Novartis drug Signifor® gains FDA approval as the first medication to treat Cushing's disease, a serious endocrine disorder

 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

- In the Phase III trial, most patients experienced a sustained decrease in
mean urinary-free cortisol levels, a key measure of disease, with a subset

- In the EU, Signifor has been previously approved for the treatment of adult
patients with Cushing's disease; other worldwide regulatory filings are

PR Newswire

EAST HANOVER, N.J., Dec. 14, 2012

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
curative^3. 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 body^1,4.
This approval follows a unanimous recommendation from the FDA Endocrinologic
and Metabolic Drugs Advisory Committee (EMDAC) in support of the use of

"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 population^1,4,5,6,7.

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 disease^3. 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 improve^2.

"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
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 a pituitary
adenoma secreting excess adrenocorticotropic hormone (ACTH). It is a rare but
serious disease that affects approximately one to two patients per million per
year. The first line and most common treatment approach for Cushing's disease
is surgical removal of the tumor^4,6,8.

PASPORT-CUSHINGS is a prospective, randomized, double-blind, Phase III study
conducted at 68 sites in 18 countries. The study evaluated the efficacy and
safety of Signifor in 162 adult patients with persistent or recurrent
Cushing's disease, as well as in patients with newly diagnosed Cushing's
disease who were not candidates for surgery^2.

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 daily^2.

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 six^2.

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, respectively^2.

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 group^2.

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

About Signifor (pasireotide)
Signifor^®(pasireotide) is approved in the US for the treatment of adult
patients with Cushing's disease for whom pituitary surgery is not an option or
has not been curative, and in the European Union for the treatment of adult
patients with Cushing's disease for whom surgery is not an option or for whom
surgery has failed.

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 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
Treatment with Signifor leads to suppression of adrenocorticotropic hormone
(ACTH) secretion in Cushing's disease patients. Suppression of ACTH may lead
to a decrease in circulating levels of cortisol and potentially
hypocortisolism. Patients need to be monitored and instructed how to monitor
for signs and symptoms of hypocortisolism. Temporary exogenous steroid
(glucocorticoid) replacement therapy and/or dose reduction or interruption of
Signifor therapy may be necessary.

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

The foregoing release contains forward-looking statements that can be
identified by terminology such as "underway," "commitment," "will,"
"expected," "can," or similar expressions, or by express or implied
discussions regarding potential additional marketing approvals for Signifor or
regarding potential future revenues from Signifor. You should not place undue
reliance on these statements. Such forward-looking statements reflect the
current views of management regarding future events, and involve known and
unknown risks, uncertainties and other factors that may cause actual results
with Signifor to be materially different from any future results, performance
or achievements expressed or implied by such statements. There can be no
guarantee that Signifor will be approved for sale in any additional markets,
or at any particular time. Nor can there be any guarantee that Signifor will
achieve any particular levels of revenue in the future. In particular,
management's expectations regarding Signifor could be affected by, among other
things, unexpected regulatory actions or delays or government regulation
generally; unexpected clinical trial results, including unexpected new
clinical data and unexpected additional analysis of existing clinical data;
competition in general; government, industry and general public pricing
pressures; unexpected manufacturing issues; the company's ability to obtain or
maintain patent or other proprietary intellectual property protection; the
impact that the foregoing factors could have on the values attributed to the
Novartis Group's assets and liabilities as recorded in the Group's
consolidated balance sheet, and other risks and factors referred to in
Novartis AG's current Form 20-F on file with the US Securities and Exchange
Commission. Should one or more of these risks or uncertainties materialize, or
should underlying assumptions prove incorrect, actual results may vary
materially from those anticipated, believed, estimated or expected. Novartis
is providing the information in this press release as of this date and does
not undertake any obligation to update any forward-looking statements
contained in this press release as a result of new information, future events
or otherwise.

About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and
markets innovative prescription drugs used to treat a number of diseases and
conditions, including cardiovascular, dermatological, central nervous system,
bone disease, cancer, organ transplantation, psychiatry, infectious disease
and respiratory. The company's mission is to improve people's lives by
pioneering novel healthcare solutions.

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

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1. Novartis Briefing Information for the November 7, 2012 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee. Available at:
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:
Accessed October 2012.

5.Newell-Price, J., et al. The Diagnosis and Differential Diagnosis of
Cushing's Syndrome and Pseudo-Cushing's States. Endocrine

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:
Accessed October 2012.

10. US National Institutes of Health. Efficacy and Safety of Pasireotide
Administered Monthly in Patients With Cushing's Disease. Available at: Accessed October 2012.

Novartis Media Relations

Julie Masow
                                       Nicole Riley
Novartis Corporation
                                       Novartis Oncology
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