Long-acting pasireotide safe, effective for recurrent Cushing’s disease

October 20, 2017

In patients with persistent or recurring Cushing’s disease after surgery, monthly pasireotide was safe and effective, leading to normal urinary free cortisol levels in about 40% of patients after 12 months, according to findings from a phase 3 clinical trial.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” Andre Lacroix, MD, professor in the department of medicine at University of Montreal teaching hospital, and colleagues wrote in the study background. “However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

Lacroix and colleagues analyzed data from 150 patients with a confirmed diagnosis of persistent, recurrent or new Cushing’s disease with mean urinary free cortisol level concentration 1.5 to five times the upper limit of normal, normal or greater than normal plasma and confirmed pituitary source of Cushing’s disease. Patients were recruited between December 2011 and December 2014; those who received mitotane therapy within 6 months, pituitary irradiation within 10 years or previous pasireotide treatment were excluded. Researchers randomly assigned patients to 10 mg (n = 74) or 30 mg (n = 76) monthly intramuscular pasireotide (Signifor LAR, Novartis) for 12 months, with investigators and patients masked to the group allocation and dose. Pasireotide was up-titrated from 10 mg to 30 mg or from 30 mg to 40 mg at month 4, or at month 7, 9 or 12 if urinary free cortisol concentrations remained greater than 1.5 times the upper limit of normal. At month 12, patients considered to be receiving clinical benefit from the therapy (mean urinary free cortisol concentration at or less than the upper limit of normal) could continue to receive it during an open-ended extension phase. The primary outcome was to assess the proportion of patients achieving mean urinary free cortisol concentration less than or equal to the upper limit of normal by month 7, regardless of dose.

Within the cohort, 41.9% of patients in the 10-mg group and 40.8% of patients in the 40-mg group met the primary endpoint at month 7, whereas 5% of patients in the 10-mg group and 13% of patients in the 40-mg group achieved partial control. Researchers did not observe between-sex differences or differences in response among those who did or did not undergo previous surgery.

The number of patients who achieved the primary endpoint at month 7 without an up-titration in dose was smaller, but not significantly different between the 10-mg and 40-mg dose groups (28.4% and 31.6%, respectively), according to researchers. Among those who received an up-titration in dose in the 10-mg and 40-mg groups (42% and 37%, respectively), 32% and 25%, respectively, were considered responders at month 7.

Researchers also observed improvements in several metabolic parameters during the 12-month course of treatment with both doses, including improvements in systolic and diastolic blood pressure; reductions in waist circumference, BMI and body weight; and improvement in scores for the Cushing’s Quality of Life questionnaire. The most common adverse events were hyperglycemia, diarrhea, cholelithiasis, diabetes and nausea.

The researchers noted that, in both dose groups, the reductions in mean urinary free cortisol concentration were observed within 1 month, with concentrations remaining below baseline levels for the 12-month study period.

“This large phase 3 trial showed that long-acting pasireotide administered for 12 months can reduce [median urinary free cortisol] concentrations, is associated with improvements in clinical signs and [health-related quality of life] and has a similar safety profile to that of twice-daily pasireotide,” the researchers wrote, adding that the long-acting formulation provides a convenient monthly administration schedule. – by Regina Schaffer

Disclosures: Novartis funded this study. Lacroix reports he has received grants and personal fees as a clinical investigator, study steering committee member and advisory board member for Novartis, Stonebridge and UpToDate. Please see the study for all other authors’ relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B55988079-312b-478d-8788-036a465b1881%7D/long-acting-pasireotide-safe-effective-for-recurrent-cushings-disease

New ACTH Detection Method Improves Cure Rates in Cushing’s Disease Patients

Researchers have identified a new, quick method for detecting ACTH-producing tumors – called Elecsys – that can improve the cure rates of Cushing’s disease patients undergoing surgery.

The study, “Long-term outcomes of tissue-based ACTH-antibody assay–guided transsphenoidal resection of pituitary adenomas in Cushing disease,” was published in the Journal of Neurosurgery.

Transsphenoidal resection (TSR) – a surgical procedure performed through the nose and sphenoid sinus to remove a pituitary tumor – has been the method of choice for treatment for Cushing’s disease.

However, it often fails to localize the tumor with precision, leading to an incomplete resection (removal). This is likely a result of the preoperative methods used to guide surgeons before surgery, which include both magnetic resonance imaging (MRI) and a minimally invasive procedure called bilateral inferior petrosal sinus sampling (BIPSS) that measures ACTH in the veins that drain the pituitary gland.

However, both “suffer from suboptimal sensitivity and thus allow for incomplete resections, specially if pathological frozen sections fail to identify tumor,” researchers wrote.

MRI, for example, detects only 50 percent of Cushing’s adenomas, limiting surgeons’ ability to conduct curative TSR surgeries. Therefore, better diagnostic and tumor localization techniques are needed to increase the likelihood that initial surgeries can remove the entire tumor and cure patients.

A team of researchers at Yale School of Medicine evaluated a new method for guiding tumor localization during TSR. The method – a double-antibody sandwich assay for ACTH – is performed in the operating room in resected pituitary samples from patients. ACTH (adrenocorticotropic hormone) is a hormone produced in the pituitary gland in the brain, that simulated cortisol production in the adrenal glands. In patients with Cushing disease the pituitary gland releases too much ACTH.

In the new method – called Elecsys – samples are squeezed between sandwich-like system composed of two antibodies that recognize two sections of the ACTH protein. The three-step procedure is quick, allowing doctors to analyze samples in the operating room and determine if they have removed the entire tumors.

The performance and outcomes associated with the Elecsys were assessed by reviewing data of tissue samples from 14 patients with ACTH-secreting adenomas, who underwent TSR surgeries between 2009 and 2014.

“The intraoperative TSR protocol was modified with the introduction of the ACTH assay such that if either the assay or the frozen-section pathology returned results positive for tumor, that area of the gland was resected,” the researchers explained.

The new ACTH method detected tumor tissue and was capable of distinguishing it from normal tissue with a 95% sensitivity and 71.3% specificity. These values are comparable to those using the standard method for tumor localization, which requires frozen sections of the tumor. This suggests that the test can be used either in conjunction with or in place of frozen sections.

Also, 85.7% of the patients achieved long-term disease remission, with the remission rate exceeding the rate with previous methods (71.9%).

Overall, “these preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing’s disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed,” the study concluded.

From https://cushingsdiseasenews.com/2017/10/19/acth-detection-method-improved-cure-rates-cushings-disease-study-shows/

Increase in Glucose Uptake by Cushing’s Disease-associated Tumors Could Improve Early Detection

An increase in glucose uptake by Cushing’s disease-associated pituitary tumors could improve their detection, new research shows.

The study, “Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1,” appeared in the journal Molecular and Cellular Endocrinology.

The study’s senior author was Dr. Prashant Chittiboina, MD, from the Department of Neurosurgery, Wexner Medical Center, The Ohio State University, in Columbus, Ohio.

Microadenomas – tumors in the pituitary gland measuring less than 10 mm in diameter – that release corticotropin, or corticotropinomas, can lead to Cushing’s disease. The presurgical detection of these microadenomas could improve surgical outcomes in patients with Cushing’s.

But current tumor visualization methodologies – magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) – failed to detect a significant percentage of pituitary microadenomas.

Stimulation with corticotropin-releasing hormone (CRH), which increases glucose uptake, has been suggested as a method of increasing the detection of adenomas with 18F-FDG PET, by augmenting the uptake of 18F-FDG – a glucose analog.

However, previous studies aiming to validate this idea have failed, leading the research team to hypothesize that it may be due to a delayed elevation in glucose uptake in corticotropinomas.

The scientists used clinical data to determine the effectiveness of CRH in improving the detection of corticotropinomas with 18F-FDG PET in Cushing’s disease.

They found that CRH increased glucose uptake in human and mouse tumor cells, but not in healthy mouse or human pituitary cells that produce the adrenocorticotropic hormone (ACTH). Exposure to CRH increased glucose uptake in mouse tumor cells, with a maximal effect at four hours after stimulation.

Similarly, the glucose transporter GLUT1, which is located at the cell membrane, was increased two hours after stimulation, as was GLUT1-mediated glucose transport.

These findings indicate a potential mechanism linking CRH exposure to augmented glucose uptake through GLUT1. Expectedly, the inhibition of glucose transport with fasentin suppressed glucose uptake.

The researchers consistently observed exaggerated evidence of GLUT1 in human corticotropinomas. In addition, human corticotroph tumor cells showed an increased breakdown of glucose, which indicates that, unlike healthy cells, pituitary adenomas use glucose as their primary source of energy.

Overall, the study shows that corticotropin-releasing hormone (CRH) leads to a specific and delayed increase in glucose uptake in tumor corticotrophs.

“Taken together, these novel findings support the potential use of delayed 18F-FDG PET imaging following CRH stimulation to improve microadenoma detection in [Cushing’s disease],” researchers wrote. The scientists are now conducting a clinical trial to further explore this promising finding.

From https://cushingsdiseasenews.com/2017/10/12/glucose-uptake-in-cushings-disease-could-improve-presurgical-tumor-detection/

Crinetics Pharmaceuticals Awarded Two SBIR Grants to Develop New Therapeutics for Congenital Hyperinsulinism and Cushing’s Disease

SAN DIEGO, Sept. 06, 2017 (GLOBE NEWSWIRE) — Crinetics Pharmaceuticals, Inc., a rare disease therapeutics company focused on endocrine disorders and endocrine-related cancers, announced today that it was awarded two new grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) that could total $2.4 million. Both are Small Business Innovation Research (SBIR) grants and include a Fast Track grant for up to $2.1 million and a Phase I grant of $0.3 million, which will be used for the development of Crinetics’ nonpeptide, oral somatostatin agonists for congenital hyperinsulinemia, and the discovery of novel small molecule drugs for Cushing’s disease, respectively.

“We are delighted with the NIH’s continuing support of our programs to develop new drugs for patients with rare endocrine disorders,” said Stephen Betz, Ph. D., Founder and Vice President of Biology of Crinetics. “These awards will enable us to advance our efforts in both hyperinsulinemia and Cushing’s disease, expanding our pipeline to include these diseases with significant unmet medical needs, and bring these treatments to the patients who need them.”

Presently, there are no medical therapies that were specifically developed to treat the life-threatening chronic hypoglycemia precipitated by congenital hyperinsulinism (CHI). The current options for patients are limited to drugs developed for other purposes in the hope that they might help. Despite their poor profiles, these drugs are prescribed because the next line of treatment is typically a partial or full pancreatectomy. Even when successful, patients who undergo the surgery often become diabetic and must actively manage glucose with multiple daily insulin injections for the rest of their lives.

Similarly, first line treatments for Cushing’s disease are surgical and involve removal of either the ACTH-secreting tumor in the pituitary or the adrenal glands themselves. As this is often unsuccessful, contraindicated or delayed, medical therapy for these patients becomes necessary. Current treatment options include inhibitors of steroid synthesis enzymes that can prevent the production of cortisol and improve symptoms, but these treatments also induce a host of unwanted side effects due to the accumulation of other steroid products.

About Congenital Hyperinsulinism (CHI)

Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures, developmental delays, learning disabilities, and even death. The most severe form of HH is inherited and referred to as CHI. CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas.

About Cushing’s Disease

Clinical signs of Cushing’s syndrome include growth of fat pads (collarbone, back of neck, face and trunk), excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disturbances resulting in high morbidity. If inadequately controlled in its severe forms, Cushing’s syndrome is associated with high mortality. The most common form of Cushing’s syndrome is Cushing’s disease which is caused by microadenomas of pituitary corticotropic cells that secrete excess adrenocorticotropic hormone (ACTH).

About the NIDDK

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. For more information about the NIDDK and its programs, visit www.niddk.nih.gov.

About Crinetics Pharmaceuticals

Crinetics Pharmaceuticals discovers and develops novel therapeutics targeting peptide hormone receptors for the treatment of rare endocrine disorders and endocrine-related cancers. Crinetics was founded by a team of scientists with a proven track record of endocrine drug discovery and development to create important new therapeutic options for endocrinologists and their patients. The company is backed by top life sciences investors, 5AM Ventures, Versant Ventures, and Vivo Capital and is headquartered in San Diego. For more information, please visit www.crinetics.com.

More: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=241628#.WbFJGNN97-Y

Glowing cancer tool illuminates benign, but dangerous, brain tumors during pituitary surgery

University of Pennsylvania School of Medicine

PHILADELPHIA – An experimental imaging tool that uses a targeted fluorescent dye successfully lit up the benign brain tumors of patients during removal surgery, allowing surgeons to identify tumor tissue, a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania shows. The tumors, known as pituitary adenomas, are the third most common brain tumor, and very rarely turn cancerous, but can cause blindness, hormonal disorders, and in some cases, gigantism.

Findings from the pilot study of 15 patients, published this week in the Journal of Neurosurgery, build upon previous clinical studies showing intraoperative molecular imaging developed by researchers at Penn’s Center for Precision Surgery can improve tumor surgeries. According to first author John Y.K. Lee, MD, MSCE, an associate professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania and co-director of the Center for Precision Surgery, this study describes the first targeted, near infrared dye to be employed in brain tumor surgery. Other dyes are limited either by their fluorescent range being in the busy visible spectrum or by lack of specificity.

“This study heralds a new era in personalized tumor surgery. Surgeons are now able to see molecular characteristics of patient’s tumors; not just light absorption or reflectance,” Lee said. “In real time in the operating room, we are seeing the unique cell surface properties of the tumor and not just color. This is the start of a revolution.”

Non-specific dyes have been used to visualize and precisely cut out brain tumors during resection surgery, but this dye is believed to be the first targeted, near infrared dye to be used in neurosurgery. The fluorescent dye, known as OTL38, consists of two parts: vitamin B9 (a necessary ingredient for cell growth), and a near infrared glowing dye. As tumors try to grow and proliferate, they overexpress folate receptors. Pituitary tumors can overexpress folate receptors more than 20 times above the level of the normal pituitary gland in some cases. This dye binds to these receptors and thus allows us to identify tumors.

“Pituitary adenomas are rarely cancerous, but they can cause other serious problems for patients by pushing up against parts of their brain, which can lead to Cushing’s disease, gigantism, blindness and death,” Lee explained. “The study shows that this novel, targeted, near infrared fluorescent dye technique is safe, and we believe this technique will improve surgery.”

Lee says larger studies are warranted to further demonstrate its clinical effectiveness, especially in nonfunctioning pituitary adenomas.

A big challenge with this type of brain surgery is ensuring the entire tumor is removed. Parts of the tumor issue are often missed by conventional endoscopy approaches during removal, leading to a recurrence in 20 percent of patients. The researchers showed that the technique was safe and effective at illuminating the molecular features of the tumors in the subset of patients with nonfunctioning pituitary adenomas.

The technique uses near-infrared, or NIR, imaging and OTL38 fluoresces brightly when excited by NIR light. The VisionSense IridiumTM 4mm endoscope is a unique camera system which can be employed in the narrow confines of the nasal cavity to illuminate the pituitary adenoma. Both the dye and the camera system are needed in order to perform the surgery successfully.

The rate of gross-total resection (GTR) for the 15 patients, based on postoperative MRI, was 73 percent. The GTR with conventional approaches ranges from 50 to 70 percent. Residual tumor was identified on MRI only in patients with more severe tumors, including cavernous sinus invasion or a significant extrasellar tumor.

In addition, for the three patients with the highest overexpression of folate, the technique predicted post-operative MRI results with perfect concordance.

Some centers have resorted to implementing MRI in the operating room to maximize the extent of resection. However, bringing a massive MRI into the operating room theater remains expensive and has been shown to produce a high number of false-positives in pituitary adenoma surgery. The fluorescent dye imaging tool, Lee said, may serve as a replacement for MRIs in the operating room.

Co-authors on the study include M. Sean Grady, MD, chair of Neurosurgery at Penn, and Sunil Singhal, MD, an associate professor of Surgery, and co-director the Center for Precision Surgery.

Over the past four years, Singhal, Lee, and their colleagues have performed more than 400 surgeries using both nonspecific and targeted near infrared dyes. The breadth of tumor types include lung, brain, bladder and breast.

Most recently, in July, Penn researchers reported results from a lung cancer trial using the OTL38 dye. Surgeons were able to identify and remove a greater number of cancerous nodules from lung cancer patients with the dye using preoperative positron emission tomography, or PET, scans. Penn’s imaging tool identified 60 of the 66 previously known lung nodules, or 91 percent. In addition, doctors used the tool to identify nine additional nodules that were undetected by the PET scan or by traditional intraoperative monitoring.

Researchers at Penn are also exploring the effectiveness of additional contrast agents, some of which they expect to be available in the clinic within a few months.

“This is the beginning of a whole wave of new dyes coming out that may improve surgeries using the fluorescent dye technique,” Lee said. “And we’re leading the charge here at Penn.”

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This study was supported in part by the National Institutes of Health (R01 CA193556), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, and the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000003).

Editor’s Note: Dr. Singhal holds patent rights over the technologies presented in this article.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

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From https://eurekalert.org/pub_releases/2017-09/uops-gct090517.php

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