New Orphan Drug Approved for Cushing's

FDA NEWS RELEASE

For Immediate Release: Dec. 14, 2012

Media Inquiries: Morgan Liscinsky, 301-796-0397; morgan.liscinsky@fda.hhs.gov 

Consumer Inquiries: 888-INFO-FDA

FDA approves Signifor, a new orphan drug for Cushing's disease

The U.S. Food and Drug Administration today approved Signifor (pasireotide diaspartate) injection for the treatment of Cushing's disease patients who cannot be helped through surgery.

Cushing's disease is caused by over-production of cortisol, a hormone made by the adrenal glands. A tumor in the pituitary gland leads to overstimulation of the adrenal gland, which results in excess cortisol production. Cortisol regulates many important functions in the body, including response to stress and injury. Patients with Cushing's disease may have increased weight, glucose intolerance or diabetes, high blood pressure, easy bruising, and increased risk for infections.

 

"Although surgery tends to be first line therapy to treat Cushing's disease, Signifor is a new treatment option for patients when surgery hasn't worked or isn't an option," said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA's Center for Drug Evaluation and Research.

The safety and effectiveness of Signifor were evaluated in a clinical trial of 162 Cushing's disease patients. Trial participants were randomly chosen to receive one of two dose levels of Signifor over a six-month treatment period. Some patients who safely responded to the medication where allowed to continue treatment. Signifor resulted in decreased cortisol levels as measured in urine collected over a 24-hour period. This reduction was seen as early as one month after starting treatment. About 20 percent of patients in the clinical trial were able to reduce urine cortisol levels into the normal range.

Signifor caused increases in blood sugar levels, which could be detected as early as two weeks after starting treatment. Continued treatment caused or worsened diabetes in some patients; therefore, patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin.

The FDA is requiring three postmarketing studies for Signifor: a clinical trial to assess high blood sugar (hyperglycemia) management; a long-term prospective observational cohort study (registry) of patients with Cushing's disease treated with Signifor; and focused safety monitoring for reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency.

Signifor is administered under the skin (subcutaneously) twice daily, and will be dispensed with a Medication Guide, including instructions for patients and caregivers that describe the risks and adverse reactions people should be mindful of when using the product.

The most common adverse reactions observed in the clinical trial included hyperglycemia, diarrhea, nausea, abdominal pain, and gallstones.

Signifor is manufactured by Novartis Pharma Stein AG, Stein, Switzerland.

For more information:

• FDA Approved Drugs: Questions and Answers 
• FDA: Drug Innovation  

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332351.htm

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See http://www.signifor.us/index.jsp for more information.

Spotlight on Cushing's: Lori on Dr Oz

Be sure to watch Lori's heartbreaking 

and informative segments 

on the Dr Oz show.

Thank you Dr Oz!

Out of Control Obesity: 

One Woman's Struggle with 

Cushing's Disease

http://www.doctoroz.com/videos/out-control-obesity-one-womans-struggle-cushings-disease-pt-1

My Friend Lori Featured in News

Doctors, Patient From Ohio State Wexner Medical Center To Be Featured On 'Dr. Oz' Show

Wednesday December 19, 2012 5:39 PM

COLUMBUS, Ohio - An innovative operation conducted at The Ohio State University Wexner Medical Center will be featured on "The Doctor Oz Show."

Doctors used the operation to treat Cushing's Disease, an illness Lori Genser Burkhoff has suffered from for most of her life.

Cushing's Disease is caused by a tumor on the pituitary gland, the master gland of the body. Burkhoff was diagnosed when she was 14, when she gained 60lbs in a few months.

"The shape of my face was sort of as if somebody injected air into it. I was weak. I was losing my hair. I was just falling apart," Burkhoff said.

Doctors operated on her pituitary gland three times, but the problems persisted.

"Having a fourth pituitary surgery is sort of unheard of in the medical community, and there are very few doctors in the country who would even attempt to do this," Burkhoff said.

Then Burkhoff, a New York resident, heard of a new way to remove brain tumors, pioneered at the OSU Wexner Medical Center.

Instead of cutting open her head to reach the tumor and remove it, doctors went in through her nose. A brain surgeon worked through one nostril, while Dr. Ricardo Carrau, an ear nose and throat doctor, worked through the other.

"The advantage of doing is through the nose is you have an actual corridor. The nose has some air space. The sinuses have some air space," Carrau said. "So if you can connect the two, you can get to the pituitary gland."

Carrau said that avoiding incisions during surgery helps patients heal faster.

"They recover incredibly better than what they were doing before," Carrau said.

Burkhoff needed two surgeries. CBS' Dr. Oz was there to see for himself how it was done.

Now Burkhoff said she plans to come home to her husband and daughter.

"I'm hoping for a real start to 'Act Two,'" she said.

Doctors removed Lori's entire pituitary gland and part of the nearby bone to avoid a return of Cushing's Disease. Since the surgery, Lori has lost 30 pounds.

The Dr. Oz Show will have Lori's full story Thursday at 4 p.m. on 10TV.

 

©2012 by 10TV.com. All rights reserved. 

http://www.10tv.com/content/stories/2012/12/19/columbus-woman-to-appear-dr-oz-cushings-disease.html

Cushing's to be Featured in National News

In September 2012, Dr. Oz from the Dr Oz Show joined my dear friend Lori and her amazing surgical team for her 4th (and ultimately 5th) brain surgery in Columbus, Ohio.  Lori has been battling Cushing's for 20 years.  

Please tune in to/ DVR this network television show this Thursday, December 20 to learn more about Cushing's. Check your local listings.

(Show lists the topics as sextuplets and Marlo Thomas/ cancer).

From the Dr Oz Show:

"Can you imagine gaining so much weight, despite a healthy lifestyle, that it would eventually lead you to die from obesity?  It's a real illness, and it's called Cushing's Disease.  Dr. Oz met Lori, a woman desperate to survive this devastating and rare condition, and he joined her in the operating room as she underwent the dangerous surgery that could end her life or improve it forever. Dr. Oz shares his journey and he introduces Dr. Daniel Prevedello from Ohio State University Medical Center who performed Lori's ground-breaking procedure."

Lori has also created a web site crushingcushings.com to help share her story. 

I hope you will be able to watch. This is a big day in Cushie World.

Melissa

Australian Pituitary Foundation

Our friends in Hobart, Tasmania, Australia gathered to discuss the pituitary gland today.

Click here for more program details.

http://www.gpsouth.com.au/Consumers/News/Pituitary%20in%20Tassie.pdf

Click here for brochure:
http://www.pituitary.asn.au/portals/0/pdfs/resources/APF%20Brochure.pdf

Images courtesy of Australian Pituitary Foundation. 

http://www.pituitary.asn.au/  

All rights reserved.

Therapy of Adrenal Insufficiency

This new article from our friends in Italy is a comprehensive yet easy-to-read look at adrenal insufficiency. I find this information so valuable in understanding the mechanics of sufficient and timely cortisol replacement for Cushies post-op pituitary surgery or, for me, combined with nighttime ketaconazole as a medical therapy for persistent Cushing's disease. I applaud the authors for their wondrous graphs and tables highlighting the most important aspects of cortisol control. In particular, my heart sang when reading about the future of cortisol replacement section. Hope is on the way.

*******

Therapy of adrenal insufficiency: an update

• Alberto Falorni, 
• Viviana Minarelli, 
• Silvia Morelli

Endocrine

November 2012

Abstract

Adrenal insufficiency may be caused by the destruction or altered function of the adrenal gland with a primary deficit in cortisol secretion (primary adrenal insufficiency) or by hypothalamic-pituitary pathologies determining a deficit of ACTH (secondary adrenal insufficiency). The clinical picture is determined by the glucocorticoid deficit, which may in some conditions be accompanied by a deficit of mineralcorticoids and adrenal androgens. The substitutive treatment is aimed at reducing the signs and symptoms of the disease as well as at preventing the development of an addisonian crisis, a clinical emergency characterized by hypovolemic shock. The oral substitutive treatment should attempt at mimicking the normal circadian profile of cortisol secretion, by using the lower possible doses able to guarantee an adequate quality of life to patients. The currently available hydrocortisone or cortisone acetate preparations do not allow an accurate reproduction of the physiological secretion pattern of cortisol. A novel dual-release formulation of hydrocortisone, recently approved by EMEA, represents an advancement in the optimization of the clinical management of patients with adrenal insufficiency. Future clinical trials of immunomodulation or immunoprevention will test the possibility to delay (or prevent) the autoimmune destruction of the adrenal gland in autoimmune Addison's disease.

View the complete article in .pdf form here:

http://download.springer.com/static/pdf/580/art%253A10.1007%252Fs12020-012-9835-4.pdf?auth66=1354599590_c8e2d487dd479af815146acdc2d7e633&ext=.pdf

or view HTML:

http://link.springer.com/article/10.1007%2Fs12020-012-9835-4

Aggressive Cushing's

I have been so sick for the 75 days with adrenal insufficiency. As a result, I have been unable to determine the right ketoconazole dose at 8 pm and 10 pm or stabilize my Cortef/ hydrocortisone replacement at 8 am. Only in the last few days have I even thought of looking to the medical journals for more knowledge. Today, I share this full article (pdf).

Journal of Oncololgy. 2012; 2012: 685213.

Published online 2012 August 9.

Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

Carlotta Pozza, Chiara Graziadio, Elisa Giannetta, Andrea Lenzi, and Andrea M. Isidori^*

Abstract

Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone "RU-486"). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ"PPAR-γ" ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.

---

Articles from Journal of Oncology are provided here courtesy of Hindawi Publishing Corporation

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425913/pdf/JO2012-685213.pdf

Cushies can die after exhausting all treatment options

This makes me incredibly sad.  I have had two unsuccessful pituitary surgeries, and I am currently doing medication therapy (pm ketoconazole with am Cortef) until the tumor culprit comes out of hiding and presents itself on the pituitary MRI for a third pituitary surgery.  No one knows how long that will take.

After my first pituitary surgery, I developed ptosis, or drooping eyelid.

**************

Cushing’s: the worst case scenario

Viv Thornton-Jones

Churchill Hospital, Oxford, UK.
Endocrine Abstracts (2008) 15 S58

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We present the case of a 40-year-old female who was referred to our Department in 1993, for further management following the diagnosis of Cushing’s disease. She proceeded to a transsphenoidal adenenomatectomy (TSA, note: pituitary surgery) which resulted in a biochemical cure.

In 1998 she presented with recurrence of Cushing’s Disease, which was managed by a 2nd TSA (pituitary surgery) followed by external beam irradiation.

Bilateral adrenalectomy followed a year later, due to the inability to control her disease.

In 2001 she presented with Nelson’s Syndrome managed by a 3rd TSA (pituitary surgery) followed this time with Gamma Knife surgery.

In 2004 she presented with manifestations consistent with recurrence of Nelson’s Syndrome and proceeded to a 4th TSA (pituitary surgery). 

Despite the risk of blindness, the patient agreed to a second course of Gamma Knife treatment for the possibility of tumour control.

Over the next 2 years her clinical picture deteriorated, resulting in a right partial ptosis and a sixth nerve palsy.

She was referred to an Oncologist who offered her Chemotherapy, but she refused treatment.

The patient was then in the care of the Palliative Care Team and she died peacefully at home in 2006.

---

Endocrine Abstracts (2008) 15 S58

Thank you to Ami and MaryO for finding this abstract.

Europe Continues to Lead Research on Cyclical Cushing's

It is my strong belief that European endocrinologists and research will pave the way for cyclical patients in the United States, who continue to struggle.

Don't believe me?

Well, I point you to many articles that consistently come out of Ireland, Italy, Germany, France, England, Serbia, Spain, and others I can't remember now. When I get a chance, I'll try to post a link with all of these articles in one place. Until then, please, I beg you. Trust me on this.

I have read many articles on cyclical Cushing's -- after searching high and low for them. These articles come primarily from our European friends. 

Common knowledge about cyclical Cushing's must be racing around the continent on those bullet trains (which I adore, by the way!).

A Comparison of the Use of Urinary Cortisol to Creatinine Ratios and Nocturnal Salivary Cortisol in the Evaluation of Cyclicity in Patients with Cushing's Syndrome Authors 1.    U. M. Graham, 2.    S. J. Hunter, 3.    M. McDonnell, 4.    K. R. Mullan and 5.    A. B. Atkinson 1.   Regional Centre for Endocrinology and Diabetes (U.M.G., S.J.H., K.R.M., A.B.A.) and Regional Endocrine Laboratory (M.McD.), Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom 1.    Address all correspondence and requests for reprints to: Dr. Una Graham, Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, United Kingdom. E-mail: qublbc8@hotmail.com. Abstract Context: Cyclical Cushing's syndrome is detected in our center by collecting sequential early morning urine (EMU)* samples for cortisol to creatinine ratio over 28 d. The Endocrine Society suggests that nocturnal salivary cortisol (NSC)* may be used to assess patients for cyclical Cushing's. However, there is only very limited evidence that it correlates with early morning urine testing or that it demonstrates cycling over 28 d. Objective: We sought to correlate nocturnal salivary cortisol with early morning urine results collected the following morning and to determine whether nocturnal salivary cortisol could be used to detect cyclical Cushing's. Design and Setting: An observation study of 28-d collections for nocturnal salivary cortisol and early morning urine was performed in a tertiary referral center over 1 yr. Patients: A 28-d collection of nocturnal salivary cortisol and early morning urine was performed in 10 patients with confirmed or suspected Cushing's syndrome. Main Outcome Measure: The main outcome of the study was the correlation of salivary and urinary cortisol with graphical assessment of results for cycling. Results: Eleven collections were performed. One patient with cyclical Cushing's completed the collection before and after cabergoline therapy. Two hundred seventy matched salivary and urinary results were correlated (r = 0.79; P < 0.001). In two patients with cyclical Cushing's, early morning urine and nocturnal salivary cortisol followed a similar cyclical pattern. In one patient with recurrent cyclical Cushing's, cortisol was elevated in both saliva and urine but with more prominent cycles in saliva. Conclusion: Nocturnal salivary cortisol correlated well with early morning urine (EMU). Nocturnal salivary cortisol detected all cases of cyclical Cushing's. Therefore, nocturnal salivary cortisol may prove to be an additional option or replacement for early morning urine in detecting cyclical Cushing's syndrome.

* For ease of reading, blogger changed all EMU to early morning urines and all NSC to nocturnal salivary cortisol. A Cushie brain is far too foggy to keep even these simple conventions straight even when reading a brief article. 

Dogs and Cortisol

Any person researching Cushing's is sure to come encounter as many articles about dogs as humans. Horses and cats get Cushing's as well. Wanna know which doctors seem to be the most compassionate and know the most about Cushing's? Veterinarians.

This morning, as cortisol woke me as it often does at 3:45 am on the dot, I was reading news online on my beloved and ever-present companion, my iPhone.

Fiona Apple cancels tour, citing dying dog: Read her handwritten note | The Music Mix Mobile | EW.com

http://music-mix.ew.com/2012/11/20/fiona-apple-cancels-tour-dog/

Fiona explains her dog has Addison's, a disease that plagues the patient with low cortisol (while Cushing's does it with high cortisol). She mentions her dog needing shots to keep her alive. Might this be the same Solu-cortef doses that we Cushing's patients need when we face secondary adrenal insufficiency, even years after pituitary surgery?

I admire Fiona Apple's love, compassion, and courage for her 14-year old "pacifist" rescue dog. While her music has never found its way to my speakers in the past, I will be sure that it soon will.  

Fiona, my thoughts are with you and your lovely canine friend at this time.