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Corcept Update:Our Thoughts on Cushing's Competitors and Future Product Portfolio Development
23:28 EST 24 Dec 2017 | Biotech Watcher
Along with many other biotechs, Corcept Therapeutics (CORT) recently experienced a gradual hit on its valuation. On October 5, 2017, CORT closed at $20.72 and on Friday, December 22, it closed at $17.89. We want to address a couple issues as well as provide our updated thoughts.
.4M in Grants for Development of CHI & Cushing’s Disease Treatment
The Setting
Corcept’s lead drug is Korlym(RU486) to treat Cushing’s syndrome. CORT’s rising valuation has been related to its also rising sales revenues. It’s a rarity: a small biotech with positive cash flow that can fund its own R&D.
It also has another rarity: investors interested in its status as a profitable biotech. This apparently drives the bulk of its valuation. The rest of the investors have the usual motivation: optimism for its research portfolio, especially in oncology.
Net USA Sales Korlym to Treat Cushing’s Syndrome | |||||||
Q3-2017 | Q2-2017 | Q1-2017 | Q4-2016 | Q3-2016 | 2017 Total | FY-2017 Guidance | FY-2016 Actual |
$42.8M | $35.6M | $27.6M | $23.6M | $21.7M | $106.0M | $157M-$162M | $81.1M |
As you can see, the sales uptake exceeded expectations. Corcept’s sales guidance for 2017 was upwardly revised with each quarterly report - the original guidance was $120M-$130M. Management wasn’t trying to blatantly sandbag. The market penetration required for “critical mass” was difficult to identify, even for Corcept management.
The increase in overall sales revenue is broadly based, with additional patients on prescription and additional prescribing physicians. Corcept is in a good space. What are the potential dark clouds?
Cushing’s Market Space: Any Challengers?
Korlym is also known as RU-486, “the abortion drug”. It blocks two different receptors and thus has deployed for different uses. To be an abortifacient, Korlym (RU-486) is a progesterone receptor inhibitor. To mitigate the metabolic consequences of Cushing’s, Korlym blocks the glucocorticoid receptor.
While Korlym does a good job at reducing Cushing’s metabolic symptoms, patients actually “feel” better. This isn’t true with the competitor drugs, which have a high dropout rate. 88% of Cushing’s patients experience a “global clinical response” on Korlym, and so it’s unsurprising that improved quality of life is similarly reported.
Recorlev from Strongbridge (SBBP)
Recorlev from Strongbridge Biopharma is in late-stage testing to treat Cushing’s syndrome. The company expects to report top-line data from its global Phase III trials in 1H & 2H of 2018. If Recorlev reaches the market, we don’t expect it before early 2020.
Recorlev is a “special version” of ketoconazole. Ketoconazole was once the market leader for treating Cushing’s syndrome. In 2013, the FDA issued a warning against the oral tablet as first-line therapy and off-label usage, due to the risk of liver injury. Recorlev is supposed to be less toxic than ketoconazole.
This cleared the way for Korlym to build faster sales momentum and interest, although even before the FDA warning, Korlym was making inroads.
Background
Before Strongbridge, Recorlev was called DIO-902 and was being developed for diabetes by DiObex Pharma in San Francisco. DiObex closed in 2009 as it was unable to raise more venture funds. Recorlev’s liver safety was deemed inadequate for treating diabetes.
Strongbridge purchased Recorlev from the ashes of DiObex.. The Strongbridge team obtained orphan status for Recorlev in Europe and the USA. It is also pursuing a 505(b)2 strategy for an abbreviated approval pathway.
Recorlev had some beneficial effects with treating the metabolic effects associated with diabetes. We can see why Strongbridge is instead pursuing Cushing’s syndrome: it is a serious disease that throws patients into an acute crisis and so the FDA should be more lenient about approving a toxic agent.
Like Korlym’s other competitors, it blocks cortisol synthesis. The primary endpoint is serum cortisol levels, measured through urinary free cortisol (UFC). The figure below shows serums cortisol level as measure by the urine test. Recorlev is compared to patients on ketoconazole (KTZ) and placebo. The Recorlev figures are taken from a recent Strongbridge presentation.
If you remove ketoconazole’s or Recorlev’s toxicity, it appears to have a superior side effect profile. Nevertheless, Korlym’s advantage is that patients “feel better” when taking the drug. This seems to be a problem with other Cushing’s drug candidates besides Korlym.
On the other hand, Recorlev is the less toxic “version” of ketoconazole. It’s also possible that it is also more effective than ketoconazole. In Stonebridge’s filing, management states: Recorlev has the potential to become the new standard of care for the drug therapy of endogenous Cushing's syndrome.
We are less confident of this claim. Why?
1) Liver toxicity is liver toxicity. Even if much better than regular ketoconazole, physicians will still have to monitor for liver toxicity. Remember, it wasn’t considered safe enough for treating diabetes.
Early clinical testing implies that Recorlev should have less impact on the liver. That’s good! But much earlier data also suggested problems. That’s bad.
We will simply have to wait for the Phase 3 data. We would guess Recorlev will indeed be much gentler on the liver than regular ketoconazole, but that monitoring will remain an issue…. but until the Phase 3 data arrives, we’re speculating.
2) Urinary Free Cortisol versus Cortisol Receptor Activity – Corcept continues to validate the FKBP5test as a superior assessment of Cushing’s syndrome severity. The Corcept folks maintain it is really about the glucocorticoid receptor’s (GR) activity level, not about “apparent” cortisol levels in the blood.
Measuring cortisol in the blood doesn’t necessarily tell you about how much is in the tissues because some tissues, particularly fat can recycle their cortisol and may have high levels inside the tissue even though it’s low in the blood.[1]
Recorlev is known for its effect on serum cortisol via a urine test. There are a couple problems. Serum cortisol only accounts for a small minority of total cortisol. The rest is embedded in the tissues, and this may be wreaking havoc in many Cushing’s patients.
If this is indeed true, then serum cortisol tests fall short and Corcept’s FKBP5 test comes to the forefront. Furthermore, current thoughts about treatment will also change. Corcept’s competitors rely on reducing serum cortisol levels.
If true, this is a reason why many patients “feel better” on Corcept’s drugs. If you can’t adequately interdict the disease at the beginning, then perhaps you can interdict it at the end. Corcept’s drugs hit the “funnel” at the end, inhibiting the receptor activity.
If Corcept wins this battle with the FKBP5 test, then this should secure a major market segment to Corcept’s drugs.
3) The Real Fight: Recorlev vs. Relacorilant + FKBP5 Test – The fight won’t be Recorlev against Korlym. By the time Recorlev is running at full steam in the market, CORT125134 (AKA relacorilant). CORT125134 has fewer side effects than Korlym and may even be a tad more effective. Furthermore, the FKBP5 test should slowly rearrange how endocrinologists view Corcept’s drugs.
In sum, Recorlev will be a welcome drug in the Cushing’s treatment armament. We await the Phase 3 results. We suspect Recorlev will first be battling the other drugsas they share a common mechanism of action (MOA): inhibiting cortisol synthesis. Corcept’s drugs currently stand alone with a unique MOA: inhibiting the GR receptor.
Our best guess: Recorlev will blunt the sales uptake for Korlym at the margins. The endocrinologists who liked using ketoconazole will have their drug “returned”. Also, not every patient can be adequately treated by Korlym alone. There should be room for Strongbridge to make a few dollars.
We would be shocked if Recorlev alone does significant damage to relacorilant’s revenue. There’s a couple years between now and 2020, and we will certainly develop greater clarity. Until then, we expect Korlym to continue its upward sales momentum.
Corcept’s Immediate Future
With improving sales revenues, Corcept can either bank additional cash or increase clinical development. We forsee additional in-house clinical development. Right now, Corcept has 4 or 5 ongoing clinical trials. Over the next 12 months, Corcept will have ended or launched about 15 trials.
Phase 3 Recorilant in Cushing’s Syndrome
Phase 2a CORT118335 for Metabolic Syndrome with NASH
Phase 2a CORT118335 for Anti-Psychotic Weight Gain
Phase 1b CORT118335 Extended Trial in Prednisone Challenge
Phase 2 Recorilant + Pembrolizumab in Solid Tumors
Phase 2 Recorilant + Abraxane in Triple-Negative Breast & Ovarian Cancer
Phase 1 CORT125281 + Xtandi in Healthy Patients
Phase 1b CORT125281 + Xtandi in Prostate Cancer
What else? What other indications could be targeted? The list is a bit speculative, but we would not be surprised if these indications were tested in 2019 or 2020, if not 2018.
Phase 2a Recorilant + Chemotherapy in Other Solid Tumors (e.g. Melanoma, Lung, etc)
Phase 1b Drug TBA to treat Ethanol Withdrawal
Phase 2 Recorilant for Adrenal Incidentaloma
Phase 1 Drug TBA + Prednisone to mitigate side effects with Steroid Treatment
We do not expect an in-house trial on post-traumatic stress disorder (PTSD) in 2018, at least not without an external grant.
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 | Q1-2018* | ||
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 While a December 2017 finish date is published, we are cautious. The University of Chicago investigators have sometimes been slow with publicizing their results. | |
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. 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 | 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 | TBA* |
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* |
not well-controlled on oral medications – (Drew University) - Results (60 pts) | Mid-2020 |
Metabolic Markers, Depression in Older Adults | |
Middle-Aged & Older Adults (Stanford University) – Results – 40 pts | 2H-2017* |
*Guesstimate
Our Thoughts
With each quarterly report, Corcept Therapeutics (CORT) announces increasing sales, and the valuation marches upward. We expect Corcept to still report increasing Korlym sales through 2018. This will fuel a growing in-house development portfolio.
It wasn’t too long ago that we were impatient, somewhat rankled by management’s approach: grow within current sales revenues. Given that the first 18 months of sales were miserable, we voiced our concerns with this approach.
We were wrong.
CEO Joe Belanoff is like a good card player: play the odds and be patient. Corcept’s valuation has risen, and we expect Korlym sales to exceed $225M in FY2018. This will enable Corcept to fund multiple trials while staying slightly cash-flow positive. Our main caveat is that Corcept’s expenditures will be lumpy, and there might be an odd quarter in which the earnings are neutral or even slightly negative.
We expect Corcept’s future valuation to be increasingly driven by clinical results rather than just sales. In Q1 2018, we expect noteworthy results: recorilant’s Phase 2 trial for treating Cushing’s syndrome.
If CORT investors aren’t into the “profitable biotech” story, then most of the rest are into the “oncology treatment” story. We respectfully disagree. The valuation lies elsewhere. The odds for success are much greater for Corcept’s metabolic program. The markets are large and accessible, especially for mitigating weight gain due to antipsychotic usage.
(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:
[1]https://aspirenaturalhealth.com/cortisol-its-more-complex-than-we-thought-post-200-by-dr-tim-gerstmar-7172012/
Original Article: Corcept Update:Our Thoughts on Cushing's Competitors and Future Product Portfolio Development
