by Megan Brooks
October 1, 2010 (Liege, Belgium) — In a phase 3 study of patients with Cushing's disease, the investigational somatostatin analogue SOM230 (pasireotide; Novartis) significantly reduced urinary free cortisol (UFC) levels in a majority of subjects and normalized UFC levels in about one fourth.
As mean UFC decreased, there was improvement in associated clinical signs and symptoms, including reductions in blood pressure, total cholesterol, and body weight, the investigators say.
The study results were presented here at the European Neuroendocrine Association 14th Congress by Beverly M. Biller, MD, an endocrinologist at Massachusetts General Hospital in Boston.
"Cushing's disease represents a high unmet medical need," Dr. Biller and colleagues write in a meeting abstract.
"A sizable number of patients with Cushing's disease are not adequately treated with surgery, and there is currently no effective medical treatment for Cushing's," William H. Ludlam, MD, PhD, who has been involved in studies of pasireotide, added in an interview with Medscape Medical News. Dr. Ludlam is director of the Seattle Pituitary Center at the Swedish Neuroscience Institute in Washington.
"While there are other somatostatin analogues available, they do not have as broad an effect as pasireotide," noted Dr. Ludlam. "There are 5 subtype receptors of somatostatin," he explained, "and most available drugs only target 1 subtype. Pasireotide targets 4 of them, and, importantly, it targets subtype 5, which is frequently expressed by the pituitary tumors common in Cushing's disease."
"Several studies on this drug have shown an effect in Cushing's, with approximately half of the patients having clinically relevant improvement," Dr. Ludlam said.
The PASPORT-CUSHINGS Study
PASPORT-CUSHINGS (Pasireotide Clinical Trial Portfolio–Cushing's Disease) is the largest randomized study to evaluate a medical therapy in patients with Cushing's disease. In the 12-month trial, 135 patients with moderate to severe persistent/recurrent Cushing's disease and 27 with de novo Cushing's disease who were not eligible for surgery were randomized in a double-blind fashion to receive either 600 or 900 μg subcutaneous injections of pasireotide. In the group as a whole, baseline UFC levels were higher in the 600- than in the 900-µg group (1156 vs 782 nmol/24 h). The primary end point was the proportion of patients who achieved normalization of UFC after 6 months without dose up-titration, relative to randomized dose.
At 6 months, 12 patients in the 600-µg group (14.6%; 95% confidence interval [CI], 7.0 - 22.3) and 21 in the 900-µg group (26.3%; 95% CI, 16.6 - 35.9) met the primary end point. After 12 months, the proportion of responders, regardless of dose up-titration, was 13.4% and 25.0%, respectively, for the 600 and 900-μg groups.
The median reduction in UFC at 6 months was 47.9% for both groups. At 12 months, median UFC was reduced by 67.6% in the 600-μg group and by 62.4% in the 900-μg group. Serum and salivary cortisol and plasma ACTH decreased with both doses, the study team notes.
They also report that patients who failed to achieve a reduction of 50% from baseline in UFC levels by month 2 were unlikely to show improvement at 6 or 12 months.
Adverse Effects Were Common But Mostly Mild
The most frequently reported adverse effects with pasireotide were diarrhea (58.0%), nausea (46.9%), hyperglycemia (38.9%), cholelithiasis (29.6%), abdominal pain (20.4%), diabetes mellitus (17.9%), fatigue (11.7%), and increased glycosylated hemoglobin (10.5%). Most adverse effects were grade 1 or 2.
"Most of the drugs used to treat Cushing's have significant side effects," Dr. Ludlam said. "Cholelithiasis is not ideal, but is not a life-threatening side effect, and hyperglycemia can easily be managed; besides, cortisol itself causes hyperglycemia. I have had a number of patients on the drug and have seen first hand that the drug is pretty well tolerated, and I have seen the benefits," Dr. Ludlam added.
Linda S. Werner, MD, a diabetes, metabolism, and endocrinology specialist with Endocrine Associates, of Bridgeport, Connecticut, who was not involved in the study, said: "If this new drug can normalize the free cortisol in one fourth and reduce the UFC in 48% [of patients], it should have a real role in treating Cushing's."
Dr. Werner made the point that "drugs are used to treat Cushing's when surgery is either not possible or doesn't fully work. Cushing's is so rare," she added, "that even tertiary care centers only have a handful of patients. I do have one patient, but he had successful surgery and so doesn't need anticortisol drugs."
According to a statement from Novartis, the data from this trial will form the basis for regulatory filing for pasireotide later this year. The drug currently has orphan drug status for Cushing's disease in the United States and Europe.
The study was funded by Novartis AG. Several of the investigators work for Novartis or have financial relationships with the company. Dr. Werner has disclosed no relevant financial relationships.
European Neuroendocrine Association (ENEA) 14th Congress: Abstract OC-1.7. Presented September 22, 2010.
From http://www.medscape.com/viewarticle/729756?src=rss
Showing posts with label Dr. William Ludlam. Show all posts
Showing posts with label Dr. William Ludlam. Show all posts
Sunday, October 3, 2010
Friday, September 24, 2010
Promising Phase III results of pasireotide, a new therapy for Cushing’s disease
Novartis’ pasireotide effective in Cushing’s disease trial
The Swiss pharmaceutical company Novartis reported the results of a Phase III study of an experimental therapy pasireotide, also known as SOM230, which showed reduced cortisol levels in patients with Cushing’s disease. Pasireotide is first medical therapy to show efficacy in a Phase III trial in Cushing’s disease. Detailed results will be presented at the 14th Congress of the European Neuroendocrine Association (ENEA).
As the largest clinical trial in Cushing’s disease, PASPORT-CUSHINGS study was conducted at 68 sites in 18 countries involving 162 patients with persistent or recurrent Cushing’s disease, and in patients with newly diagnosed Cushing’s disease who are not suitable for surgery. The goals of the phase III trial are to evaluate the efficacy and safety of the experimental drug pasireotide.
The study showed that the majority of evaluable patients (91/103) experienced a reduction from baseline in urinary free cortisol (UFC) levels at six months. The UFC levels, which are major biomarkers of biochemical control of the disease, were reduced to normal in 26% of patients randomized to pasireotide 900ug twice daily, meeting the primary endpoint of the study. Additionally, median UFC was reduced by 48% in both the 900ug and 600ug dose groups. After 12 months of treatment, results confirmed the durability of the effect. On average, as UFC levels were reduced, clinical symptoms of Cushing’s disease improved including reduction of blood pressure, total cholesterol, weight and body mass index (BMI).
The trial results gave Novartis’ development pipeline another boost, only a few days after the approval of its potential blockbuster drug Gilenya by FDA. The company said the trial will be basis for first regulatory filing planned by year end.
Cushing’s disease is caused by a benign tumor in the pituitary gland that secretes adrenocorticotropic hormone (ACTH), which triggers the adrenal glands to produce excess cortisol. Cushing’s disease can cause severe cardiovascular and metabolic-related illnesses or death. There are currently no approved medicines to treat Cushing’s disease.
“There is a critical need for a medical treatment for people with Cushing’s disease because currently available options, such as surgery or radiotherapy, are ultimately not effective for many of the patients who suffer from this debilitating disease,” said William H. Ludlam, MD, PhD, Director, Seattle Pituitary Center at the Swedish Neuroscience Institute in Seattle, WA. “The results of this study suggest that pasireotide may help patients achieve biochemical control of their Cushing’s disease and its symptoms by directly targeting the pituitary tumor that triggers excess cortisol production.”
Pasireotide is a metabolically stable cyclohexapeptide, which targets multiple subtypes of the receptor for somatostatin. Its highest affinity is to sst5, a receptor subtype frequently expressed by the pituitary tumors associated with Cushing’s disease. Pasireotide was assigned orphan drug designation for Cushing’s disease in Europe and the US.
Monday, July 5, 2010
The diagnosis and treatment of growth hormone deficiency in adults
Current Opinion in Endocrinology, Diabetes & Obesity:
August 2010 - Volume 17 - Issue 4 - p 377–383
doi: 10.1097/MED.0b013e32833b6bc7
Neuroendocrinology: Edited by William H. Ludlam
Clemmons, David R
Abstract
Purpose of review: This review summarizes the recent published information regarding efficacy and complications of growth hormone replacement therapy. Several recent reports have monitored patients for periods of up to 10 years. Additionally, a consensus conference has been held regarding needed improvements in diagnostic testing and the recommendations of consensus panels regarding diagnostic criteria and laboratory test utilization are summarized.
Recent findings: Long-term studies show growth hormone can be administered safely and that muscle strength and function as well as lipoprotein abnormalities and low-bone mineral density show sustained improvement over extended periods of time. The complications that occur are generally dose-dependent and once attenuated do not tend to recur. Long-term safety studies regarding improvement in cardiovascular mortality and/or worsening prognosis for patients who develop malignancies are available only in the form of observational studies and randomized controlled long-term trial information is not yet available. The studies reported provide a means for clinicians to ascertain the patients who are likely to derive the greatest benefit from growth hormone when the appropriate diagnostic testing and treatment paradigms are utilized.
Summary: The studies that are summarized provide useful information for assessing the response to treatment, selecting patients who are candidates for long-term replacement therapy and for selecting those in whom the need for therapy may need to be reassessed.
© 2010 Lippincott Williams & Wilkin
Wednesday, June 30, 2010
Radiation therapy and stereotactic radiosurgery for the treatment of Cushing's disease: an evidence-based review
Current Opinion in Endocrinology, Diabetes & Obesity:
August 2010 - Volume 17 - Issue 4 - p 356–364
doi: 10.1097/MED.0b013e32833ab069
Neuroendocrinology: Edited by William H. Ludlam
Starke, Robert M; Williams, Brian J; Vance, Mary Lee; Sheehan, Jason P
Abstract
Purpose of review: The indications, efficacy, and safety of radiation therapy and stereotactic radiosurgery for Cushing's disease are evaluated.
We queried PubMed using the terms, ‘Cushing's disease’, ‘radiotherapy’, and ‘radiosurgery’, then evaluated each study for the number of patients, method of radiation delivery, type of radiation therapy or radiosurgical device used, treatment parameters (e.g. maximal dose, tumor margin dose), length of follow-up, tumor-control rate, complications, rate of hormone normalization, newly onset loss of pituitary function, and method used to assess endocrine remission.
Recent findings: A total of 39 peer-reviewed studies with 731 patients were included. The reported rates of tumor-volume control following radiotherapy and radiosurgery vary considerably from 66–100%. Additionally, the reported rates of endocrine remission vary substantially from 17–100%. The incidence of serious complications following radiosurgery is quite low. Although post-treatment hypopituitarism and disease recurrence were uncommon, they did occur, and this underscores the necessity for long-term follow-up in these patients.
Summary: Radiosurgery and, in the modern era, less commonly, radiation therapy, offer both well tolerated and reasonably effective treatment for recurrent or residual Cushing's adenomas.
Monday, May 4, 2009
About Cushing's from OHSU
From http://www.ohsupituitary.com/patients/cushing.asp
Discuss on the Message Boards here: http://cushings.invisionzone.com/index.php?showtopic=41007
Cushing's Disease
Cushing's disease is a form of Cushing's syndrome that is caused by an ACTH secreting pituitary adenoma. About 10% of pituitary adenomas secrete excess ACTH. This elevated ACTH in turn stimulates the adrenal glands to produce excess cortisol. This disease process is called Cushing's disease (named after the famous neurosurgeon, Harvey Cushing).
Signs and Symptoms
Cushing's disease has a myriad of signs and symptoms, many of which are listed in Table 1 (below). Cushingoid features are often pronounced but may be subtle in some cases. ACTH secreting pituitary adenomas are often small (less than 10 mm) at the time of discovery but, if large, may manifest with "mass effects" (visual field disturbances, headaches, pituitary hormone deficiencies, etc). Cortisol influences virtually every cell in the body and Cushing's patients often complain of severe dysfunction due extreme fatigue and weakness. Many of the features of Cushing's disease are common to other diseases (non-specific symptoms) and thus Cushing's patients often suffer for years prior to appropriate diagnosis. Insights into how a patient can work with their primary care provider can be found in the section: How Do I Work With My Doctor To Find Out if I have a Pituitary Disorder?.
Table 1 - Features of Cushing's Disease
- Rounding of the face (moon face)
- Facial redness (facial plethora)
- Hump on back of neck (dorsocervical fat deposition)
- Weight gain around the belly with thinner arms and legs (truncal obesity)
- Purple stretch marks (violaceous stria)
- Facial hair growth (hirsutism)
- Acne
- Muscle weakness
- Easy bruising
- Bone thinning (osteoporosis - sometimes with recurrent fractures)
- Recurrent infections
- Sleep disturbances
- Fatigue
- High blood pressure
- Diabetes mellitus
Diagnosis
Biochemically confirming the presence of Cushing's disease can be very difficult in some cases since there is no "gold standard" for making the diagnosis. Stated otherwise, virtually every test available for diagnosing Cushing's disease will sometimes falsely diagnose a "normal" person with the disease and conversely will sometimes fail to diagnose the disease in those who have it. However, a thorough history and physical exam combined with multiple tests can correctly rule in or rule out the disease in most cases.
The diagnosis of Cushing's is often made by measuring free cortisol in a 24-hour urine collection (UFC). Most clinicians consider a level of more than four times the upper limit of normal as diagnostic. For example, a urine cortisol of more than 300 mcg/24 hours with the normal being 8-70 is diagnostic of Cushing's. If the UFC is elevated but less than four times the upper limit of normal, more tests are necessary. This is because other entities can lead to small elevations in urine cortisol (e.g., depression, alcoholism, chronic and severe stress, etc). Conversely, a "normal" 24hour UFC suggests the absence of Cushing's but does not rule it out (i.e., there is a population of surgically proven Cushing's disease patients who had a "normal" UFC as part of their evaluation).
There are many other tests available for evaluating a patient for Cushing's disease. This author primarily uses two additional tests. The first is the sampling of serum cortisol over a 24-hour period. Normal individuals typically have serum cortisol levels of 18 ug/dl or higher around 8:00 a.m. The serum cortisol level steadily drops through the day and is typically undetectable around midnight. This is referred to as diurnal variation. Cushing's tumors typically do not follow this pattern and serum cortisol levels greater than 5 ug/dl at midnight are very suggestive of Cushing's. A second useful test is the "low dose" dexamethasone suppression test followed by CRH stimulation. ACTH secreting pituitary adenomas are typically less sensitive to suppression by dexamethasone than are normal pituitary cells but are typically more sensitive to stimulation by CRH (normally released by the hypothalamus). Therefore, a serum cortisol that is not suppressed (i.e., greater than 1.4 ug/dl) 15 minutes after CRH stimulation is suggestive of Cushing's. A multitude of other tests for evaluating Cushing's are also available (e.g., salivary cortisol measurements, "high dose" dexamethasone suppression test, etc.) As with virtually all tests for the evaluation of Cushing's disease, there can be false positive and false negative results.
Once the diagnosis of Cushing's has been made, the second step is to confirm that the serum ACTH level is not suppressed. This is important so as to rule out other causes of Cushing's syndrome (i.e., confirm that an ACTH secreting tumor is driving the disease). Third, it is important to localize the tumor to a pituitary versus a non-pituitary (or "ectopic") source. If a pituitary tumor (greater than 4mm) is clearly seen on MRI, many clinicians will proceed with surgery to treat ACTH dependant Cushing's. Alternatively cavernous or petrossal sinus sampling may be helpful to clearly localize the ACTH source. In this procedure, a catheter is placed in the vein of each leg and fed up past the heart up into the blood sinuses around the pituitary. Blood is then sampled from either side. This test not only confirms whether the tumor is in the pituitary, but helps the surgeon know which side of the pituitary to look for the tumor. In the hands of a good interventional radiologist experienced in the procedure, this process is relatively straightforward. Bad patient experiences with the procedure usually result from having it performed by an interventional neuroradiologist inexperienced in the procedure. The dexamethasone suppression test is also sometimes used for tumor localization but it is not as reliable as sinus sampling.
Treatment
The treatment of choice for Cushing's disease is pituitary surgery. A good surgeon will most often be able to cure Cushing's with one attempt. More details on the process of selecting a qualified neurosurgeon are available in the section: I Have Been Diagnosed with a Pituitary Tumor - What Should I Do Next?. Alternate treatments include steriotactic radiosurgery, adrenalectomy, and medications. All of these alternate treatments have potential complications making surgery in the hands of an expert pituitary surgeon the treatment of choice. In the case of large ACTH producing tumors (macroadenomas), deficiencies of other pituitary hormones may be present due to the damaging "mass effect" of the tumor. Patients with pituitary macroadenomas should be evaluated for pituitary hormone deficiencies as discussed in the section: How Do I Work With My Doctor To Find Out if I have a Pituitary Disorder? Pituitary hormone replacement therapy is discussed in the section: Pituitary Hormone Deficiency and Replacement.
The experience of cortisol withdrawal during the first several months after being cured of Cushing's can be very unpleasant. During this period, cortisol must be given back to the patient and then tapered off over time. Classic symptoms of this withdrawal process include fatigue, aching, and depression. Abdominal pain, nausea and vomiting, and dizziness are indicators that the cortisol withdrawal is occurring too quickly (adrenal insufficiency is occurring) and the hydrocortisone taper should be slowed.
There are two main phases that a cured patient will go through after surgery. The first is the cortisol withdrawal phase. The features of Cushing's disease are due to cortisol excess and the body reacts to having the cortisol withdrawn. To make the process tolerable (and safe), large doses of glucocorticoids are given to the postoperative patient and then tapered over a month or so as symptoms allow. This can be an awful experience for the patient marked by fatigue, depression, and body aches. Headache may be present but if severe (especially if accompanied by nausea and dizziness) may indicate that the taper is happening to quickly. After the initial withdrawal phase, the second phase is marked by the temporary need for continued glucocorticoid replacement (typically 20 mg hydrocortisone or 5 mg prednisone) until the hypothalamic/pituitary/adrenal (HPA) axis awakens. This phase may last many months and may last over a year. Until this axis awakens, the patient is adrenally insufficient and should be treated accordingly.
Assessment of Cure
Just as the initial diagnosis of Cushing's disease can be difficult to make, "proving" someone has been cured of Cushing's can be very challenging as well. One early indicator of biochemical cure is the measurement of very low (or undetectable) post-operative morning cortisol levels (typically measured 72 hours after surgery). In this post-operative setting, morning cortisol levels are typically low because normal ACTH producing cells in the pituitary have been suppressed by elevated serum cortisol levels. Therefore, the removal of the ACTH secreting tumor leaves no source of ACTH, the adrenal glands are no longer stimulated and cortisol levels plummet. It is important to note that as high as 30% of patients with long term cure of cushing's disease do not have a history of undetectable 72 hour post-operative serum cortisol levels. Therefore, if 72-hour post-operative cortisols are not below 5 ug/dl, further evidence should be obtained to confirm the presence or absence of cure.
After a patient has been tapered off replacement glucocorticoids post-operatively, it is important to demonstrate the normalization of the tests that were initially used to diagnose Cushing's disease. For example if a patient had a significantly elevated 24-hour UFC pre-operatively, it should normalize if a cure was obtained. Other evidence of cure is the dramatic resolution of the features of Cushing's disease. For example, many patients note a dramatic weight reduction in the first few months after surgery. By contrast, even in the context of a biochemical cure, features may resolve slowly. Even in the context of a biochemical cure, the symptoms of fatigue and depression can persist for many months since they are also the symptoms of cortisol withdrawal. It is important to note that even with an incomplete cure (i.e., not all the pituitary tumor was removed), many symptoms will begin to resolve at first but they usually return over time.
In general, when a cure is obtained, most of the features of Cushing's disease will reverse over time. Some of these changes can be dramatic. Some may take years. Of note, the need for medical treatment for high blood pressure and diabetes should be evaluated closely and will likely need to be tapered.
Finally, even in the hands of an excellent neurosurgeon, there is a recurrence rate of about 10% over time for Cushing's disease. Therefore, even in the context of a "biochemical cure", Cushing's patients should be monitored by history, physical, and biochemistry over time for possible recurrence of their disease. Work up and treatment are similar to those done at initial presentation.
Long-term Course and Potential Complications
Cured Cushing's are typically delighted with the resolution of most of their Cushing's symptoms. This can, however, take from months to even years to fully happen. As stated above, recurrence does occur and should be watched for by the patient and their clinician. Associated diseases such as diabetes mellitus, hypertension, and osteoporosis should be followed (and treated if necessary) although each may resolve fully over time as well.
This page is a "printer friendly" version of content presented in full at OHSUpituitary.com
This section was written by William H. Ludlam, M.D., Ph.D. for: www.OHSUpituitary.com.
Email: pituitary@ohsu.edu
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