New treatments offer ‘glimmers of optimism,’ possible cure for Cushing’s disease
Click Here to Manage Email Alerts
More than a century has passed since neurosurgeon and pathologist Harvey Cushing described the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure.
Endogenous Cushing’s syndrome — caused by chronic hypercortisolism — is rare, with estimates ranging from 40 to 70 people per million affected worldwide, according to the National Institute of Diabetes and Digestive and Kidney Diseases. Cushing’s syndrome that is caused by an adrenocorticotropin-producing pituitary adenoma, known as Cushing’s disease, accounts for more than 70% of cases among adults and affects about three times as many women as men, according to NIDDK.
Photo by Jill Rollet for Endocrine Today.
Clinicians confront several key challenges in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, told Endocrine Today. Patients who present with Cushing’s disease typically have multiple features including hypertension, elevated blood glucose, depression and impaired mental function and are at high risk for infections, stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if the disorder remains uncontrolled is roughly 5 years, according to Melmed.
“This truly is a malignant metabolic disorder,” said Melmed, who is an Endocrine Today Editorial Board Member. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”
The outlook for Cushing’s disease is now beginning to change. New targets are emerging for treatment, and newly discovered molecules show promise for reducing the secretion of adrenocorticotropic hormone (ACTH), decreasing pituitary tumor size or suppressing adrenal cortisol production or action.
“Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — including somatostatin receptor SST5, epidermal growth factor receptor and cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.”
In the past decade, medical treatment for Cushing’s disease has progressed from a few steroidogenesis inhibitors to three novel drug groups, according to Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the School of Medicine at Oregon Health and Science University and director of the OHSU Northwest Pituitary Center. These include new inhibitors for steroidogenic enzymes with possibly fewer adverse effects, pituitary-directed drugs that aim to inhibit the pathophysiological pathways of Cushing’s disease and glucocorticoid receptor antagonists that block cortisol’s action.
“We have made clear progress over the last 100 years in treating Cushing’s disease, but we are definitely not where we should be in achieving patient outcomes,” Fleseriu, also an Endocrine Today Editorial Board Member, said in an interview. “Further optimization is still needed. Mortality from Harvey Cushing’s era, which was elevated fourfold compared with the normal population, has reversed to almost normal in patients who achieved remission, mostly due to multimodal therapy. Thus, we should focus more on achieving remission and not just improvement after treatment. However, it has been shown over and over again that the patient’s quality of life never returns to normal despite remission.”
Challenges in diagnosis, treatment
Overall, approximately 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average adenoma size is only 6 mm and 40% are not visible, Melmed said. In people with Cushing’s disease, surgery is effective in only 60% to 70% of patients for initial remission, and overall, there is approximately a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes.
“There are thousands of those patients for every patient with proven Cushing’s disease who we will encounter,” Melmed said.
The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term biochemical control without recurrence.
“This is a difficult challenge for us to meet,” Melmed said.
Diagnosis of Cushing’s disease remains complicated. While some individuals may present with physical symptoms as well as biochemical tests showing substantially elevated cortisol levels, others do not have clear-cut and obvious findings, according to Laurence Katznelson, MD, an Endocrine Today Editorial Board Member and professor of neurosurgery and medicine and medical director of the pituitary center at the Stanford University Medical Center.
“These patients may have a more subtle presentation or may have biochemical testing that shows some positive and some normal results,” Katznelson told Endocrine Today. “Further, there can be variability in the different tests we have for cortisol, such as urinary free cortisol measurements, which can be highly variable from day to day, so we often perform multiple measurements using different techniques for the diagnosis. This can lead to delay in the final diagnosis, as well as questioning the validity of the diagnosis.”
Even in remission, Cushing’s disease has a substantial negative effect on quality of life and is associated with increased mortality. In a review article published in October in The Lancet Diabetes & Endocrinology, Alan Kelsall, MBChB, and John Newell-Price, PhD, FRCP, professors in the department of oncology and metabolism at The Medical School at The University of Sheffield, United Kingdom, noted that mortality is normal for those undergoing only one pituitary surgery, emphasizing the importance of surgical expertise.
“However, what drives the long-term impairment in quality of life is not clear, which is worse compared with other patients with pituitary disease,” Kelsall and Newell-Price wrote. “Improved understanding and solutions for this key issue will benefit patients greatly.”
Treatment options
Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, according to James Findling, MD, director of community endocrinology services and clinical professor of medicine at the Medical College of Wisconsin in Milwaukee. There are several advantages to pituitary surgery, including rapid initial remission, a one-time cost and a potential cure. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications.
“Most think that surgical intervention for the majority of individuals with significant cortisol excess of pituitary/adrenal origin or an ectopic tumor is certainly the initial treatment of choice, and the guidelines reflect this,” Findling told Endocrine Today. “However, having said that, at least in patients with pituitary Cushing’s, it is clear now that within 5 to 10 years, about 50% of patients initially diagnosed have persistent or recurrent hypercortisolism, so other treatment options are needed.”
Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said.
“The reality of Cushing’s disease is that these patients first undergo surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to increased mortality,” Melmed said. “Medical therapy is appropriate at every step of the natural history spectrum.”
Radiation can be a useful adjuvant therapy for a tumor inaccessible to surgery and can lead to a long-term cure, Katznelson said; however, adverse effects can include hypopituitarism, rare cases of secondary malignancy and cases of atherosclerosis in adjacent arteries.
Radiation can also take years to be effective, Fleseriu said.
“Patients need medications even if they undergo radiation, as radiation effects, despite newer techniques such as proton beam and gamma knife, can take up to 5 years,” Fleseriu said. “Hypopituitarism postradiation is frequent, and patients will need lifelong follow-up.”
Currently, there are two FDA-approved treatments for Cushing’s disease. In June 2018, the FDA approved pasireotide for the treatment of people with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. In 2012, the FDA approved mifepristone (Korlym, Corcept Therapeutics) as a once-daily oral medication to treat adults with Cushing’s syndrome who had elevated blood glucose due to type 2 diabetes.
In an open-label extension study published in September in Clinical Endocrinology, Fleseriu and colleagues demonstrated that monthly pasireotide therapy was safe and effective, leading to normal urinary free cortisol levels in 47% of patients after 2 years.
As seen in other pasireotide studies, and expected based on the mechanism of action, researchers observed hyperglycemia-related adverse events in 39.5% of participants, with diabetes medications initiated or escalated in some patients, Fleseriu said. However, mean fasting glucose and HbA1c were stable during the extension phase, after increasing in the main study. Within the cohort, 81.5% had type 2 diabetes when they entered the extension phase, and 88.9% had type 2 diabetes at last assessment.
Susan Samson, MD, PhD, FRCPC, FACE, an Endocrine Today Editorial Board Member and associate professor in the department of endocrinology, diabetes and metabolism at Baylor College of Medicine in Houston, said choosing the right patients for pasireotide therapy is key.
“Some of my patients with acromegaly are on long-acting pasireotide and on long-acting insulin,” Samson told Endocrine Today. “When pasireotide starts to work, their insulin needs actually decrease due to better control of growth hormone levels and improved insulin sensitivity. For some patients, if you choose wisely, you can actually have a benefit with respect to glycemia. I have been disappointed with the lower rate of use of this medication as a choice for our patients with challenging growth hormone secreting tumors. There is fear and trepidation among endocrinologists because of the glucose issue. When I use this medication in a carefully chosen patient, that has not been my experience.”
An additional option is the azole antifungal ketoconazole, a racemic mixture of two enantiomers that acts on the adrenal cortex and prevents steroid production. The drug is approved only in Europe and is used off-label for Cushing’s syndrome in the U.S. Ketoconazole has been associated with risk for hepatotoxicity in observational studies, for which weekly monitoring is recommended by the FDA.
“The advantage of ketoconazole is it is relatively inexpensive and can normalize cortisol in 40% to 50% of patients,” Katznelson said. “The problem with this is, one, it is off-label, and two, there is risk for hepatic damage, though this is rare and I have not seen this in my practice.”
Bilateral adrenalectomy is reserved as a third-line treatment option for patients with uncontrolled hypercortisolism despite pituitary surgery, appropriate medical therapy and pituitary radiation, Fleseriu said.
“It can be lifesaving among patients with severe and prolonged Cushing’s syndrome who require rapid and permanent control of hypercortisolism,” Fleseriu said. “I also recommend it more frequently for women who desire pregnancy.”
Pipeline promise
Several new medical therapies are in development, some in phase 3 trials, Fleseriu said.
The steroidogenesis inhibitor levoketoconazole (Recorlev, Strongbridge Biopharma), an enantiomer of ketoconazole, was shown in the recent SONICS study to be effective in reducing and normalizing morning urinary free cortisol concentrations and biomarkers of cardiovascular risk among a large cohort of adults with endogenous Cushing’s syndrome; the agent also improved clinical signs of the disease and quality of life measures. Of the 77 participants who advanced to the maintenance phase, 62 (81%) had urinary free cortisol normalization by the end of dose titration. However, at the end of the 6-month maintenance phase, only 29 participants (31%) were responders; the least-squares mean estimate of the proportion of responders was 0.3 (95% CI, 0.21-0.4).
Fleseriu said the findings from SONICS indicate that levoketoconazole was overall well tolerated with lower liver toxicity vs. off-label ketoconazole, although compared indirectly, therefore potentially requiring a less-restrictive monitoring schedule.
“It is important to be clear that levoketoconazole is not ketoconazole,” Fleseriu said. “Levoketoconazole is the pure 2S,4R enantiomer of ketoconazole and, based on recent data, may be a more potent inhibitor of cortisol secretion compared with ketoconazole.”
Osilodrostat (Novartis), an oral nonsteroidal corticosteroid biosynthesis inhibitor originally developed for hypertension management, inhibits 11-beta-hydroxylase with higher affinity than metyrapone (Metopirone, HRA Pharma) and has a longer half-life. In in a phase 2 clinical trial, osilodrostat showed efficacy in almost 80% of participants at week 22. In a phase 3 trial, osilodrostat was superior to placebo at maintaining normal urinary free cortisol after randomized withdrawal and normalized urinary free cortisol for two-thirds of enrolled patients at week 48, with few patients discontinuing treatment because of adverse events.
“The early data showed 11 of 12 patients had normalized urinary free cortisol by 10 weeks, and you could really see an impact when you washed out the drug because the cortisol rose again,” Samson said. “This drug has potential not just for inhibiting cortisol production, but also as a diagnostic testing molecule, much like the way we use metyrapone.”
Emerging pituitary-targeted drug treatments not yet in clinical trials include heat shock protein inhibitors, histone deacetylase inhibitors and monoclonal ACTH antibodies, among others, Fleseriu said.
Zebrafish clues
Searching for new options, Melmed, Ning-Ai Liu, MD, assistant professor of medicine at Cedars-Sinai and colleagues introduced into zebrafish a pituitary tumor transforming gene discovered in his lab, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high.
Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH.
In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said.
“Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule that suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.”
Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial to evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib, Cyclacel Pharmaceuticals) among patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and then enrolled in sequential cohorts based on efficacy outcomes.
“Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s disease. Hopefully, this will light the pathway for a phase 2 trial.”
Offering optimism
Practitioners face a unique paradigm when treating patients with Cushing’s disease. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life.
“Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.”
That shift is exciting for researchers who have worked to draw attention to the condition for decades, Katznelson said.
“It’s been remarkable how the horizon has changed in just the past 10 years,” Katznelson said. “Just 10 years ago, we did not have any FDA-approved medications. We were speaking only about the use of ketoconazole, metyrapone, maybe cabergoline, which has been useful in some of these patients, but again, none of these were FDA approved. In a relatively short time, we have had two FDA-approved drugs and likely several more on the horizon. We have gone from very limited options to many more options, which leads to much better management of our patients and much better control for patients.”
Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy.
“He was imagining this ‘elixir of youth’ that we could offer patients who are very ill, and in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer
- References:
- Fleseriu M, et al. Clin Endocrinol. 2019;doi:10.1111/cen.14081.
- Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;doi:10.1016/s2213-8587(19)30313-4.
- Kelsall A, et al. Lancet Diabetes Endocrinol. 2019;doi:10.1016/S2213-8587(19)30343-2.
- Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.
- For more information:
- James Findling, MD, can be reached at Medical College of Wisconsin, Endocrinology Center and Clinics, W129 N7055 Northfield Drive, A-203, Menomonee Falls, WI 53051; email: james. findling@froedtert.com.
- Maria Fleseriu, MD, FACE, can be reached at the School of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239; email: fleseriu@ohsu.edu.
- Laurence Katznelson, MD, can be reached at Stanford Pituitary Center, 213 Quarry Road, Palo Alto, CA 94304; email: katznels@stanford.edu.
- Shlomo Melmed, MD, ChB, FRCP, MACP, can be reached at Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048; email: melmed@csmc.edu.
- Susan Samson, MD, PhD, FRCPC, FACE, can be reached at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030; email: ssamson@bcm.edu.
Disclosures: Findling reports he has served as a consultant and investigator for Corcept Therapeutics and Novartis. Fleseriu reports she has received research funding paid to her institution and consultant fees from Novartis and Strongbridge. Samson reports she has received consultant or advisory fees from Corcept Therapeutics and is steering chair of SOM 230B2219 trial for Novartis (pasireotide). Katznelson and Melmed report no relevant financial disclosures.
Click here to read the Point/Counter, "New treatments offer ‘glimmers of optimism,’ possible cure for Cushing’s disease."
Collapse
Click Here to Manage Email Alerts