BioWatch Commentary Corcept Therapeutics AACE Clinical Presentations Part 2

BioWatch Commentary - Corcept Therapeutics - AACE Clinical Presentations - Part 2

21:25 EDT 8 May 2019 | Biotech Watcher


We made a quick summary of one presentation: the updated results from the recent Phase 2a of relacorilant to treat Cushing’s syndrome. In this article, we completed our commentary on this clinical trial. We also commented on the other Corcept presentations. This article represents our “Part 2” on Corcept’s AACE posters.

Background Reading

Every Spring, two important endocrinology conferences are held: First, the Annual Meeting of the Endocrine Society (ENDO); and then Second, the Annual Congress of the American Association of Clinical Endocrinologists. For the past few years, Corcept investigators have presented at either or both conferences. This year, BioWatch Newscommented on these presentations.

BioWatch Commentary on Recent Endocrinology Presentations

As in prior years, Corcept investigators provide teasers on how the drugs can treat extensions to its “Cushing’s market”. It is picking up speed. Feel free to examine our commentaries.

Corcept’s AACE Presentations

While we focused on the results involving relacorilant and Cushing’s syndrome, we also looked at the rest of Corcept’s AACE presentations, including:
Case Study: Improvement in Muscle Strength and Psychiatric Symptoms in Cushing’s
Mifepristone Provides Beneficial Clinical Improvement in Community Practice
Case Study: Consequences of Untreated Cortisol Producing Adenoma

Relacorilant & Cushing’s Syndrome – More Phase 2 Results

The data for this article comes from two different clinical trials to treat Cushing’s syndrome:
The registration trial (SEISMIC) that led to Korlym’s FDA approval; and
The AACE Presentation of the Phase 1/2, dose-ranging trial of relacorilant.

Secondary Endpoints

Relacorilant & Cushing’s Syndrome
Phase 2a Results
Selected Secondary Endpoints
Improvement from Baseline
Low & High Dose Cohorts Combined
Metric
P-Value
Glucose Levels
AUCglucose (h·mmol/L) ↓
0.0214
Fructosamine(μmol/L) ↓
0.0021
Liver Functioning
↓
< 0.0001
AST↓
0.0013
Coagulability-Related Metrics
Partial Thromboplastin Time (aPTT) Test ↓
0.0456
Factor VIII (%)↓
0.0219
Platelet count(109/L) ↓
< 0.0001
Cognitive & Neuropsychiatric Measures
Beck Depression Inventory II ((BDI-II) ↓
0.0044
Cushing QoL Score↑
0.0024
Trail-Making Test Part A ↓
0.003
Trail-Making Test Part B ↓
< 0.0001
Other
Serum Osteocalcin ↑
0.0097
Absolute eosinophils ↑
0.006

These are striking improvements, especially as the dose cohorts were combined. We generally expect stronger improvements with higher doses, as seen with weight loss.[1]

Safety Data

Common Adverse Events
Adverse Events
N (%)
Low-Dose
(N=17)
High-Dose
(N=18)
Total
(N=36)
Korlym[2]
(N=29)
Backpain
15 (88.2)
18 (100)
33 (94.3)
8/50 (16.0)
Headache
4 (23.5)
5 (27.8)
9 (25.7)
11/29 (37.9)2
Peripheral Edema
4 (23.5)
5 (27.8)
9 (25.7)
13/50 (26.0)[3]
Nausea
3 (17.7)
5 (27.8)
8 (22.9)
15/29 (51.7)2
Pain in Extremity
4 (23.5)
4 (23.5)
8 (22.9)
6/50 (12.0)3
Diarrhea
4 (23.5)
3 (16.7)
7 (20.0)
6/50 (12.0)3
Dizziness
3 (16.7)
4 (23.5)
7 (20.0)
11/50 (22.0)3
Abnormal Vaginal Bleeding
0
0
0
5/29 (25.0)2
Hypokalemia
0
0
0
14/29 (48.3)2
Vaginal bleeding and hypokalemia were common occurrences with Korlym treatment. Also unlike Korlym, there were also no clinically significant changes in serum ACTH or cortisol levels.
Compared to the Phase 2 trial, the GRACE studypatients receive a “gentler introduction” to relacorilant. Patients start treatment at 100 mg/day for 2 weeks. This should reduce the incidence and severity of cortisol withdrawal syndrome, as well as the adverse events.

Our Thoughts

The secondary endpoint and safety results confirm the main results: relacorilant improves Cushing’s syndrome and is an improvement over Korlym. If the GRACE study repeats these results, then relacorilant will be deemed superior to Korlym. For the most part, generic Korlym will be moot. 

Hypercortisolism Prevalence in Type 2 Diabetes with Adrenal Adenoma: Pilot Results

Abnormal levels of cortisol are much more frequently found in T2Ds. In a “regular” T2D population, hypercortisolism is found in 1% to 10% of the patients.
The pilot results on hypercortisolism the prevalence among type 2 diabetes (T2Ds) with adrenal tumors stands out.[4] Although the pilot sample is small (N=12), it was worth reporting.
Hypercortisolism Prevalence
Type 2 Diabetes Studies
Study
Population Characteristics
Hypercortisolism
%
Sachemechi (2019)4
T2D with Adrenal Adenomas. Only 1 positive test result used to identify hypercortisolism
7/12
(58%)
Matthews (2017)[5]
Brittle T2Ds that require concentrated insulin. 21 patients had symptoms and/or biochemical indicators suggesting hypercortisolism. 13 of these patients had imaging - revealing 9 patients with adrenal hyperplasia or adrenal adenoma(s).
21/34
(62%)
Steffensen (2019)[6]
384 recently diagnosed T2Ds were screened and if necessary, given multiple tests. 20 pts with hypercortisolism; imaging reveals 10 pts with adenomas.
20/384 (5.2%)
Costa (2016)[7]
393 T2D outpatients screened for hypercortisolism with overnight DST and additional tests.
33/393
(8.6%)
Newsome (2008)[8]
171 consecutive overweight T2D outpatients. Pts screened with 1 mg overnight DST and follow-up testing. 31 pts had a positive overnight DST test. Most were disconfirmed through follow-up tests.
(0%)
Chiodini (2005)[9]
12-month study with 294 consecutive T2D inpatients versus 189 consecutive matched non-diabetic inpatients. Inpatient T2Ds were much more likely than non-diabetics to have hypercortisolism (9.4% vs. 2.1%).
(9.4%)
Catargi (2003)[10]
200 consecutive inpatient T2Ds. 17 of 200 (8.5%) patients had impaired DST plus one or more additional signs. Abnormal imaging in 11 patients (5.5%).
17/200 (8.5%)
11/200
(5.5%)

Key Points

1. The rates for hypercortisolism and confirmed Cushing’s are higher in T2Ds than the general population. One review article examined 14 different studies with a total of 2,827 T2Ds. The pooled prevalence for hypercortisolism was 3.4% and for Cushing’s syndrome was 1.4%. Imaging in the T2Ds with hypercortisolism reveals that over 52% have adrenal or pituitary tumors.
2. The rates are especially high among special T2D segments. Corcept investigators have found very high rates among brittle diabetics and among T2Ds with confirmed adrenal adenomas (benign tumors). It also appears to be more likely among severe T2Ds and those with concurrent hypertension. In a study of 423 patients with resistant hypertension, 34 (8.0%) had confirmed hypercortisolism. None had overt Cushing’s syndrome.[11]
3. At last year’s AACE, Corcept-associated investigators showed that Korlym successfully reduced the use of concentrated insulin in brittle diabetics.[12]14 brittle diabetics with confirmed hypercortisolism were treated with Korlym. 4 patients had nodiscernible adenomas nor hyperplasia. At 6 months, the average reduction in the daily insulin dose was 41%. There have also been small studies and case reports in which Korlym (AKA mifepristone) successfully treated patients with adenomas, even those with mildhypercortisolism.[13]

Our Thoughts

Over the years, there have been several small studies in which mifepristone successfully treated general T2D patients and also mild disease coupled with adrenal adenomas. Although hypercortisolism is a component a small but steady percentage of general T2D patients, there are T2D segments that represent “low-hanging fruit”.
T2Ds with adrenal or pituitary adenomas
Severe T2Ds and so-called Brittle Diabetics
Hypertensive T2Ds
The extended markets may be larger than expected. Corcept’s drugs apparently work on some T2Ds with only mild hypercortisolism. We also discussed that HPA overactivation may occur in the absence of adenomas. Lastly, Corcept investigators have been building the case for using its drugs as a preoperative treatment and bridge treatment in Cushing’s.[14]

The Rest of the Presentations

Case Study: Improvement in Muscle Strength and Psychiatric Symptoms in Cushing’s
Mifepristone Provides Beneficial Clinical Improvement in Community Practice
Case Study: Consequences of Untreated Cortisol Producing Adenoma
The “Community Practice” poster was really a double treat. It illustrated two Cushing’s cases: reducing diabetes & hypertension as well as medications; and weight reduction in a patient previously treated with pasireotide (Signifor). More importantly, these cases demonstrate Korlym’s robust effects as “real-life” patients may adhere to inconsistent follow-up.
The “Untreated Female Patient” involves a Type 1 Diabetic (T1DM) with an adenoma…and did not meet the technical criteria for hypercortisolism for several years. The presentation reports on 10+ years of progressive disease without mifepristone. She also did not qualify as a surgical candidate because of poor health.She was then “successfully” treated with mifepristone. Over the first months of treatment: twice she had to cease treatment due to side effects. Nevertheless, she had a rapid reduction in weight (281 lbs at baseline; 240 lbs at 4 months) and a “dramatic decrease in insulin requirements”.
The implications for this individual are clear: First, earlier treatment would have been warranted to prevent damage and mitigate progressive disease. Second, it’s not always about the absolute level of free cortisol. We’ve now seen multiple instances in which severe diabetics respond to Corcept’s drugs, even without high levels of free cortisol.
In the remaining case study, a post-surgical patient still suffers from multiple severe and progressive symptoms. She resided at a rehab facility, on a cocktail of psychiatric medications and had severe muscle weakness and diabetic symptoms.
Over 22 months, her weight reduced from an unhealthy 250 pounds to 180. Her HbA1c descended from 6.6% to 5.3%. She was able to discontinue several psychiatric meds, and resolve her sleep apnea (no longer needed a CPAP machine). She was no longer required to reside at the rehab facility.

Our Thoughts

Every year, Corcept investigators tantalize with extensions to the current market. The accumulating research is compelling and there is enough justification for a clinical trial in a few of these indications. Is there also a financial justification? It’s difficult to say. The incidence and prevalence rates have yet to be established.
We think there’s something there, but it’s a question of priorities.
Corcept’s current clinical portfolio is full. The new clinical trials in the metabolic syndrome area must take precedence.
We would not be surprised if Corcept is merely setting the table for funded studies, to be performed with NIH or an independent investigator. If a small company has a full plate, then “free” studies should come first.
The accumulating research also encourages endocrinologists and other physicians to try Corcept’s drugs on their treatment-resistant patients. Given that relacorilant (and the other next-generation drugs) has a much milder side effect profile than Korlym, the picture changes with approval.
(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]42.9% (15/35) of patients lost weight. 35.3% (6/17) of low-dose patients lost weight (mean loss = 2.2 kg) versus 60% (9/15) of high-dose patients (mean loss = 5.1 kg).
[2]Fein et al. (2015) Sustained weight loss in patients treated with mifepristone for Cushing’s syndrome: A follow-up analysis of the SEISMIC study and long-term extension, 15(63), doi: 10.1186/s12902-015-0059-5
[3]Fleseriu et al. (2012) Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing’s Syndrome, The Journal of Clinical Endocrinology & Metabolism, 97,doi:10.1210/jc.2011-3350.
[4]Sachmechi I, et al. (April 25, 2019) Prevalence of Hypercortisolism in Patients with Type 2 Diabetes Mellitus with Incidentally Found Adrenal Adenomas: An Interim Analysis. Poster presented at the Annual Congress of American Association of Clinical Endocrinologists.
[5]Mathews JW, et al. (April 2017). Screening of Diabetic Patients using U500 Insulin Uncovers a High Percentage of Undiagnosed Hypercortisolism Consistent with Cushing Syndrome. Poster presented at the Annual Congress of American Association of Clinical Endocrinologists.
[6]Steffensen C, et al. (2019). Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients. Hormone and Metabolic Research. 51, 62-68.
[7]Costa DS, et al. (2016). Prevalence of subclinical hypercortisolism in type 2 diabetic patients from the Rio de Janeiro Type 2 Diabetes Cohort Study. Journal of Diabetes and Its Complications, 30, 1032-1038.
[8]Newsome S, et al. (2008). Cushing’s syndrome in a clinic population with diabetes. Internal Medicine Journal, 38, 178-182.
[9]Chiodini I, et al. (2005). Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients. European Journal of Endocrinology, 153, 837-844.
[10]Catargi B, et al. (2003). Occult Cushing’s Syndrome in Type-2 Diabetes. The Journal of Clinical Endocrinology & Metabolism. 88, 5808-5813.
[11]Martins LC, et al. (2012).Prevalence and associated factors of subclinical Hypercortisolism in patients with
resistant hypertension. Journal of Hypertension, 30, 967-973.
[12]Mathews JW, et al. (April 2018). Mifepristone Decreased the Use of Concentrated U500 Insulin in Patients with Endogenous Hypercortisolism who have Type 2 Diabetes Mellitus. Poster presented at the Annual Congress of American Association of Clinical Endocrinologists.
[13]Debono M, et al. (2013). Mifepristone Reduces Insulin Resistance in Patient Volunteers with Adrenal Incidentalomas That Secrete Low Levels of Cortisol: A Pilot Study. PLoS ONE 8(4): e60984. doi:10.1371/journal.pone.0060984. Also Macfarlane DP, et al. (2014). Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver. American Journal of Physiology-Gastrointestinal and Liver Physiology, 307: G760–G768, doi:10.1152/ajpgi.00030.2014.
[14]Terzolo M, et al. (2019, March 24). Tumor Shrinkage with Preoperative Relacorilant Therapy in Two Patients with Cushing Disease Due to Pituitary Macroadenomas. Poster presented at the Annual Meeting of the Endocrine Society, New Orleans, LA.
AlsoMikhael A, et al. (2018, March 17). Mifepristone as Bridging Therapy Before Transsphenoidal Surgery for Cushing’s Disease: Implications for Diagnosing Immediate Remission. A Case Report. Poster presented at the Annual Meeting of the Endocrine Society, Chicago, IL.
And Sack PA & Smith JJ (2018, March 17). Mifepristone Therapy Prior to Pituitary Surgery in Cushing Disease Prevented Need for Long-Term Glucocorticoid Replacement. Poster presented at the Annual Meeting of the Endocrine Society, Chicago, IL.

More From BioPortfolio on "BioWatch Commentary - Corcept Therapeutics - AACE Clinical Presentations - Part 2"