Corcept Therapeutics Picks Up Speed - Near-Term Clinical Milestones Ahead

02:22 EDT 10 Oct 2018 | Biotech Watcher

On Monday, October 1, 2018, Corcept Therapeutics announcedthat relacorilant received an orphan designation from the FDA for treating pancreatic cancer. This article examines the following:

1. A primer on orphan drugs and orphan oncology.

2. A new cancer trial involving relacorilant to treat prostate cancer.

3. Expanded List of Clinical Milestones

Orphan Drug Designation

The Orphan Drugincentives were enacted to encourage drug development for rare diseases. In the United States, a rare disease includes under 200,000 patients.

Orphan Disease Classification
United States	Afflicts less than 200,000 patients
European Union	Fewer than 1 case per 2,000 (around 250,000)
Japan	Fewer than 1 per 2,500 (around 50,000)
Australia	Prevalence less than 1 in 10,000 (less than 2,000 total)

·There are currently about 7,500 rare diseases that qualify as orphan indications plus weekly additions

·The number of FDA Orphan Drug Approvals ↑ in recent years

·7% of the population has a rare disease

·25M in the USA, 30M in the EU, 60M worldwide

Orphan Incentives
	USA	European Union	Japan
Tax Credit	50% of Clinical Trial Costs	Depends upon each country	6% for any study up to 10% of total tax
Research Grants	Yes	Yes	Yes
Market Exclusivity	7 Years	10 Years	-

·Orphan designated drug submissions have a higher chance of approval (the figures vary)

·Orphan drugs are historically approved 40% faster – nearly 75% received priority review

·Over 25% received breakthrough therapy designation

Clinical trials for Orphan drugs are typically permitted to be smaller with flexible designs. This is in large part due to the difficulty in recruiting large numbers of patients as well as the desire to rapidly facilitate approval.

Orphan Oncology

Oncology Drug Development[1]
Non-Orphans (N = 12)	Orphans (N = 15)
Mean for Approval = 3.8 Pivotal Trials	Mean for Approval = 1.7 Pivotal Trials
Pivotal Trial Design 80% were randomized 33% were double-blinded	Pivotal Trial Design 30% were randomized 4% were double-blinded
Primary Endpoints Overall Survival = 27% Disease Response = 27%	Primary Endpoints Overall Survival = 8% Disease Response = 68%
Mean Pivotal Sample Size = 290	Mean Pivotal Sample Size = 96

Rare Cancers

Most cancers are rare diseases, except for the “Big 4”: breast, prostate, lung, and colorectal. Many subtypes within the “Big 4” qualify as rare. For example, only 15% of breast cancers are diagnosed as “Triple-Negative”. About 1/3 of orphan designations are for rare cancers.

In Corcept’s case, GR+ Triple Negative Breast Cancer and GR+ ER- Breast Cancer are assuredly rare.

Pancreatic cancer is the fourth leading cause of cancer-associated mortality, with a five-year survival rate of five percent. In the United States, an estimated 33,000 patients are diagnosed with the disease each year. (Corcept Press Release)

However, the incidence of pancreatic cancer appears to be rising, and a recent report speculates it may be related to increasing obesity and diabetes. There are expert predictions that it will soon become the 2nd leading cause of cancer-related deaths

Pancreatic Cancer

We recently summarizedour thoughts about pancreatic cancer treatment and Corcept’s prospects.

1. Pancreatic cancer is a terrifyingly difficult cancer to treat, traditionally effective cancer drugs are ineffective;

2. Clinically meaningful progress means lengthening survival by mere weeks. Stable disease (SD) is just as big a step as a partial response (PD) in other cancers.

3.Oncology investors are used to seeing giant steps in survival and response rates. Relacorilant’s earlier results involved “stable disease”, and that’s good treatment performance for pancreatic cancer.

Corcept is treating very sick cancer patients. Corcept’s ongoing and future studies may be the first to treat so many 3^rd-line and 4^th-line therapy patients.

New Prostate Cancer Trial

An independent investigator study (University of Chicago) involves relacorilant with Xtandi to treat metastatic castration resistant prostate cancer (mCRPC) in an open-label design. This contrasts with the ongoing studies involving Korlym (mifepristone) and CORT125281 also paired with Xtandi in similar patient populations.

Korlym + Xtandi (Open-Label, Randomized, 108 Pts)

CORT125281 + Xtandi (Open-Label, Dose-expansion, 80 Pts)

Relacorilant + Xtandi (Open-Label, Single-group, 24 Pts)

Rationale

1. It’s a logical next step. Relacorilant is showing early signals for treating ovarian and pancreatic cancers. That provides enough motivation by itself. Were there specific signals for prostate cancer patients too?

2) The NCI is a listed collaborator. They’re paying for some, if not all of it. While the independent investigator strategy has its drawbacks, this isn’t one of them.

3) Beyond efficacy, relacorilant’s relative lack of side effects motivates a clinical trial in almost everything that Korlym is applied. Are there efficacy signals in the just completed prostate cancer trial (involving Korlym and Xtandi) with the University of Chicago?

4) When the results arrive for this new relacorilant study, there should be meaningful results from all three studies.

Design

24 patients will be enrolled in 6 patient cohorts with a 6+3 design and a 28 day DLT period. Doses of relacorilant, enzalutamide will be adjusted based on safety and pharmacokinetics (PK). Once a safe dose with appropriate drug levels (PK) has been established, the cohort will be expanded to a total of 12 patients to refine safety and PK at the recommended phase II dose (RP2D).

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 incidentalomas).
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 incidentalomas. 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* *relacorilant*) 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 (PR). It lacks some of Korlym’s off-target effects, especially its ability to terminate pregnancies.
Phase 2a Top-Line High Dose Results (35 pts) – Relacorilant Group 2: 250 mg/day for 4 weeks, then 300 mg/day for 4 weeks, then 350 mg/day for 4 weeks, and then 400 mg/day for 4 weeks.	October 2018
Phase 2 Extension – Ongoing Results (75 pts) – Relacorilant	TBA Q3- 2021 (Final)
Phase III GRACE STUDY Launch – Randomized Withdrawal 130 Patients -Open-label dose titration, then responders enter randomized withdrawal - Relacorilant vs. Placebo	Oct/Nov 2018
Phase III GRACE STUDY Results – Randomized Withdrawal 130 Patients - Relacorilant vs. Placebo	1H-2020*

CORT118335 CEO Belanoff stated thatCORT118335produced 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 patentfor 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 inanimalmodels.
Metabolic Syndrome In the Phase 1 trial, it is a 3-part, single center study of single and multiple ascending doses in healthy subjects. Quotient Clinical in the UK is conducting the trial, the same group that executed the Phase 1 for relacorilant. 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 – 136 Healthy Patients – Dose Ranging, Double-Blind CORT118335 ± Prednisone, Glucose, Placebo	Q3-2018
Phase 2 Launch – Antipsychotic Weight Gain Mitigation CORT118335	Q4-2018
Phase 2 Launch – NASH Treatment CORT118335	Q4-2018
Cancer Program Cortisol modulation may play a role in treating solid tumors through two mechanisms. First, in cancers where the tumors express GR, such as pancreatic, triple negative breast, and ovarian cancer. cortisol stimulates genes that retard apoptosis – the programmed suicide of dysfunctional cells. Chemotherapies aim to provoke apoptosis. Cortisol modulators should reverse this effect and downregulate the “apoptosis suppressing genes”. This enables chemotherapy to make a stronger impact. Second, cortisol modulation may help the immune system fight cancer. A healthy body regularly produces cancer cells, but the immune system identifies and destroys them. Even at normal levels, cortisol suppresses the immune system. Unfortunately, the stress of cancer and its treatment raise cortisol activity above normal levels and creates even greater immunosuppression. Cortisol modulators counter this effect by mitigating cortisol’s effects, thus freeing the immune system to act more potently. Corcept’s oncology program builds on preclinical and clinical research at the University of Chicago and confirmed by researchers at Sloan Kettering. There is great interest in therapies that stimulate the immune system to fight cancer because it can be a powerful weapon.
Solid Tumors CORT125134 (relacorilant) 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). Corcept expects to open additional expansion cohorts in patients with other tumor types, most likely ovarian and triple-negative breast cancer in 2018. Corcept is opening a cohort of pancreatic cancer patients. Given the preclinical animal results, we aren’t surprised. Relacorilant has shown potential. Besides lacking a couple side effects associated with Korlym, the animal models and early clinical data for treating solid tumors looks good, especially for pancreatic and ovarian cancers. Relacorilant 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 like Korlym but lacks some of its side effects. Relacorilant is already being paired with a checkpointinhibitor, namelyPembrolizumab(Keytruda).
Ongoing Results –Relacorilant (100 mg/ daily) + Abraxane (80 mg/m²) 20 Patients with Pancreatic Cancer		Q4-2018
Phase II Results – Expansion Cohorts – (~24 pts per Cohort) Relacorilant + Abraxane (ovarian & triple-negative breast cancer) Relacorilant + Pembrolizumab (Keytruda)		Q2-2019*
Phase II Results – Expansion Cohorts – (~24 pts per Cohort) Relacorilant + Abraxane (Pancreatic Cancer)		Q4-2018 / Q1-2019
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 a single ascending dose (SAD) phase and then later, 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. The trial is being conducted in London. The SAD part of the study is double-blind, randomized and placebo-controlled with two cohorts, each of 9 subjects. Each subject will receive three sequential single doses of either CORT125281 at the assigned dose level or placebo, in a partial within-subject crossover manner. The starting dose is CORT125281, 40 mg. The PD effects of CORT125281 will be examined by a concomitant dose of prednisone. The MAD part of the study will be double-blind, randomized, placebo-controlled and parallel-group with up to four cohorts of 8 subjects. Each group is randomized so that 6 receive CORT125281 and 2 receive placebo, so that up to four dose levels of CORT125281 are studied. An exploratory assessment will be made of the effect of repeated doses of CORT125281 on exposure to pioglitazone, probe substrate for CYP2C8. On Day1, subjects will receive a single oral dose of pioglitazone, 15mg. From Day3 to Day16 (14 days), subjects will be dosed daily with IMP (CORT125281 at the selected dose or placebo). On Day13, subjects will receive a second dose of pioglitazone, 15 mg. The Phase 1/2 Trial involves pairing CORT125281 with enzalutamide (Xtandi)to treat 80 mCRPC (metastatic, castration-resistant prostate cancer) patients. The study aims to find the maximum tolerated dose (MTD) of the combination therapy. At least one cohort of patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies.
Phase Ia Results – CORT125281 – 50 Healthy Patients			2H-2018
Phase 1b Ongoing Results – CORT125281 + Xtandi – Dose Escalation 80 Metastatic Castration Resistant Prostate Cancer (Open Label)			TBA
Phase 1b Final Results – CORT125281 + Xtandi – Dose Escalation 80 Metastatic Castration Resistant Prostate Cancer (Open Label)			Mid-2021*

*Guesstimate

Independent Investigator Sponsored Trials
Cancer Program
Advanced GR+ Triple Negative Breast Cancer Patients are treated in a randomized, double-blinded, placebo-controlled design.
Phase II Results (University of Chicago) (64 pts) Korlym + Abraxane	Q3-2019
Advanced HER2-negative Breast Cancer & Checkpoint Inhibitor The open-label 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)
Phase IIa – Dose Expansion – Final Results Pembrolizumab + Mifepristone - (University of Chicago) (74 pts)	2H-2020*
Prostate Cancer In the Phase 2 study, patients are given Xtandi vs. Xtandi + Mifepristone. While these patients failed prior therapy, they are naïve to 2^nd generation AR antagonists (Xtandi, AR509). We are certain that the primary endpoint data has been collected. The University of Chicago investigators are sometimes slow with releasing their results. The investigators will wait to present at their chosen academic conference. Relacorilant Study In the other study, relacorilant is combined with Xtandi to treat metastatic castration resistant prostate cancer (mCRPC) in an open-label design.. 24 patients will be enrolled in 6 patient cohorts with a 6+3 design and a 28 day DLT period. Doses of relacorilant, enzalutamide will be adjusted based on safety and pharmacokinetics (PK). Once a safe dose with appropriate drug levels (PK) has been established, the cohort will be expanded to a total of 12 patients to refine safety and PK at the recommended phase II dose (RP2D).
Phase I/II Extended Results – Metastatic Hormone Resistant Xtandi ± Mifepristone - (University of Chicago) - 108 pts	2H-2018*
Launch Phase Ib – Metastatic Hormone Resistant Xtandi + relacorilant – (University of Chicago) – 24 pts	November 2018
Top-line Phase Ib Results – Metastatic Hormone Resistant Xtandi + relacorilant – (University of Chicago) – 24 pts	Mid-2020*
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 Recentcommentaryimplicates 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” studyin which cortisol levels predicted the drinking intensity in alcoholics. There are some impressive research labs, including the current NIAAA Director’slabat UCSD, that have been using Corcept’s drugs with alcohol withdrawal. Nevertheless, we don’t expect Corcept to initiate an in-house program before 2019. We speculate that management will wait until the metabolic program has returned some Phase 2 results, which enables a closer look at the effect of Corcept’s drugs on the liver.
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	December 2019*
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 1^st week, 400 mg/daily for 2^nd week	Q4-2018*
Phase II Results in Heavy Drinkers (Johns Hopkins) (150 pts) 6 doses of Mifepristone vs. CORT125134 vs. Placebo	Q1-2022
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 indirectevidenceincluding 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 incidentalomas (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
Phase I/II NICHD Study in Obese Adults – Results (63 pts) Crossover, Double-Blind	2H-2018*
Phase II - Type 2 Diabetics not associated with Cushing’s and not well-controlled on oral medications – (Drew University) - Results (60 pts)	Mid-2020

*Guesstimate

Our Thoughts

It appears that Corcept has added more clinical milestones for the remainder of 2018. The next 3.5 months are active. The once slow train is picking up speed. The Q3-2018 announcement and conference call now looms large.

Upcoming Clinical Milestones

Oct/Nov 2018 – Phase 1 CORT118335 Prednisone Challenge Results – Metabolic Syndrome

Oct/Nov 2018 – Phase 2a Relacorilant Highest Dose Results – Cushing’s Syndrome

Oct/Nov 2018 – Phase 3 GRACE Study Launch - Relacorilant - Cushing’s Syndrome

Nov 2018 – Phase 1 Relacorilant + Xtandi Launch – Prostate Cancer

Q4-2018– Phase 1/2 Korlym + Xtandi Results – Prostate Cancer*

Dec 2018– Phase 2a Relacorilant + Abraxane Results – Pancreatic Cancer

Dec 2018– Launch Phase 2a CORT118335 – Antipsychotic Weight Gain

Dec 2018– Launch Phase 2a CORT118335 – NASH & Metabolic Syndrome

*Independent Investigators

Notes

The Phase 3 GRACE Pivotal Study for Cushing’s syndrome is published. We expect the trial to launch in November 2018.

At the same time, Corcept continues to validate the FKBP5 assay expression test. Although the current investor ecosystem will largely ignore these results, success creates a paradigm shift that supports the use of Korlym and relacorilant for treating Cushing’s syndrome. We expect the patents associated with this treatment method to be approved.

With the arrival of the relacorilant Phase 2a results andthe launch of CORT118335 Phase 2 trials, the long-awaited metabolic story begins to chug. For years, we have stated that the metabolic syndrome story for Corcept will eventually generate more value than the cancer story. It will bring new investors. Significant valuation impacts should arrive with positive Phase 2 results in 2019.

If the Phase 2 metabolic syndrome results are good, then we’re greedy. We’d like to see Corcept launch additional indications within that program.

While we have been impressed with the early efficacy signals in the cancer trials, we also expect some of the trials to return “snake eyes”. Even if Corcept’s drugs are proven effective, it won’t be in every cancer and every intended situation. The dice just won’t roll that way. Nevertheless,

1. Relacorilant’s early signals with pancreatic and ovarian cancer are heartening

2. We await the results from the other solid tumor trials over the next several months.

Even if there are strong efficacy signals for Korlym with breast cancer, we fully expect Corcept to also push relacorilant or another next generation drug forward.

Summation

Corcept Therapeutics has a large clinical program that is a mix of independent investigator and company-driven trials. It was a slow, methodical system that “played the odds”, to minimize the cash burn associated with examining new indications.

…and now we’re finally here. The train is picking up speed and the investor community awaits the next quarterly release and conference call. Today, Corcept is quiet around its investor community. Soon, things get considerably noisier.

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

This blog post is from The Biotech Watcher:

And about us, see http://alanhobbes.blogspot.com/2014/12/welcome-to-my-personal-thoughts-about.html

[1]The data in the table below was taken from oncology drug approvals granted during 2004 through 2010. It’s old but still applicable. We are looking for the original source, but much of this info was replicated at: http://bit.ly/2OiuLlK with Kesselheim AS, et al. (2011) Characteristics of Clinical Trials to Support Approval of Orphan vs Nonorphan Drugs for Cancer. JAMA, 305 (22), 2320-2326.