NEW ORLEANS — The investigational drug osilodrostat (Novartis) continues to show promise for treating Cushing's disease, now with new phase 3 trial data.
The data from the phase 3, multicenter, double-blind randomized withdrawal study (LINC-3) of osilodrostat in 137 patients with Cushing's disease were presented here at ENDO 2019: The Endocrine Society Annual Meeting by Beverly M.K. Biller, MD, of the Neuroendocrine & Pituitary Tumor Center at Massachusetts General Hospital, Boston.
"Osilodrostat was effective and shows promise for the treatment of patients with Cushing's disease," Biller said.
Osilodrostat is an oral 11β-hydroxylase inhibitor, the enzyme that catalyzes the last step of cortisol biosynthesis in the adrenal cortex. Its mechanism of action is similar to that of the older Cushing's drug metyrapone, but osilodrostat has a longer plasma half-life and is more potent against 11β-hydroxylase.
Significantly more patients randomized to osilodrostat maintained a mean urinary free cortisol (mUFC) response versus placebo at 34 weeks following a 24-week open-label period plus 8-week randomized phase, with rapid and sustained mUFC reduction in most patients.
Patients also experienced improvements in clinical signs of hypercortisolism and quality of life. The drug was generally well-tolerated and had no unexpected side effects.
Asked to comment, session comoderator Julia Kharlip, MD, associate medical director of the Pituitary Center at the University of Pennsylvania, Philadelphia, told Medscape Medical News, "This drug is incredibly exciting because over 80% of people were controlled fairly rapidly. People could get symptom relief but also a reliable response. You don't have to wonder when you're treating a severely affected patient if it's going to work. It's likely going to work."
However, Kharlip cautioned that it remains to be seen whether osilodrostat continues to work long-term, given that the older drug metyrapone — which must be given four times a day versus twice daily for osilodrostat — is known to become ineffective over time because the pituitary tumor eventually overrides the enzyme blockade.
"Based on how osilodrostat is so much more effective at smaller doses, there's more hope that it will be effective long term...If the effectiveness and safety profile that we're observing now continues to show the same performance years in a row, then we've got our drug."
Osilodrostat Potentially Addresses an Unmet Medical Need
Cushing's disease is a rare disorder of chronic hypercortisolism with significant burden, increased mortality, and decreased quality of life. Pituitary surgery is the recommended first-line treatment for most patients, but not all patients remit with surgery and some require additional treatment.
Pasireotide (Signifor, Novartis), an orphan drug approved in the United States and Europe for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy, is also only effective in a minority of patients.
"There hasn't been a medicine effective for long-term treatment, so a lot of patients end up getting bilateral adrenalectomy, thereby exchanging one chronic medical disease for another," Kharlip explained.
Biller commented during the question-and-answer period, "I think because not all patients are placed in remission with surgery initially and because other patients subsequently recur — a problem that is more common than we used to believe — we do need medical therapies."
She continued, "I think it's important to have a large choice of medical therapies that work in different places in the hypothalamic-pituitary-adrenal axis.
"Even though surgery is the right initial therapy for everyone, I think in terms of subsequent medical therapy we have to tailor that to the individual circumstances of the patient in terms of the goals of treatment, and perhaps what other medicines they're on, the degree of cortisol excess [and other factors]."
Highly Significant Normalization in Mean UFC Versus Placebo
The current phase 3 study, LINC-3, was conducted on the basis of that proof-of-concept study, Biller said.
The trial was conducted in 19 countries across four continents in patients with persistent or recurrent Cushing's disease screened for mUFC > 1.5 times the upper limit of normal and other entry criteria. In total, 137 patients were enrolled and randomized.
Participants were a median age of 40 years, 77% were female, and 88% had undergone prior pituitary surgery. Nearly all (96%) had received at least one previous treatment for Cushing's.
At baseline, patients' mean mUFC (364 µg/24 hours) was 7.3 times the upper limit of normal, which is "quite significant hypercortisolemia," Biller noted.
All patients initially received osilodrostat, with a rapid dose uptitration every 2 weeks from 2 to 30 mg orally twice daily until they achieved a normal UFC.
They continued on open-label medication until week 24, when urine samples were collected. Patients who had an mUFC less than the upper limit of normal and had not had a dose increase in the prior 12 weeks were eligible for the double-blind phase. Those who were ineligible continued taking open-label drug.
The 70 eligible patients were randomized to continue taking osilodrostat (n = 36) or were switched to placebo (n = 34) for another 8 weeks. After that, the patients taking placebo were switched back to osilodrostat until week 48. A total of 113 patients completed the 48 weeks.
The primary efficacy endpoint was mUFC at 34 weeks (the end of the 8-week randomized phase).
For those randomized to continue on the drug, mUFC remained in the normal range in 86.1% of patients versus just 29.4% of those who had been switched to placebo for the 8 weeks. The difference was highly significant (odds ratio, 13.7; P < .001), Biller reported.
A key secondary endpoint, proportion of patients with an mUFC at or below the ULN at 24 weeks without up-titration after week 12, was achieved in 53%.
The mean dose at 48 weeks was 11.0 mg/day, "a fairly low dose," she noted.
Clinical features were also improved at week 48, including systolic and diastolic blood pressure (percentage change –6.8 and –6.6, respectively), weight (–4.6), waist circumference (–4.2), fasting plasma glucose (–7.1), and HbA1c (–5.4).
Scores on the Cushing Quality of Life scale improved by 52.4 points, and Beck Depression Inventory scores dropped by 31.8 points.
Most Adverse Events Temporary, Manageable
The most commonly reported adverse events were nausea (41.6%), headache (33.6%), fatigue (28.5%), and adrenal insufficiency (27.7%), and 10.9% of patients overall discontinued because of an adverse event.
Adverse events related to hypocortisolism occurred in 51.1% of patients overall, with 10.2% being grade 3 or 4. However, most of these were single episodes of mild-to-moderate intensity and mainly occurred during the initial 12-week titration period. Most patients responded to dose reduction or glucocorticoid supplementation.
Adverse events related to accumulation of adrenal hormone precursors occurred in 42.3% of patients overall, with the most common being hypokalemia (13.1%) and hypertension (12.4%).
No male patients had signs or symptoms related to increased androgens or estrogens. However, 12 female patients experienced hirsutism, most of those patients also had acne, and one had hypertrichosis. None discontinued because of those symptoms.
Kharlip commented, "What's really inspiring was that even though half of the patients had symptoms related to adrenal insufficiency, it sounded as if they were quickly resolved with treatment and none discontinued because of it."
"And it may have been related to study design where the medication was titrated very rapidly. There is probably a way to do this more gently and get the good results without the side effects."
Kharlip also praised the international consortium that devised the protocol and collaborated in the research effort.
"It's incredibly exciting and gratifying to see the world come together to get these data. It's such a rare disease. To be able to have something like that in the field is a dream, to have a working consortium. The protocol was effective in demonstrating efficacy. It's just a win on so many levels for a disease that currently doesn't have a good therapy...I struggle with these patients all the time so I'm thrilled that there is hope."
An ongoing confirmatory phase 3 study, LINC-4, is evaluating patients up to 48 weeks.
Biller is a consultant for and has received grants from Novartis and Strongbridge. Kharlip has reported no relevant financial relationships.
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Cite this: Osilodrostat Continues to Show Promise for Cushing's Disease - Medscape - Mar 25, 2019.