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Novartis drug Signifor® gains FDA approval as the first medication to treat Cushing's disease, a serious endocrine disorder
- As the only pituitary-directed therapy, Signifor represents a novel therapeutic approach by addressing the underlying mechanism of Cushing's disease(1)
By: PR Newswire
Dec. 14, 2012 08:27 PM
EAST HANOVER, N.J., Dec. 14, 2012 /PRNewswire/ -- Novartis announced today that the US Food and Drug Administration (FDA) has approved Signifor® (pasireotide) injection for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative3. Signifor is the first medicine to be approved in the US that addresses the underlying mechanism of Cushing's disease, a serious, debilitating endocrine disorder caused by the presence of a non-cancerous pituitary tumor which ultimately leads to excess cortisol in the body1,4. This approval follows a unanimous recommendation from the FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) in support of the use of Signifor.
"The FDA approval of Signifor for Cushing's disease brings a novel pituitary-directed therapy to patients with limited treatment options," said Herve Hoppenot, President, Novartis Oncology. "Today's milestone reinforces Novartis' commitment to addressing unmet needs and advancing treatments for rare pituitary-related disorders."
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. Cushing's disease can cause severe illness and death with mortality up to four times higher than in the healthy population1,4,5,6,7.
The approval is based on data from 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 disease3. Results from the PASPORT-CUSHINGS study found that a decrease in mean urinary-free cortisol (UFC), the key measure of biochemical control of the disease, was sustained during the treatment period in most patients, with a subset of patients reaching normal levels. The study also showed that certain clinical manifestations of Cushing's disease tended to improve2.
"Patients with Cushing's disease may suffer from debilitating manifestations, and there are many serious health complications associated with the disease," said Mary Andrews, CEO and Co-Founder of the US non-profit, The MAGIC Foundation. "The FDA approval of Signifor offers the option of a medical therapy that may help certain patients with Cushing's disease."
In April 2012, the European Commission approved Signifor for 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.
About Cushing's disease
Patients with UFC levels greater than 1.5 times the upper limit of normal (ULN) were randomized to receive Signifor subcutaneous (sc) injection in doses of 0.9 mg (n=80) or 0.6 mg (n=82) twice daily2.
The primary endpoint, the proportion of patients who achieved normalization of UFC after six months without dose up-titration relative to randomized dose, was met in patients treated with 0.9 mg twice daily. Mean UFC levels were normalized in 26% and 15% of the patients randomized to receive Signifor 0.9 mg and 0.6 mg, respectively, at month six2.
The median reduction in mean UFC from baseline to month six was around 47% in both dose groups. Reductions in UFC were observed after one month of treatment with Signifor and were sustained during the treatment period in most patients. In addition, 34% and 41% of patients experienced a reduction in mean UFC from baseline less than or equal to ULN or greater than or equal to 50% in the 0.6 mg and 0.9 mg groups, respectively2.
Decreases in blood pressure, weight, body mass index and waist circumference were observed during the study. Limited conclusions can be drawn on these decreases due to variability of response across patients and the absence of a control group2.
The most common adverse events (AE) (greater than or equal to 20%) occurring in patients in either dose group receiving Signifor were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue and diabetes mellitus. The safety profile of Signifor was similar to that of other somatostatin analogs with the exception of the greater degree of hyperglycemia2.
About Signifor (pasireotide)
Signifor is expected to be available in the US by March 2013 and will be dispensed exclusively through a single specialty pharmacy. For more information about Signifor distribution, doctors and patients can contact Patient Assistance Now Endocrinology (PAN Endo) at 1-877-503-3377 (Press Option 3 for Signifor) or visit www.Signifor.us for more information. PAN Endo also offers quick and easy access to information about the many reimbursement and support programs available for its endocrinology medicines. Enrollment into PAN Endo will begin in January 2013.
For the treatment of Cushing's disease, Signifor 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. Signifor is a multireceptor targeting somatostatin analog that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5)6,9,10.
Important Safety Information about Signifor
Elevations in blood glucose levels have been frequently reported in healthy volunteers and patients treated with Signifor. Cushing's disease patients with poor glycemic control may be at higher risk of developing severe hyperglycemia and associated complications. Glycemic status should be assessed prior to starting treatment with Signifor. Patients need to be closely monitored for hyperglycemia; if hyperglycemia develops, the initiation or adjustment of antidiabetic treatment is recommended. Dose reduction or treatment discontinuation should be considered if uncontrolled hyperglycemia persists. After treatment discontinuation, glycemic monitoring (e.g., FPG or HbA1c) should be done according to clinical practice.
Bradycardia has been reported with use of Signifor. Patients with cardiac disease and/or risk factors for bradycardia need to be closely monitored. Signifor is associated with QT prolongation. Caution should be exercised in patients who have or may develop QT prolongation. Hypokalemia or hypomagnesemia must be corrected prior to initiating therapy and monitored thereafter. A baseline electrocardiogram should be performed prior to the start of Signifor therapy and monitoring for an effect on QTc interval is advisable during therapy.
Elevations in AST (aminotransferases) or ALT (alanine aminotransferase) were reported with the use of Signifor. Monitoring of liver function is recommended prior to starting treatment with Signifor. Liver function should be monitored again after one or two weeks on treatment, then monthly for the first three months and every six months thereafter. Therapy should be discontinued if AST or ALT increase five times the upper limit of normal or greater.
Cholelithiasis has been frequently reported with the use of Signifor. Ultrasonic evaluation of the gallbladder prior to treatment, and thereafter at six and 12 month intervals is recommended.
Monitoring of pituitary hormones is recommended prior to initiating treatment and periodically thereafter as clinically appropriate.
Signifor should not be used during pregnancy unless medically necessary. Breast feeding should be discontinued during treatment with Signifor.
Signifor may affect the way other medicines work, and other medicines can affect how Signifor works. Caution should be exercised with the concomitant use of bromocriptine, cyclosporine, anti-arrhythmic medicines or drugs that may lead to QT prolongation.
The most common adverse events (AE) (greater than or equal to 20%) occurring in patients in either dose group receiving Signifor were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue and diabetes mellitus.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group's continuing operations achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 127,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.
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1. Novartis Briefing Information for the November 7, 2012 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM326812.pdf. Accessed November 2012.
2. Colao, A. A 12-Month Phase III Study of Pasireotide in Cushing's Disease. New Engl J Med. 2012; 366(10):914-924.
3. Signifor® (pasireotide) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharmaceuticals Corporation; December 2012.
4. 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.
5. 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.
6. Pedroncelli, A. Medical Treatment of Cushing's Disease: Somatostatin Analogues and Pasireotide. Neuroendocrinology. 2010;92(suppl1):120-124.
7. Extabe, J. and Valquez E. Morbidity and Mortality in Cushing's Disease: An Epidemiological Approach. Clinical Endocrinology. 1994;40:479-484.
8. 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.
9. 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.
10. 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.
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