Osilodrostat Continues to Show Promise for Cushing’s Disease

Posted on April 1, 2019 by MaryO

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

In a prior 22-week phase 2 study (LINC-2), osilodrostat normalized mUFC in most patients. Results of the extension phase were reported by Medscape Medical News 2 years ago.

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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From https://www.medscape.com/viewarticle/910864#vp_1

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Medical Therapies in Cushing’s Syndrome

Posted on December 4, 2016 by MaryO
Chapter

The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease

pp 165-179

Date: 03 December 2016

Medical Therapies in Cushing’s Syndrome

Abstract

Medical therapy has an important, albeit secondary, role in patients with Cushing’s syndrome. While medications are not currently used as definitive therapy of this condition, they can be very effective in controlling hypercortisolism in patients who fail surgery, those who are not surgical candidates, or those whose tumor location is unknown. Medical therapies can be particularly helpful to control hypercortisolism in patients with Cushing’s disease who underwent radiation therapy and are awaiting its salutary effects.

Currently available treatment options include several steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane, etomidate), which block one or several steps in cortisol synthesis in the adrenal glands, centrally acting agents (cabergoline, pasireotide), which decrease ACTH secretion, and glucocorticoid receptor antagonists, which are represented by a single agent (mifepristone). With the exception of pasireotide and mifepristone, available agents are used “off-label” to manage hypercortisolism. Several other medications are at various stages of development and may offer additional options for the management of this serious condition.

As more potential molecular targets become known and our understanding of the pathogenesis of Cushing’s syndrome improves, it is anticipated that novel, rationally designed medical therapies may emerge. Clinical trials are needed to further investigate the relative risks and benefits of currently available and novel medical therapies and examine the potential role of combination therapy in the management of Cushing’s syndrome.

Keywords

Cabergoline, Etomidate, Ketoconazole, Levoketoconazole, Metyrapone, Mifepristone, Mitotane, Osilodrostat, Pasireotide, Pituitary adenoma

From http://link.springer.com/chapter/10.1007/978-3-319-45950-9_9

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Experimental Drug Improves Cushing’s Disease

Posted on August 12, 2016 by MaryO

International phase 3 trial is largest study ever of rare endocrine disorder

A new investigational drug significantly reduced urinary cortisol levels and improved symptoms of Cushing’s disease in the largest clinical study of this endocrine disorder ever conducted.

Results of the clinical trial conducted at centers on four continents appear in the March 8 issue of the New England Journal of Medicine and show that treatment with pasireotide cut cortisol secretion an average of 50 percent and returned some patients’ levels to normal.

“Cushing’s disease is a rare disorder, with three to five cases per million people. It can affect all ages and both genders but is most common in otherwise healthy young women,” says Harvard Medical School Professor of Medicine Beverly M.K. Biller of the Massachusetts General Hospital (MGH) Neuroendocrine Unit, senior author of the study.

“Often misdiagnosed, Cushing’s is associated with a broad range of health problems – causing physical changes, metabolic abnormalities, and emotional difficulties – and if not controlled, significantly increases patients’ risk of dying much younger than expected,” Biller says.

Cushing’s disease, one of several conditions that lead to Cushing’s syndrome, is characterized by chronically elevated secretion of the hormone cortisol. The disease is caused by a benign pituitary tumor that oversecretes the hormone ACTH, which in turn induces increased cortisol secretion by the adrenal glands.

Symptoms of Cushing’s syndrome include weight gain, hypertension, mood swings, irregular or absent periods, abnormalities of glucose processing (insulin resistance, glucose intolerance, and type 2 diabetes), and cardiovascular disease. Because those symptoms are associated with many health problems, physicians may not consider the rare possibility of Cushing’s. The diagnosis can be difficult to make and usually requires the expertise of an endocrinologist. Because cortisol levels normally fluctuate during the day, a single blood test is unlikely to identify chronic elevation, and thus the most common diagnostic test measures a patient’s 24-hour urinary output.

First-line treatment for Cushing’s disease is surgical removal of the ACTH-secreting tumor, which leads to remission in 65 to 90 percent of patients. But symptoms return in 10 to 30 percent of those patients, requiring repeat surgery, radiation therapy, or treatment with drugs that interfere with part of the cortisol control system. Until last month, there was no specific FDA-approved medical treatment for Cushing’s syndrome; the newly approved drug mifepristone should benefit some patients, but it does not affect the pituitary source of the condition or reduce cortisol levels.

The current phase 3 trial of pasireotide — the first drug that blocks ACTH secretion by binding to somatostatin receptors on the pituitary tumor — was sponsored by Novartis Pharma. The trial enrolled 162 patients at 62 sites in 18 countries. Nearly 85 percent of participants had either persistent disease that had not responded to surgery or had recurrent disease; the other 15 percent were recently diagnosed but not appropriate candidates for surgery.

Participants were randomly assigned to two groups, one starting at two daily 600-microgram injections of pasireotide and the other receiving 900-microgram doses. Three months into the 12-month trial, participants whose urinary cortisol levels remained more than twice the normal range had their dosage levels increased. During the rest of the trial, dosage could be further increased, if necessary, or reduced if side effects occurred.

At the end of the study period, many patients had a significant decrease in their urinary cortisol levels, with 33 achieving levels within normal range at their original dosage by month six of the trial. Participants whose baseline levels were less than five times the upper limit of normal were more likely to achieve normal levels than those with higher baseline levels, and the average urinary cortisol decrease across all participants was approximately 50 percent. Many Cushing’s disease symptoms decreased, and it became apparent within the first two months whether or not an individual was going to respond to pasireotide.

Transient gastrointestinal discomfort, known to be associated with medications in the same family as pasireotide, was an expected side effect. Another side effect was elevated glucose levels in 73 percent of participants, something not seen to the same extent with other medications in this family. These elevated levels will require close attention, because many Cushing’s patients already have trouble metabolizing glucose. Biller explains, “Those patients who already were diabetic had the greatest increases in blood sugar, and those who were pre-diabetic were more likely to become diabetic than those who began with normal blood sugar. However, elevations were even seen in those who started at normal glucose levels, so this is real and needs to be monitored carefully.”

Additional trials of pasireotide are in the works, and a phase 3 study of a long-acting version of the drug was recently announced. Biller notes that the potential addition of pasireotide to available medical treatments for Cushing’s disease would have a number of advantages. “It’s very important to have medications that work at different parts of the cortisol control system – which is the case for the currently used medications that work at the adrenal gland level; pasireotide, which works at the pituitary gland; and mifepristone, which blocks the action of cortisol at receptors in the body. Having more options that work in different ways is valuable because not all patients respond to one medicine and some may be unable to tolerate a specific drug’s side effects.

“As we have more drugs available to treat Cushing’s,” Biller adds, “I think in the long run we may start using combinations of drugs, which is the approach we use in some patients with acromegaly, another disorder in which a pituitary tumor causes excess hormone secretion. Ultimately, we hope to be able to give lower doses leading to fewer overall side effects, but that remains to be determined by future studies.”

Annamaria Colao, University of Naples, Italy, is the lead author of the report. Additional co-authors are Stephan Petersenn, University of Duisberg-Essen, Germany; John Newell-Price, University of Sheffield, U.K.; James Findling, Medical College of Wisconsin, Milwaukee; Feng Gu, Peking Union Medical College Hospital, Beijing; Mario Maldonado, Ulrike Schoenherr, and David Mills, Novartis Pharma; and Luiz Roberto Salgado, University of São Paulo Medical School, Brazil.

From http://dailyrecords.us/experimental-drug-improves-cushings-disease/

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Osilodrostat for Cushing’s

Posted on November 12, 2015 by MaryO

The study looked at a drug to treat Cushing’s disease. The article, in the journal Pituitary, is called Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease.
Fleseriu M, Pivonello R, Young J, Hamrahian AH, Molitch ME, Shimizu C, Tanaka T, Shimatsu A, White T, Hilliard A, Tian C, Sauter N, Biller BM, Bertagna X.
Pituitary. 2015 Nov 5. [Epub ahead of print]

Abstract

PURPOSE:
In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing’s disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing’s disease.

METHODS:
Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50 % decrease from baseline) at weeks 10 and 22.

RESULTS:
Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.

CONCLUSIONS:
Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

KEYWORDS:
11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat

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