Medications Used to Treat Cushing’s

Dr. Friedman uses several medications to treat Cushing’s syndrome that are summarized in this table. Dr. Friedman especially recommends ketoconazole. An in-depth article on ketoconazole can be found on goodhormonehealth.com.

 

 

 Drug How it works Dosing Side effects
Ketoconazole  (Generic, not FDA approved in US) blocks several steps in cortisol biosynthesis Start 200 mg at 8 and 10 PM, can up titrate to 1200 mg/day • Transient increase in LFTs
• Decreased testosterone levels
• Adrenal insufficiency
Levoketoconazole (Recorlev) L-isomer of Ketoconazole Start at 150 mg at 8 and 10 PM, can uptitrate up to 1200 mg nausea, vomiting, increased blood pressure, low potassium, fatigue, headache, abdominal pain, and unusual bleeding
Isturisa (osilodrostat) blocks 11-hydroxylase 2 mg at bedtime, then go up to 2 mg at 8 and 10 pm, can go up to 30 mg  Dr. Friedman often gives with spironolactone or ketoconazole. • high testosterone (extra facial hair, acne, hair loss, irregular periods)  • low potassium
• hypertension
Cabergoline (generic, not FDA approved) D2-receptor agonist 0.5 to 7 mg • nausea,  • headache  • dizziness
Korlym (Mifepristone) glucocorticoid receptor antagonist 300-1200 mg per day • cortisol insufficiency (fatigue, nausea, vomiting, arthralgias, and headache)
• increased mineralocorticoid effects (hypertension, hypokalemia, and edema
• antiprogesterone effects (endometrial thickening)
Pasireotide (Signafor) somatostatin receptor ligand 600 μg or 900 μg twice a day Diabetes, hyperglycemia, gallbladder issues

For more information or to schedule an appointment with Dr. Friedman, go to goodhormonehealth.com

Korlym: Failure to Show a Reasonable Expectation of Success Dooms Obviousness Allegations

In Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.,1 the Federal Circuit affirmed the obviousness analysis performed by the Patent Trial and Appeal Board (“PTAB”), which found that Corcept’s patent for methods of treating Cushing’s disease by co-administering two different types of drugs with a specific range of dosing amounts was not obvious—even where the prior art directed one to combine the two—because there was no reasonable expectation of success for the specific dose claimed in the patent.

Background

The patent relates to methods for treating Cushing’s syndrome by co-administering mifepristone and a strong CYP3A inhibitor. Cushing’s syndrome is a metabolic disorder caused by excess cortisol.,2 Mifepristone was recognized in the prior art as a potential treatment for Cushing’s syndrome in the 1980’s.,3 Decades later, Corcept sponsored the first major clinical trial of mifepristone in patients with Cushing’s syndrome, in which participants were dosed with 300 to 1200 mg per day of mifepristone. Thereafter, Corcept filed a New Drug Application (“NDA”) with the U.S. Food and Drug Administration (“FDA”) to seek marketing approval for Korlym®, a 300 mg mifepristone tablet to control “hypercalcemia secondary to hypercortisolism” in patients with Cushing’s syndrome.,4

The FDA approved the NDA, including the prescribing information contained in the label.5 The label “recommended [a] starting dose [of] 300 mg once daily” and allowed for a dosage increase “in 300 mg increments to a maximum of 1200 mg once daily.”6 The label specifically warned against using mifepristone “with strong CYP3A inhibitors” and limited the dose to “300 mg per day when used with strong CYP3A inhibitors.”7

However, when it approved the NDA, the FDA issued several post market requirements, one of which was that Corcept must conduct a drug-drug interaction study with mifepristone and a strong CYP3A inhibitor.8 A memo from the Office of Clinical Pharmacology was provided to Corcept by the FDA (“the Lee memo”), which explained that “[t]he degree of change in exposure of mifepristone when co-administered with strong CYP3A inhibitors is unknown” and “may present a safety risk.”9 The concern was that without the required study the patients with Cushing’s syndrome that take strong inhibitors may be unable to use mifepristone.10

Corcept conducted the study requested in the Lee memo.11 Based on the resulting data, Corcept sought a patent claiming a method of treating Cushing’s syndrome by co-administering mifepristone and a strong CYP3A4 inhibitor, which is the patent at issue here.12 Claim 1, which is representative of the claims, reads:

A method of treating Cushing’s syndrome in a patient who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:

reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,

administering the adjusted once-daily dose of 600 mg mifepristone and a strong CYP3A inhibitor to the patient,

wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfmavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.13

Procedural Posture

In 2018 Corcept brought suit against Teva in the District of New Jersey alleging that Teva’s proposed generic infringed the patent, among others.14 Teva then sought post-grant review of the patent’s claims at the PTAB, arguing that the claims would have been obvious over the Korlym® label and the Lee memo, optionally in combination with FDA guidance on drug-drug interaction studies.15

The PTAB instituted review, “construed the claims to require safe administration of mifepristone,” and found that Teva failed to meet its burden of showing that a “skilled artisan would have had a reasonable expectation of success for safe co-administration of more than 300 mg of mifepristone with a strong CYP3A inhibitor.”16 Thus, the PTAB concluded that Teva failed to prove obviousness.17

Teva’s Arguments on Appeal

Teva argued to the Federal Circuit that the PTAB committed two legal errors in finding that Teva did not prove obviousness: (1) it “required precise predictability, rather than a reasonable expectation of success in achieving the claimed invention,” and (2) it found that Teva “failed to prove the general working conditions disclosed in the prior art encompassed the claimed invention” instead of applying the Federal Circuit’s “prior-art-range precedents.”18

The Federal Circuit Panel, consisting of Chief Judge Moore and Judges Newman and Reyna, rejected both of Teva’s arguments.19

The Panel determined that the PTAB “did not err by requiring Teva to show a reasonable expectation of success for a specific mifepristone dosage.”

In discussing the proper standard for evaluating a reasonable expectation of success, the Panel cited prior Federal Circuit decisions explaining that the analysis “must be tied to the scope of the claimed invention.”20 It noted that because the claims of the patent require administration of a specific dosage of mifepristone, the PTAB was required to frame its analysis around that specific dosage.21 The Panel emphasized that Teva was not “required to prove a skilled artisan would have precisely predicted safe co-administration of 600 mg of mifepristone” because “[a]bsolute predictability is not required.”22 Teva was, however, required “to prove a reasonable expectation of success in achieving the specific invention claimed, a 600 mg dosage.”23

The Panel explained that the PTAB found that Teva failed to prove a reasonable expectation of success.24 Based on the prior art, a skilled artisan would not have reasonably “expected co-administration of more than 300 mg of mifepristone with strong CYP3A inhibitor to be a safe treatment of Cushing’s syndrome or related symptoms in patients.”25 Moreover, the PTAB found that a skilled artisan “would have had no expectation as to whether co-administering dosages of mifepristone above the 300 mg/day threshold” would be successful.26 Thus, because there was no expectation of success for any dosage over 300 mg, the PTAB concluded that there could not have been an expectation of success for the specific dosage of 600 mg per day.27 The Panel found that this analysis by the PTAB was correct under Federal Circuit precedent, and that “[n]othing about this analysis required precise predictability, only a reasonable expectation of success tied to the claimed invention.”28

The Panel decided that the PTAB did not err in finding that “the prior art ranges do not overlap with the claimed range”

The Panel next considered the applicability of the Federal Circuit’s precedent concerning claimed ranges that overlap with those disclosed in the prior art.29 The PTAB refused to apply that line of cases, finding that “Teva had failed to prove the general working conditions disclosed in the prior art encompass the claimed invention.”30

The Panel noted a Federal Circuit decision that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”31 In other words, “a prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”32 “But overlap is not strictly necessary for a conclusion of obviousness” and can exist even where the ranges are “close enough” that a skilled artisan would expect them to exhibit similar properties.33

Here, the Panel explained that “[s]ubstantial evidence supports the [PTAB’s] finding that the general working conditions disclosed in the prior art did not encompass the claimed invention, i.e., there was no overlap in ranges.”34 The Korlym® label warned against taking mifepristone with a strong CYP3A inhibitor altogether, and stated that anyone nonetheless combining the two should take a maximum of 300 mg/day of mifepristone.35 This 300 mg/day cap was also repeated in other industry publications.36 The PTAB found that “the prior art capped the range of co-administration dosages at 300 mg per day.”37 The Panel agreed with this finding, concluding that the claimed range was not disclosed in the prior art.38

Teva attempted to argue that the claimed range overlaps with monotherapy dosages—which were dosages of mifepristone alone—in the prior art.39 However, because “monotherapy dosages alone cannot create an overlap with the claimed range, which is limited to co-administering mifepristone with a strong CYP3A inhibitor,” the PTAB had to determine “whether a skilled artisan would have expected “monotherapy and co-administration dosages to behave similarly.”40 As the Panel had already concluded in its reasonable expectation of success analysis, a “skilled artisan would have no such expectation.”41

Conclusion

Although Teva argued that this was an “uncommonly clear-cut obviousness case” where the prior art discloses “the problem, . . . the solution, . . . and the way to find the solution,” the Panel disagreed, explaining that: “At best, the prior art directed a skilled artisan to try combing the Korlym Label, Lee, and the FDA guidance. But without showing a reasonable expectation of success, Teva did not prove obviousness.”42 Thus, the Panel’s decision helps to clarify that evaluating obviousness based on ranges disclosed in the prior art is a fact-specific analysis, in which bright lines should not be drawn.

1 Teva Pharm. USA, Inc. v. Corcept Therapeutics, Inc., No. 21-1360, slip op. (Fed. Cir. Dec. 7, 2021).
2 Id. at 2.
3 Id.
4 Id. at 2-3.
5 Id. at 3.
6 Id.
7 Id. at 3-4.
8 Id. at 3.
9 Id.
10 Id.
11 Id. at 4.
12 Id.
13 Id. at 3.
14 Corcept Therapeutics, Inc. v. Teva Pharmaceuticals USA, Inc., No. 18-3632 (D.N.J.).
15 Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc., PGR2019-00048, 2020 WL 6809812 (P.T.A.B. Nov. 18, 2020) (Final Decision).
16 Id. (emphasis added).
17 Id.
18 Teva Pharm. USA, Inc. v. Corcept Therapeutics, Inc., No. 21-1360, slip op. at 5 (Fed. Cir. Dec. 7, 2021)
19 See generally id.
20 Id. at 6 (citing Allergan, Inc. v. Apotex Inc., 753 F.3d 952, 966 (Fed. Cir. 2014); Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016)).
21 Id.
22 Id.
23 Id.
24 Id.
25 Id. at 6-7 (citing Final Decision at *22).
26 Id. at 7.
27 Id.
28 Id.
29 Id. at 8.
30 Id.
31 Id. (citing E.I. DuPont de Nemours & Co. v. Synvina C. V., 904 F.3d 996, 1006 (Fed. Cir. 2018)).
32 Id. at 8-9.
33 Id. at 9.
34 Id.
35 Id.
36 Id.
37 Id.
38 Id.
39 Id.
40 Id. at 9-10.
41 Id. at 10.
42 Id.

No Synthetic Steroid Version of Korlym at This Time

Teva Pharmaceuticals suffered a fresh legal setback on Tuesday in its effort to market a generic version of the synthetic steroid Korlym to treat Cushing’s syndrome.

The Israeli drugmaker failed to convince the U.S. Court of Appeals for the Federal Circuit that the Patent Trial and Appeal Board improperly denied its bid to cancel a patent held by Corcept Therapeutics covering a method for using Korlym to treat the hormone disorder.

Menlo Park, California-based Corcept last year made over $353 million from sales of Korlym, the company’s only drug, according to a filing with the U.S. Securities and Exchange Commission.

Corcept’s patent relates to using a specific dose of Korlym’s active ingredient mifepristone and another drug to treat Cushing’s syndrome, which creates an excess of the hormone cortisol and causes high blood sugar, among other things.

Corcept sued Teva in New Jersey in 2018, alleging its proposed generic version of Korlym infringed the patent and others, in a case that is still ongoing. Teva asked the Patent Trial and Appeal Board to cancel the patent because earlier publications made it obvious that Corcept’s method would work to treat the disorder.

The board ruled for Corcept last year, and Teva appealed. Teva told the Federal Circuit that the PTAB held it to an improperly high standard for proving that the patent was invalid based on prior art.

Chief U.S. Circuit Judge Kimberly Moore, joined by Circuit Judges Pauline Newman and Jimmie Reyna, rejected Teva’s argument on Tuesday. Moore said the board found that a person of ordinary skill wouldn’t have reasonably expected Corcept’s treatment to be safe and effective before Corcept created it.

Moore also rejected Teva’s argument that the prior art disclosed a range of potential dosages that covered Corcept’s treatment.

Teva, Corcept and lawyers for the two companies didn’t immediately respond to requests for comment.

The case is Teva Pharmaceuticals USA Inc v. Corcept Therapeutics Inc, U.S. Court of Appeals for the Federal Circuit, No. 21-1360.

For Teva: John Rozendaal of Sterne Kessler Goldstein & Fox

For Corcept: Eric Stops of Quinn Emanuel Urquhart & Sullivan

From https://www.reuters.com/legal/transactional/teva-loses-bid-cancel-corcept-drug-patent-federal-circuit-2021-12-07/

Corcept Therapeutics Announces Allowance of Additional Patent Covering the Use of Korlym to Treat Patients With Cushing’s Syndrome

MENLO PARK, Calif., Aug. 28, 2019 (GLOBE NEWSWIRE) — Corcept Therapeutics Incorporated (NASDAQ: CORT) announced today that the United States Patent and Trademark Office has issued a Notice of Allowance for a patent covering the administration of Korlym® with food.  The patent will expire in November 2032.

“This patent covers an important finding of our research – that for optimal effect, Korlym must be taken with food,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “Korlym’s label instructs doctors that ‘Korlym must always be taken with a meal.’”

Upon issuance, Corcept plans to list the patent, entitled “Optimizing Mifepristone Absorption” (U.S. Pat. App. 13/677,465), in the U.S. Food and Drug Administration’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”).  Korlym is currently protected by ten patents listed in the Orange Book.

Hypercortisolism

Hypercortisolism, often referred to as Cushing’s syndrome, is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. In the United States, an estimated 20,000 patients have Cushing’s syndrome, with about 3,000 new patients diagnosed each year. Symptoms vary, but most people with Cushing’s syndrome experience 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. Hypercortisolism can affect every organ system in the body and can be lethal if not treated effectively.

About Corcept Therapeutics Incorporated

Corcept is a commercial-stage company engaged in the discovery and development of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of the stress hormone cortisol.  Korlym® (mifepristone) was the first treatment approved by the U.S. Food and Drug Administration for patients with Cushing’s syndrome.  Corcept has discovered a large portfolio of proprietary compounds, including relacorilant, exicorilant and miricorilant, that selectively modulate the effects of cortisol but not progesterone. Corcept owns extensive United States and foreign intellectual property covering the composition of its selective cortisol modulators and the use of cortisol modulators, including mifepristone, to treat a variety of serious disorders.

Forward-Looking Statements

Statements in this press release, other than statements of historical fact, are forward-looking statements, which are based on Corcept’s current plans and expectations and are subject to risks and uncertainties that might cause actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, Corcept’s ability to generate sufficient revenue to fund its commercial operations and development programs; the availability of competing treatments, including generic versions of Korlym; Corcept’s ability to obtain acceptable prices or adequate insurance coverage and reimbursement for Korlym; and risks related to the development of Corcept’s product candidates, including regulatory approvals, mandates, oversight and other requirements. These and other risks are set forth in Corcept’s SEC filings, which are available at Corcept’s website and the SEC’s website. In this press release, forward-looking statements include those concerning Corcept’s plans to list the patent “Optimizing Mifepristone Absorption” in the Orange Book; Korlym’s current protection by ten patents listed in the Orange Book; and the scope and protective power of Corcept’s intellectual property. Corcept disclaims any intention or duty to update forward-looking statements made in this press release.

CONTACT:
Christopher S. James, MD
Director, Investor Relations
Corcept Therapeutics
650-684-8725
cjames@corcept.com
www.corcept.com

Relacorilant Effectively Manages Cortisol Effects in Cushing’s Patients

Relacorilant, an investigational therapy developed by Corcept Therapeutics, may effectively manage the effects of excess cortisol in patients with Cushing’s syndrome, interim data from an ongoing Phase 2 trial show.

In particular, the treatment significantly improved sugar tolerance and the levels of osteocalcin, a bone growth biomarker  commonly suppressed by excess cortisol.

Corcept announced in a press release that the trial (NCT02804750) has completed patient enrollment. Results from the first patients will be presented during the upcoming 27th American Association of Clinical Endocrinologists (AACE) annual meeting, May 16-20 in Boston. Full data is expected by the third quarter of 2018.

Relacorilant, also known as CORT125134, was designed to prevent the effects of excess cortisol by blocking one of its receptors, the glucocorticoid receptor.

In a Phase 1 trial with healthy volunteers, multiple doses of relacorilant had a similar effect as Korlym (mifepristone) — an approved medicine for Cushing’s patients — without its known side effects.

In addition to the early efficacy data, the study showed that the treatment was generally safe and well-tolerated by the patients, with adverse events reportedly mild in severity.

These findings supported the launch of the Phase 2 trial in patients with Cushing’s syndrome. In the trial, roughly 30 patients are receiving escalating doses of relacorilant for a total of 12 weeks.

Patients were divided into two groups. The first group, which includes 17 patients, receives the lowest dose — 100 mg/day of relacorilant for four weeks, followed by 150 mg/day for four weeks, and then 200 mg/day for the last four weeks. The second group, called the high-dose cohort, is treated with a similar regimen but with a starting dose of 250 mg/day and a final dose of 350 mg/day.

Patients in the low-dose group had a significant improvement in their glucose tolerance and a 60% increase in blood osteocalcin.

In addition, the treatment reduced the blood pressure in 45% of patients with uncontrolled high blood pressure from cortisol excess. Importantly, the results after 12 weeks of relacorilant were similar to those seen after six months of Korlym treatment.

Safety data continues to show a positive profile, with no evidence of serious adverse effects and no affinity toward the progesterone receptor, which is a major drawback of Korlym.

“Relacorilant’s clinical results are striking because the doses these patients received were the study’s lowest. We did not expect patients to experience any meaningful clinical benefit, but they clearly did,” Robert S. Fishman, MD, chief medical officer of Corcept, said in the release. “We look forward to presenting data from these low-dose patients at the AACE meeting next week. With the trial’s final, high-dose cohort fully enrolled, we will have final data in the third quarter.”

Supported by these preliminary data, Corcept has accelerated the preparations for a Phase 3 trial on relacorilant in Cushing’s syndrome patients.

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