A recent clinical trial reveals encouraging news for a Cushing’s disease treatment
A poster from ENDO 2025 showed that osilodrostat provides sustained clinical benefits in Cushing’s patients who experienced positive outcomes by the end of the treatment period. Richard Auchus, MD, PhD, discusses how the data reinforces the drug’s use, which was well-tolerated for extended periods.
Not that long ago, the only way to treat Cushing’s was through surgery. This isn’t news to anyone reading this. But many patients with Cushing’s – especially after long-term illness – become too sick for surgery. Risk of blood clots, infections. And then there’s the myopathy that might not ever resolve.
During ENDO 2025 in San Francisco, Richard Auchus, MD, PhD, of the Division of Metabolism, Endocrinology & Diabetes at the University of Michigan in Ann Arbor, presented encouraging findings the LINC rollover study on the long-term safety and effectiveness of the medication osilodrostat in patients with Cushing’s disease.
The study demonstrated that osilodrostat — an 11β-hydroxylase inhibitor — provides sustained clinical benefits, with the majority of patients continuing to experience positive outcomes by the end of the treatment period. The data reinforce existing evidence of the favorable safety profile of osilodrotat, highlighting its well-tolerated nature during extended use. The study reported low discontinuation rates due to treatment-related adverse events, and no new safety concerns were identified. The results come from the LINC rollover study – for participants who completed the LINC 2, 3, and 4 Phase 2 and 3 trials studying osilodrostat.
“This is a very potent inhibitor of 11β-hydroxylase and aldosterone synthase,” Auchus says.
“It’s quite effective in treating cortisol excess. And it is, I think now the most popular cortisol synthesis inhibitor that’s used.”
Durable Effects
Even when patients with Cushing’s have surgery, there’s no guarantee of a cure. Auchus tells Endocrine News of patient he treated who had surgery, but Cushing’s didn’t resolve, so the patient entered the LINC3 study and remained on osilodrostat for seven years through the extension phase and then using commercial drug with sustained control of cortisol production. “I don’t think it was that unexpected because that’s what we saw in the course studies, that the effects [of osilodrostat] are durable,” Auchus says. He was imaged periodically, and after all this time, the small focus of residual tumor became visible. This time, surgery did the trick. “We were able to cure him, or at least send him into remission and stop treatment.”
“By giving [osilodrostat] once daily, you start to emulate the circadian rhythm and sleep improves. As we get these new tools and we show that they are safe and effective, now it’s time for us to use them more effectively and to try to do even better than just normalizing the urinary free cortisol.” — Richard Auchus, MD, PhD, professor, internal medicine, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan
Auchus explains that sometimes there is no choice but to treat people with medication preoperatively in order to get these patients’ cardiovascular and musculoskeletal status in a state where they can survive the surgery. “Even the skin thinning causes the wounds to tear,” he says. “Many of us find that if you rehab them for a period of time with medical therapy, then they have less risk of having complications when they go to surgery.”
Staying in Control
According to Auchus, osilodrostat was developed as an aldosterone synthase inhibitor, but the selectivity over 11β-hydroxylase, two enzymes that are 93% identical, was not high enough for it to be administered for treating hypertension without affecting cortisol, so the drug was repurposed for treating Cushing’s, and the trials began.
LINC 3 was a randomized withdrawal trial in which all participants were given osilodrostat with the primary endpoint being the loss of control during that randomized withdrawal period. Auchus says that the FDA wanted a placebo-controlled trial as well, so LINC 4 became the first placebo-controlled trial from the beginning that was ever done in Cushing’s.
“It turns out that we learned a lot from LINC 3 and we were able to titrate the medication more safely by taking our time and using fewer steps, because the drug is so potent, we didn’t really have to go up very high in most people,” Auchus says. “Based on the information we learned from LINC 3, we conducted LINC 4 very effectively, I think, and the data really showed a tremendous difference between osilodrostat and placebo.”
Researchers are now on LINC 6, a long-term efficacy trial for people who have been prescribed osilodrostat long-term. “It’s all about the long-term safety and efficacy. And the thing about osilodrostat that was borne out both in the core studies from LINC 3 and LINC 4, the extension phase, and now being studied in LINC 6, is that when people are controlled, they don’t escape control, they stay in control.”
The Work Continues
For now, osilodrostat is dosed twice a day, although Auchus says there are researchers looking at whether the drug can be taken just once a day, or even switching up dosing depending on the severity of the disease. “The urinary free cortisol was the primary endpoint in the LINC 2, 3 and 4 trials, but cortisol is supposed to follow a circadian rhythm,” he says. “Now, just getting the urinary free cortisol to normal may not be good enough, so people are experimenting with asymmetric dousing.”
“I like to tell people normal is normal. We want people not to just be okay, we want them to be normal, and how can we use these tools in the best way to make people as close as possible to where they should be without the disease?” — Richard Auchus, MD, PhD, professor, internal medicine, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan
“By giving it once daily, you start to emulate the circadian rhythm, and sleep improves,” Auchus continues. “As we get these new tools and we show that they are safe and effective, now it’s time for us to use them more effectively and to try to do even better than just normalizing the urinary free cortisol.”
Auchus says that when he was a fellow, there were no FDA-approved drugs to treat Cushing’s, no interest even from the industry. There is of course interest now. Osilodrostat was approved by the FDA in 2020. (Recordati Rare Diseases, Inc. markets the medication as ISTURISA®.) And while osilodrostat is promising, Auchus is careful to say it’s just like any other medication; it can have serious side effects. For example, Auchus says, osilodrostat is that it’s so potent you can easily over-treat people and cause adrenal insufficiency.
Still, the drug seems promising for patients with Cushing’s disease – people who can’t sleep, or have myopathy so bad they can’t climb stairs or even sometimes lift themselves off the floor. So the works continues. Several drugs are still being studied or in development. “I think it’s great for patients, but I think we are going through, in a very short period of time, from using off-label kind of seat-of-the-pants things to using highly effective drugs,” Auchus says. “But now it’s like, how can we do even better than that? Because I like to tell people normal is normal. We want people not to just be okay, we want them to be normal, and how can we use these tools in the best way to make people as close as possible to where they should be without the disease.”
Bagley is the senior editor of Endocrine News. He wrote about the relationship between type 2 diabetes and liver disease, and how endocrinologists can take the lead in treatment in the August issue.
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