The Cushing's syndrome market is heating up with three second-generation drugs in late-stage development to join the two approved medications, Signifor (pasireotide, Recordati SpA) and Korlym (mifepristone, Corcept Therapeutics Inc.), as well as a couple of off-label options.

The disease is characterized by high levels of cortisol, which can lead to obesity, hypertension and diabetes that often gets misdiagnosed as the symptoms rather than the underlying problem.

"It is a long and sordid journey for most Cushing's syndrome patients. The average time to diagnosis is approximately six years," Matthew Pauls, president and CEO of Strongbridge Biopharma plc, told BioWorld.

Once properly diagnosed by an endocrinologist, about 70% of patients can have surgery to remove the benign adenomas that stimulate the adrenal gland to make cortisol. But because the tumors are small, they often aren't fully removed and about 50% of patients have recurrence of the disease. "Six, eight, 10 years down the line, they're back to square one," Pauls pointed out.

At that point, chronic treatment with medicinal therapy is usually prescribed: Ketoconazole and Metopirone (metyrapone, Laboratoire HRA Pharma) are used off-label as steroidogenesis inhibitors; Signifor, which activates somatostatin receptors in the pituitary adenoma; and Korlym, which works as a glucocorticoid receptor (GR) antagonist, blocking the effects of cortisol.

But each drug has issues. Ketoconazole produces liver toxicity that requires routine monitoring. Metopirone results in the buildup of cortisol precursors that can cause hypokalemia, hirsutism (male-pattern hair growth in women) and acne. Signifor works on the tumor, but doesn't effectively control cortisol levels and has liver toxicity and hyperglycemia as side effects. Finally, Korlym blocks the effect of cortisol, but doesn't lower the level, causing hypokalemia; it also binds to the progesterone receptor, leading to anti-progesterone side effects.

The better half

Strongbridge's next-generation drug, Recorlev (levoketoconazole), is one of the two enantiomers that make up ketoconazole. Preclinical studies suggest that the half Strongbridge picked has better inhibition of cortisol synthesis, while reducing liver toxicity.

In the single-arm phase III Sonics study, 30% of patients achieved normalization of mean urinary free cortisol (UFC) after six months of maintenance treatment with Recorlev without a dose increase (p=0.015 vs. null hypothesis of ≤20%). Equally important, there were no severe drug-induced liver injury, Hy's law, transaminases greater than 20 times the upper limit of normal (ULN), although 10.6% of patients had an alanine aminotransferase measurement of greater than three times ULN and 3.2% exceeded five times the ULN. (See BioWorld, Aug. 9, 2018.)

The reduced cortisol levels resulted in improved downstream effects. Secondary endpoints for cardiovascular risk, including fasting blood glucose, hemoglobin A1C, total cholesterol, low-density lipoprotein-cholesterol, body weight and body mass index, were all improved from baseline (p<0.0001 for each).

Strongbridge, of Trevose, Pa., is currently testing Recorlev in a second phase III study, dubbed Logics. The withdrawal study will test Recorlev's ability to prevent relapse and recurrence compared to placebo in up to 54 patients. Data from Logics are expected in the first quarter of 2020, with positive data allowing the company to file with the FDA by the end of the third quarter of next year.

"We're in the proverbial home stretch," Pauls said.

Beating the generics

Corcept, of Menlo Park, Calif., is facing generic competition for Korlym, but it has a next-generation compound, relacorilant, that should be able to beat generics to the market if it can win a post-grant review by the Patent Trial and Appeal Board and a lawsuit brought on by Teva Pharmaceutical Industries Ltd., of Jerusalem, which would push back a generic launch to the 2035-2036 time frame.

Relacorilant is more selective than Korlym, so it doesn't bind to the progesterone receptor and cause subsequent side effects. In a phase II study, relacorilant also appeared to have a better effect on diabetes and hypertension than Korlym does.

The pivotal phase III Grace study is underway with enrollment expected to be complete by the end of this year and data expected in late 2020.

"Relacorilant appears to be sufficiently differentiated, particularly on the adverse-event profile, as to not be negatively impacted by the generics entry. We note the timing of the generics entry could influence the adoption of relacorilant as relacorilant needs time to become a preferred GR antagonist," Jefferies analyst Chris Howerton wrote in a note to clients.

Novartis castoffs

Recordati, of Milan, Italy, recently acquired Signifor, a long-acting version of the drug called Signifor LAR and osilodrostat from Novartis AG, of Basel, Switzerland, for $390 million. Recordati is also on the hook for undisclosed milestone payments for the approval and market access of osilodrostat and royalties on sales of osilodrostat.

Osilodrostat is a steroidogenesis inhibitor working at the same step as Metopirone, but it appears to be a more potent inhibitor of 11-beta hydroxylase. In a phase III study, 86% of patients achieved normal mean UFC at week 34, compared to 29% for placebo (p<0.001). By week 48, 66% of patients had achieved normal mean UFC.

Marketing applications for osilodrostat have been submitted to the EMA and FDA, but the agencies may end up waiting for data from an ongoing confirmatory phase III study that's expected to be completed in early 2021.

Multiple winners?

There appears to be plenty of room for new drugs to come to market. A survey of 25 U.S. endocrinologists by Jefferies found that no drug had a median duration of more than a year despite this being a chronic disease. "This suggests that patients are cycling through drugs, either due to insufficient efficacy and/or unmanageable tolerability," Jefferies' Howerton wrote.

With Cushing's being a heterogeneous disease, there may be room for more than one next-generation drug. "We note there is unlikely to be a dominant player in the Cushing's syndrome market, with the potential for four to five drugs used by physicians based on patient characteristics and response/tolerance to those drugs." Howerton wrote while noting that "cost/access is expected to be the key hindrance to adoption" of the next-generation drugs.

Of course, the new drugs might not even need to compete with each other. Jefferies' survey found that 23% of patients currently get combination therapies, with ketoconazole and Korlym most often used as part of combinations, which could bode well for Strongbridge and Corcept as they develop next-generation versions of their drugs.

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