 pts)
  Crossover, Double-Blind, 600 mg/day, 7 days
Q1-2018*
  Phase IV MIFCOG TRIAL Results(King’s College – London) (120 pts)
Cognitive Impairment & Depression in Alcoholics
Double-blind, 12-Month Follow-up 
  600 mg/daily for 1st week, 400 mg/daily for 2nd week
Q4-2017*
  Phase II Results in Heavy Drinkers (Johns Hopkins) (150 pts)
  6 doses of Mifepristone vs. CORT125134 vs. Placebo
Q1-2022
Cocaine Relapse Prevention
The trial information was updated in Q4-2016. It is still unclear when the results will be released, but at least the study recruitment is over (it took 6 years).
  Phase II/III Results (NY State Psychiatric Institute) (59 pts)
  600mg, 3x/wk. for 4 weeks 
Q1-2018*
Tobacco Use Disorder - Mifepristone may be a potential treatment for Tobacco Use Disorder (TUD). No previous studies have examined the therapeutic potential of mifepristone for TUD. There is indirectevidence including the relation between cortisol levels and nicotine craving. but this study is a first attempt at exploring a direct intervention.

This is a double-blind, placebo-controlled design on the effects of a 7-day treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal severity, and smoking behavior.
  Phase 1a Results (Yale University) (40 pts)
  600mg, daily, for 7 days
Q4-2019*
Metabolic Syndrome
A recent study treated patients who suffered from benign adrenal incidentilomas (adrenal tumors) with diabetes and mild hypercortisolism. Mifepristone treated patients experienced: decreased waist size and insulin resistance, and improved quality of life. These (very) mild cases of Cushing’s syndrome should be viewed as a human proof of concept for treating other forms of metabolic syndrome.
Diabetes, Obesity
  Crossover, Double-Blind
Q1-2018*
Mid-2020
Metabolic Markers, Depression in Older Adults
Middle-Aged & Older Adults (Stanford University) – Results – 40 pts
2H-2017*
Miscellaneous
Central Serous Chorioretinopathy – We are not sure what to expect with this study. While cortisol plays a role in some CSCR patients, we would not be surprised if the study fails to show efficacy across all patients. It represents a small market and so we aren’t too concerned.  
  Phase II Top-line Results  (STOMP-CSCR) (30 pts)
  300mg or 900mg/day for 4 weeks
AAO 2017
Nov. 11-14
    *Guesstimate

(At the time this post was written, one or more BioWatch authors held a position in CORT)

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Original Article: Updated Clinical Milestones - Corcept Therapeutics (CORT)

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