Osilodrostat Continues to Show Promise for Cushing’s Disease

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

Even in Remission, Cushing’s Patients Have Excess Mortality

Cushing’s disease patients in Sweden have a higher risk of death than the general Swedish population, particularly of cardiovascular complications, and that increased risk persists even in patients in remission, a large nationwide study shows.

The study, “Overall and disease-specific mortality in patients with Cushing’s disease: a Swedish nationwide study,” was published in the Journal of Clinical Endocrinology and Metabolism.

The outcomes of Cushing’s disease patients have improved with the introduction of several therapeutic approaches, such as minimally invasive surgery and cortisol-lowering therapies. However, mortality is still high, especially among those who do not achieve remission.

While currently patients in remission are thought to have a better prognosis, it is still unclear whether these patients still have a higher mortality than the general population. Understanding whether these patients are more likely to die and what risk factors are associated with increased mortality is critical to reduce death rates among Cushing’s patients.

A team of Swedish researchers thus performed a retrospective study that included patients diagnosed with Cushing’s disease who were part of the Swedish National Patient Registry between 1987 and 2013.

A total of 502 patients with Cushing’s disease were included in the study, 419 of whom were confirmed to be in remission. Most patients (77%) were women; the mean age at diagnosis was 43 years, and the median follow-up time was 13 years.

During the follow-up, 133 Cushing’s patients died, compared to 54 expected deaths in the general population — a mortality rate 2.5 times higher, researchers said.

The most common causes of death among Cushing’s patients were cardiovascular diseases, particularly ischemic heart disease and cerebral infarctions. However, infectious and respiratory diseases (including pneumonia), as well as diseases of the digestive system, also contributed to the increased mortality among Cushing’s patients.

Of those in remission, 21% died, compared to 55% among those not in remission. While these patients had a lower risk of death, their mortality rate was still 90% higher than that of the general population. For patients who did not achieve remission, the mortality rate was 6.9 times higher.

The mortality associated with cardiovascular diseases was increased for both patients in remission and not in remission. Also, older age at the start of the study and time in remission were associated with mortality risk.

“A more aggressive treatment of hypertension, dyslipidemia [abnormal amount of fat in the blood], and other cardiovascular risk factors might be warranted in patients with CS in remission,” researchers said.

Of the 419 patients in remission, 315 had undergone pituitary surgery, 102 had had their adrenal glands removed, and 116 had received radiation therapy.

Surgical removal of the adrenal glands and chronic glucocorticoid replacement therapy were associated with a worse prognosis. In fact, glucocorticoid replacement therapy more than twice increased the mortality risk. Growth hormone replacement was linked with better outcomes.

In remission patients, a diagnosis of diabetes mellitus or high blood pressure had no impact on mortality risk.

Overall, “this large nationwide study shows that patients with [Cushing’s disease] continue to have excess mortality even after remission,” researchers stated. The highest mortality rates, however, were seen in “patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

“Further studies need to focus on identifying best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of cardiovascular and mental health in these patients,” the study concluded.

From https://cushingsdiseasenews.com/2019/02/28/even-in-remission-cushings-patients-have-excess-mortality-swedish-study-says/

Laparoscopic Removal of Adrenal Glands Safe for Obese Cushing’s Patients

Laparoscopic adrenalectomy — a minimally invasive procedure that removes the adrenal glands through a tiny hole in the abdomen — can be safely performed in obese patients with Cushing’s syndrome, a retrospective study reports.

The surgery resolved symptoms in 95% of cases, reducing cortisol levels, lowering blood pressure, and leading to a significant loss of weight in morbidly obese patients.

The study, “Minimally invasive approach to the adrenal gland in obese patients with Cushing’s syndrome,” was published in the journal Minimally Invasive Therapy & Allied Technologies.

Cushing’s syndrome results from the prolonged secretion of excess cortisol, the major glucocorticoid hormone. While most cases are caused by tumors in the pituitary gland, up to 27% result from tumors in the adrenal glands.

In these cases, the standard therapeutic strategy is to remove one or both adrenal glands, a surgical procedure called adrenalectomy. However, because glucocorticoids are key hormones regulating fat metabolism, Cushing’s syndrome patients are known to be prone to obesity, a feature that is often associated with post-operative complications.

In this study, researchers aimed to compare the outcomes of morbidly obese patients versus the mildly obese and non-obese who underwent a minimally invasive procedure to remove their adrenal glands.

The approach, called laparoscopic adrenalectomy, inserts tiny surgical tools through a small hole in the abdomen, along with a camera that helps guide the surgeon.

The study included 228 patients (mean age 53.4 years). Of them, 62 were non-obese, 87 were moderately obese, and 79 were considered morbidly obese. There were 121 patients with tumors in the right adrenal gland, 96 in the left gland, and 11 in both glands.

High blood pressure was the most common symptom, affecting 66.7% of the participants.

Surgery lasted 101 minutes on average, and patients remained in the hospital for a median 4.3 days afterward. Six patients had to be converted into an open surgery because of uncontrollable loss of blood or difficulties in the procedure. Post-surgery complications, most of which were minor, were seen in seven patients.

One patient had blood in the peritoneal cavity and had to have surgery again; another patient had inflammation of the pancreas that required a longer admission.

The analysis showed no statistical differences among the three groups regarding the length of surgery, length of stay in the hospital, or the rate of conversion into open surgery.

However, in obese women, surgeons chose a different surgical incision when removing the left adrenal gland, “suggesting that the distribution of visceral fat in these patients could constitute a drawback for the [standard] approach,” researchers said.

After the surgery, 95% of patients saw their symptoms resolve, including cortisol levels, high blood pressure, and glucose metabolism, and none had a worsening of symptoms in the 6.3 years of follow-up. Obese patients also showed a significant reduction in their weight — 2 kg by 18 months, and 5 kg by the end of follow-up.

Overall, “laparoscopic adrenalectomy is safe and feasible in obese patients affected with Cushing’s disease and it can lead to the resolution of the related symptoms,” researchers said.

The benefits of the surgery in patients with Cushing’s syndrome “could be extended to the improvements and in some cases to the resolution of hypercortisolism related symptoms (i.e. hypertension or even morbid obesity),” the study concluded.

Adapted from https://cushingsdiseasenews.com/2019/02/07/laparoscopic-removal-of-adrenal-glands-safe-for-obese-cushings-patients/

Hormonal Imbalance – Indication of Pituitary Gland Tumors

Patna: Improper functioning of the Pituitary gland usually results in excess or under production of hormones that leads to a formation of mass called tumor, which can be benign or malignant. Such tumors in this gland can create numerous serious medical conditions by interfering with the normal functioning of the endocrine system and pituitary gland.

 

“Though the occurrence of tumor is more likely after the age of 30 years, it still can impact at an early age. The survival rates of tumor due to its complicated location also depend on other factors like the patient’s age, type and size of tumor. Mostly, pituitary gland tumors are non cancerous but the exact causes are unknown. Some of them are hereditary and some are caused by a rare genetic disorder called as multiple endocrine neoplasia type 1. This disorder can also lead to over-activity or enlargement of 3 different endocrine-related glands, which also includes the pituitary gland. “Dr Aditya Gupta, Director, Neurosurgery, Agrim institute for neuro sciences, Artemis Hospital

 

Diagnosis at an early stage can help the treatment procedure to be totally non-invasive with the use of advances technology called as Cyberknife. Cyberknife which is the most advanced radiation therapy is completely non-invasive therapy available for the treatment of benign as well as malignant tumors. This therapy works the best for some pituitary tumors that are upto 2 cm in size and is a very powerful and effective technique for treating patients suffering from early stage primary and medically inoperable tumors. The treatment is safe to administer and also offers a new option in patients with recurrent disease or a single disease in the body.

 

“Highlights of the therapy being ease of access to any complex location without the need to use the surgical knife, precision of the beam with high dose radiation to the tumor location, and the safety. It is a day care procedure without pain and risk, and the patient can get back to daily chores as soon as the session gets over which depends on the tumor typically (30 minutes) and hence eliminates the requirement of any hospital stay.” Added Dr Gupta

 

Depending upon the hormonal variations in the body, there can be a variety of symptoms. The most common symptoms include Headaches, vision problem, tiredness, mood changes, irritability, changes in menstrual cycle in women, impotence, infertility, Inappropriate breast growth or production of breast milk, Cushing’s syndrome which is a combination of weight gain, high blood pressure, diabetes, and easy bruising, the enlargement of the extremities or limbs, thickening of the skull and jaw caused by too much growth hormone.

 

Pituitary gland, which is also known as the master gland has the most important function of producing hormones that regulates the critical organs of the body including thyroid, adrenal glands, ovaries and testes. It is a small pea-size gland located behind the eyes and below the front of the brain. Some tumors produce hormones known as functional tumors, and others can cause the glands to secrete too few or too many hormones. Also if the tumor pressed on the nearby structure, for instance the optic nerve, can also limit a person’s vision.

 

Moreover the procedure makes use of the most sophisticated image guidance technique to focus high doses of radiation directly to the tumor spot which eliminates the chances to damage the healthy cells as in any other methods of treatment.

 

“Each session of treatment usually lasts for about 30 -50 min and is cost effective with a success rate of 98% in such complicated tumors. Patients with pituitary adenomas receive stereotactic radio surgery with CyberKnife and are followed up for more than 12 months. After 2-3 weeks of therapy patients are monitored for positive responses and ensure there is no recurrence of any mass. Stereotactic radio surgery with the CyberKnife is effective and safe against pituitary adenomas.” Said Dr Gupta

From https://www.apnnews.com/hormonal-imbalance-indication-of-pituitary-gland-tumors-2/

3D-Printing Technology Improves Outcomes In Pituitary Adenoma Surgery

Huang X, et al. Pituitary. 2019;doi:10.1007/s11102-018-0927-x.

March 3, 2019

The use of 3D-printed models could lead to less operation time and blood loss and fewer postoperative complications in adults who undergo endoscopic endonasal transsphenoidal surgery for pituitary adenomas and other conditions, according to findings published in Pituitary.

“Several factors influence the outcome of endoscopic endonasal surgery, including the tumor volume, patient age, lesion location and sphenoid pneumatolysis,” Xiaobing Jiang, of the department of neurosurgery at Union Hospital of Tongji Medical College of Huazhong University of Science and Technology in Wuhan, Hubei, China, and colleagues wrote. “An accurate model of the target tumor structure is a major prerequisite for a successful [pituitary adenoma] resection, especially for macroadenomas, as this may avoid disastrous complications due to suboptimal treatment.”

Jiang and colleagues conducted a retrospective analysis of 20 adults who underwent endoscopic endonasal transsphenoidal surgery at Union Hospital in Wuhan. Participants were included based on similar tumor sizes, the presence of no other diseases and nonintuitive tumor identification. All surgeries in the cohort occurred between January and August 2017, with 10 participants (mean age, 44.4 years; 50% women) receiving CT and MRI before surgery; the remaining 10 also received an operation with 3D printing (mean age, 41.2 years; 50% women).

To create the 3D models, images from CT and MRIs were combined. The 3D printer then used this information to create the model, which took between 2 hours, 10 minutes, and 4 hours, 32 minutes, to design and 10 hours, 12 minutes, and 22 hours, 34 minutes, to print.

After surgery, the researchers found that mean operation time was lower in participants who had 3D models compared with participants who did not (127 minutes vs. 143.4 minutes; P = .007). In addition, there was less blood loss in participants with 3D printing compared with participants without (159.9 mL vs. 170 mL; P = .009). The researchers noted that there were postoperative complications in 20% of the 3D-printing group and 40% of the CT and MRI alone group.

“As it is highly precise and allows personalization, 3D-printing technology has started to be applied in medicine in recent years. In neurosurgery, 3D-printing technology can provide models for the patients’ disease characteristics, such as skull defects, brain tumors, intracranial aneurysms and intracranial vascular malformations,” the researchers wrote. “We believe that with its continuous development, 3D-printing technology will be applied in clinical practice in the near future.” – by Phil Neuffer

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B582c6512-708a-4900-ad20-f0adb5a79390%7D/3d-printing-technology-improves-outcomes-in-pituitary-adenoma-surgery

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