Novartis drug Signifor® recommended by FDA advisory committee for approval to treat patients with Cushing’s disease

The US Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) has voted unanimously in support of the use of Signifor® (pasireotide) for the treatment of patients with Cushing’s disease who require medical therapeutic intervention.

“We are encouraged by today’s favorable advisory committee recommendation for pasireotide in Cushing’s disease and will work closely with the FDA as it completes its review of our application,” said Hervé Hoppenot, President, Novartis Oncology. “There is a significant unmet medical need for Cushing’s disease patients and Novartis is committed to providing the endocrinology community with a novel therapeutic approach for this rare and debilitating endocrine disorder.”

The recommendation was based on data from clinical trials of pasireotide, including PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio – CUSHING’S disease), the largest randomized Phase III study to evaluate a medical therapy in patients with Cushing’s disease. Although not obliged to follow the recommendation, the FDA can seek the advice of its advisory committees as it reviews and decides whether to approve treatments[1],[4].

Results from the PASPORT-CUSHINGS study found that mean urinary-free cortisol (UFC), the key measure of biochemical control of the disease, was rapidly decreased and sustained in a majority of patients, with a subset of patients reaching normalized levels. The study also showed that, on average, as UFC levels were reduced, clinical manifestations of Cushing’s disease improved. The most frequently reported adverse events (AEs) (>10%) by investigators for pasireotide were diarrhea, nausea, hyperglycemia, cholelithiasis, abdominal pain, diabetes mellitus, injection site reactions, fatigue and increased glycosylated hemoglobin (HbA1c), with most events being Grade 1-2. The safety profile of pasireotide was similar to that of other somatostatin analogs (SSA) with the exception of the greater degree of hyperglycemia[3].

Cushing’s syndrome is an endocrine disorder caused by excessive cortisol, a vital hormone that regulates metabolism, maintains cardiovascular function and helps the body respond to stress. Cushing’s disease is a form of Cushing’s syndrome, in which excess cortisol production is triggered by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. It is a rare but serious disease that affects approximately one to two patients per million per year. Cushing’s disease most commonly affects adults as young as 20 to 50 years and affects women three times more often than men. It may present with weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. The first line and most common treatment approach for Cushing’s disease is surgical removal of the tumor[1],[2],[5],[6],[7].

About pasireotide

Pasireotide is a multireceptor targeting somatostatin analog (SSA) that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5)[2]. In April 2012, the European Commission approved pasireotide under the brand name Signiforfor the treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed. Other worldwide regulatory filings for pasireotide for this use are also underway.

For the treatment of Cushing’s disease, pasireotide has been studied as a twice-daily subcutaneous (sc) injection and is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular (IM) injection as part of a global Phase III program in Cushing’s disease and acromegaly[8],[9].

There is no guarantee that pasireotide will become commercially available anywhere else in the world. As an investigational compound, the safety and efficacy profile of pasireotide has not yet been established in all countries for the treatment of Cushing’s disease or any other indications. Access to pasireotide outside of the approved indications has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound.

Information about Novartis clinical trials for pasireotide can be obtained by healthcare professionals at www.pasporttrials.com.

References

1. National Endocrine and Metabolic Diseases Information Service. US National Institutes of Health. Cushing’s Syndrome. Available at: http://endocrine.niddk.nih.gov/pubs/cushings/Cushings_Syndrome_FS.pdf. Accessed October 2012.
2. Pedroncelli, A. Medical Treatment of Cushing’s Disease: Somatostatin Analogues and Pasireotide. Neuroendocrinology. 2010;92(suppl1):120-124.
3. Colao, A. A 12-Month Phase III Study of Pasireotide in Cushing’s Disease. New Engl J Med. 2012; 366(10):914-924.
4. US Food and Drug Administration. The Federal Advisory Committee Act. Available at http://www.fda.gov/downloads/AdvisoryCommittees/AboutAdvisoryCommittees/LawsRegulationsGuidance/UCM154704.doc. Accessed October 2012.
5. Lindholm, J., et al. Incidence and Late Prognosis of Cushing’s Syndrome: A Population-Based Study. J Clin Endocrinol Metab. 2001;86(1):117-23.
6. Newell-Price, J., et al. The Diagnosis and Differential Diagnosis of Cushing’s Syndrome and Pseudo-Cushing’s States. Endocrine Reviews.1998;19(5):647-672.
7. Bertanga, X., et al. Cushing’s Disease. Best Practice & Research Clinical Endocrinology & Metabolism. 2009;23:607-623.
8. US National Institutes of Health. Safety and Efficacy of Pasireotide Long Acting Release (LAR) vs. Octreotide LAR in Patients With Active Acromegaly. Available at: http://clinicaltrials.gov/ct2/show/NCT00600886?term=safety+and+efficacy+of+pasireotide&rank=3. Accessed October 2012.
9. US National Institutes of Health. Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing’s Disease. Available at: http://clinicaltrials.gov/ct2/show/NCT01374906. Accessed October 2012.