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Medical Therapy for Cushing’s Disease: Spotlight on the Investigational Medication SOM230 (Pasireotide)

Cortisol is a hormone (chemical messenger) made in the adrenals, which are small, triangular shaped glands located on top of the kidneys. The production of cortisol is controlled by hormonal signals from the hypothalamus and the pituitary gland, both of which are in the head. The pituitary hormone, called adrenocorticotropic hormone (ACTH), is made in specialized cells called corticotrophs. Corticotrophs release ACTH in pulses into the bloodstream. ACTH then circulates through the body to reach the adrenals, where it triggers a pulse of cortisol. Cortisol is essential to life; consistently low or high levels can cause illness. This article focuses on endogenous Cushing’s disease, meaning excess cortisol resulting from a corticotroph tumor in the pituitary gland, and a new medication under development for this condition.

Questions about Cushing’s disease and medical therapy

1. What is the difference between “Cushing’s syndrome” and “Cushing’s disease”?

A. Cushing syndrome: means all the clinical problems that can develop from having excess levels of cortisol in the body. The most common cause of Cushing’s syndrome is that it can be a side effect of prescription medications containing cortisol or cortisol-like compounds.

B. Endogenous Cushing’s syndrome means Cushing’s syndrome due to a growth (tumor) somewhere in the body resulting in consistently high cortisol levels over many months or years. These tumors can occur in three different forms: pituitary, ectopic or adrenal.

  • Cushing’s disease: About three-quarters of cases of endogenous Cushing’s are due to benign (non-cancerous) tumors called corticotroph adenomas in the pituitary gland making excess ACTH. This is known as Cushing’s disease. When the excess ACTH circulates through the body to the adrenal glands, they over-produce cortisol. Cushing’s from a pituitary source is called Cushing’s disease because the original description in the early 1900s was by Harvey Cushing, MD, a neurosurgeon who determined that a group of patients experiencing similar problems had ACTH-producing pituitary tumors.
  • Ectopic Cushing’s: This results from a tumor (which can be benign or malignant) in another part of the body that produces ACTH. These are most commonly in the lungs but can be in many other locations.
  • Adrenal Cushing’s: The third possible source of Cushing’s is a tumor (benign or malignant) on the adrenal gland itself, over-producing cortisol directly.

2. What is the best treatment for Cushing’s from these tumors?

For most patients the first choice of treatment for all types of endogenous Cushing’s is surgical removal of the tumor.

3. Why can’t Cushing’s disease be cured with a medication instead of surgery?

There is currently no approved medical therapy that acts directly on the pituitary tumors which cause Cushing’s disease.

4. Are there some situations in which medical treatment is recommended?

Yes. Certain medications can block the production of cortisol by the adrenal glands. They are usually reserved for two situations. Medical treatment may be used when surgery is not considered safe. For example, if a person has just had a myocardial infarction (heart attack) or other acute illness, so that anesthesia and surgery might be unsafe, medical treatment may be advised to control the cortisol level temporarily. When the patient has recovered from the acute condition and is able to undergo anesthesia and surgery, the medication for Cushing’s is stopped. Secondly, medication is used in cases where the entire tumor is not removed surgically. Sometimes this is done while awaiting the affects of pituitary radiation (which may take many months or years); in other patients the medication may be used indefinitely.

5. What medications are used to treat Cushing’s disease?

The medication most commonly used is called ketoconazole. It is taken in pill form 2 or 3 times a day. This medicine works in the adrenal gland to block the formation of cortisol. It does not treat the pituitary tumor, but can lower the level of cortisol, which is good for the patient’s overall health. The dose is usually adjusted with a goal of having a 24 hour urine free cortisol (UFC) in the normal range. It is tolerated well by most patients; a few have side effects and liver function should be monitored with periodic blood tests. Other oral medications that also work in the adrenal gland are sometimes used. They typically need to be taken four times a day and have a higher rate of side effects. These include metyrapone (which is only available on special request to the company by the doctor), aminoglutethimide (which will no longer be available), and mitotane.

6. Will there ever be a medication that treats the pituitary tumor in Cushing’s disease?

Extensive research is underway to develop medications that will target the pituitary tumor in Cushing’s disease. One of these is an investigational medication called SOM230 or pasireotide.

7. What is an “investigational medication”?

The term “investigational medication” is used for new drugs being studied to determine whether they are safe and effective. An investigational medication is one that has not yet been approved by the US Food and Drug Administration (FDA) and is not available by prescription.

8. What are the steps needed for a medication to be approved by the FDA?

There are many steps to the approval of a new medication, and it typically takes many years from the creation of a product in the laboratory until it reaches the stage of being available to patients. These steps are designed to be sure that it works (called “efficacy”) and to be sure that is safe. A simplified version of this complex process includes the following. The first step is called “pre-clinical”, meaning research conducted before the new compound is tried in humans. This involves laboratory work and animal studies. Many products never make it past the lab bench, but if the early studies do appear promising, Phase 1 trials are performed next. In Phase 1 studies, the medication is given to healthy normal volunteers. This provides the first information in humans regarding how the medication works, what doses might be effective, and data about safety. If the results suggest it might be useful, then studies begin in patients with the condition. Phase 2 studies are usually short term, designed to provide preliminary information about whether the medication might help patients before embarking on the larger and longer Phase 3 studies. If the results from Phase 2 are positive, Phase 3 studies may be undertaken; these offer actual treatment for a longer period of time. If results of Phase 3 clinical trials show both efficacy and safety, the findings typically are presented formally by the company making the product to the FDA to request approval. Often the results are also shown at scientific meetings and published in a scientific journal so physicians can learn about the medication. Once a drug is FDA-approved, the pharmaceutical company can make it available for sale, and doctors can write prescriptions for their patients.

9. What is SOM230 (pasireotide)?

This is an investigational medication being developed by the pharmaceutical company Novartis. It is a member of a class of drugs called somatostatin analogues. Somatostatin is a hormone made in the hypothalamus that decreases production of several pituitary hormones. Because somatostatin only lasts for minutes in the blood, analogues (similar chemical compounds) have been developed which can last longer and may have other desirable properties. There are two somatostatin analogues (octreotide and lanreotide) which have been approved by the FDA for treatment of another type of pituitary tumor called acromegaly. These medications are not very useful in Cushing’s disease, but pasireotide has certain characteristics that make it more likely to be effective in this disorder. A lab study showed that ACTH release from corticotroph tumors decreased when the tumor cells were incubated (mixed) with pasireotide. This and other research conducted in labs around the world raised the possibility that pasireotide might be useful in patients with Cushing’s disease.

10. Have Phase 1 or 2 studies been conducted with pasireotide?

Yes. After pasireotide was studied in normal volunteers in a Phase 1 study, a Phase 2 study was performed. Preliminary results were shown to endocrinologists at scientific meetings (The Endocrine Society 2006 meeting, The European Neuroendocrine Association 2007 meeting). The Phase 2 study was very brief (just 15 days), with patients giving themselves two injections a day with a small needle, similar to that used for insulin by diabetics. Of the first 21 patients treated around the world, 20 had a decrease in UFC. Several patients had complete normalization of UFC and several others were close to normal in the short treatment period. These results were very promising, so a Phase 3 treatment study is now underway.

11. Where can I learn more about the Phase 3 study with pasireotide?

All clinical trials in the US must be listed on a government website:

Typing the study identifier “NCT00434148” in the search field leads directly to information about the Phase 3 pasireotide study in Cushing’s disease. In brief, this study is for adults with active pituitary Cushing’s who are not eligible for, or who are not in remission after, transsphenoidal surgery. It is a one year treatment study in which patients take pasireotide injections twice daily. Patients are seen regularly at a research center (about once a month, but slightly more often at the beginning of the study). All study tests, the medication and injection supplies are provided at no charge. There is a stipend for each visit as well as possible reimbursement of travel expenses in some circumstances. Current plans are that patients who are well controlled on the medication (such as having a normal UFC) will will have the option of continuing on the medication at no harge beyond the year of the main study, in an “extension study”.

12. How can I find out whether I (or someone I know) might be able to participate in the Phase 3 study with pasireotide?

There are specific criteria which must be met for a patient to be eligible, some of which include UFC levels a certain amount above the upper limit of normal and no prior radiation treatment for the tumor. If patients are already taking an adrenal-blocking medication such as ketoconazole, there is a brief “wash out” period (of course, this should only be done under supervision of an endocrinologist). For more information, contact the closest study site. The research centers performing this study around the US (and a contact person and phone number at each) are listed on the website mentioned above. A patient questionnaire is also available at Endocrinologists and patients alike hope that one day there will be a medical therapy for the tumors which cause Cushing’s disease. The Phase 3 study now underway will help determine whether pasireotide might be an effective and safe medication.

Authors: Beverly MK Biller, MD and Karen JP Liebert, BSN, RN (Spring, 2008)

Editor’s Note: Beverly MK Biller, MD is a Professor of Medicine at Harvard Medical School and a member of the Neuroendocrine Unit at Massachusetts General Hospital ( Cushing’s disease is one of her special research and clinical interests. Karen JP Liebert, BSN, RN is the Research Nurse in the MGH Neuroendocrine Clinical Center and is the Study Coordinator for the Phase 3 pasireotide study there. She is a national nursing expert in pituitary disorders and has conducted many clinical research trials.

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