Novartis drug Signifor® approved in the EU as the first medication to treat patients with Cushing's disease
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Novartis drug Signifor® approved in the EU as the first medication to treat
patients with Cushing's disease
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* Signifor is first targeted approach for Cushing's disease, a debilitating
endocrine disorder caused by an underlying pituitary tumor that triggers
excess cortisol[1],[2],[3]
* Majority of patients in the Phase III clinical trial experienced a rapid and
sustained decrease in mean cortisol levels with a subset of patients
achieving normalization
* With reduced cortisol levels, key clinical manifestations of the disease
improved, including reductions in blood pressure, cholesterol, weight and
body mass index[1]
Basel, April 25, 2012 - Novartis announced today that the European Commission
has approved Signifor(®) (pasireotide) for the treatment of adult patients with
Cushing's disease for whom surgery is not an option or for whom surgery has
failed[1]. Signifor is the first medicine to be approved in the European Union
(EU) targeting Cushing's disease.
The approval is based on data from the largest randomized Phase III study to
evaluate a medical therapy in patients with Cushing's disease, a disorder caused
by excess cortisol in the body due to the presence of a non-cancerous pituitary
tumor[1],[2],[3]. In the study, mean urinary-free cortisol (UFC) levels were
normalized in 26.3% and 14.6% of the 162 patients randomized to receive Signifor
900µg and 600µg subcutaneous (sc) injection twice daily, respectively, at month
six. 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 900µg twice daily[4].
In addition, the study showed the majority of the patients remaining on the
study at month six (91 out of 103 patients; 88%) had any reduction in their mean
UFC[5]. The median reduction in mean UFC was 47.9% in both dose groups.
Reductions in UFC were rapid and sustained through the end of the study, with
the majority of patients experiencing a decrease within the first two months[4].
Overall reductions in the clinical manifestations of Cushing's disease,
including blood pressure, total cholesterol, weight and body mass index, were
observed at months six and twelve in patients with both full and partial mean
UFC control, with the greatest reductions observed in patients with normalized
UFC levels[1],[4].
"As the first therapeutic option to specifically target Cushing's disease,
Signifor has the potential to redefine treatment of this debilitating disease,"
said Hervé Hoppenot, President, Novartis Oncology. "By focusing research efforts
on our understanding of this rare disease where there is significant unmet need,
we have been able to successfully bring a novel treatment option to patients in
the European Union."
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 and full face, severe fatigue and weakness, striae
(purple stretch marks), high blood pressure, depression and
anxiety[2],[3],[6],[7].
"Patients with Cushing's disease often struggle with a variety of debilitating
health issues associated with the overproduction of cortisol and previously were
faced with a treatment approach limited to surgery," said Ellen van Veldhuizen,
board member of the Dutch Adrenal Society. "The approval of pasireotide as a new
treatment option that may help patients with Cushing's disease is welcome news."
The decision follows the positive opinion the Committee for Medicinal Products
for Human Use (CHMP) adopted for Signifor in January 2012 for the treatment of
Cushing's disease and applies to all 27 EU member states, plus Iceland and
Norway. Signifor has orphan drug designation for Cushing's disease, a condition
which affects no more than five in 10,000 people in the EU, the threshold for
orphan designation[8],[9]. Additional regulatory submissions for pasireotide for
the treatment of Cushing's disease are under way worldwide.
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 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. The first line and most common treatment approach for Cushing's disease is
surgical removal of the tumor[2],[3],[10].
About PASPORT-CUSHINGS
PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease) 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 and UFC levels
greater than 1.5 times the upper limit of normal (ULN), as well as in patients
with newly diagnosed Cushing's disease who were not candidates for surgery[4].
Patients with primarily moderate to severe hypercortisolism were randomized to
receive Signifor sc injection in doses of 900µg (n=80) or 600µg (n=82) twice
daily. The primary endpoint was the proportion of patients who achieved
normalization of UFC after six months without dose up-titration relative to
randomized dose, which was met in patients treated with 900µg twice daily[4].
About Signifor (pasireotide)
Signifor(®) (pasireotide) is approved in the European Union (EU) for the
treatment of adult patients with Cushing's disease for whom surgery is not an
option or for whom surgery has failed. 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. Signifor 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)[1],[3],[11].
Information about Novartis clinical trials for pasireotide can be obtained by
healthcare professionals at www.pasporttrials.com.
Important Safety Information about Signifor
Signifor is contraindicated in patients with hypersensitivity to the active
substances in Signifor or to any of the excipients and in patients with severe
liver impairment.
Alterations in blood glucose levels have been frequently reported in healthy
volunteers and patients treated with Signifor. Glycemic status should be
assessed prior to starting treatment with Signifor. Patients need to be
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.
Monitoring of liver function is recommended prior to starting treatment with
Signifor and after one, two, four, eight and twelve weeks during treatment and
thereafter as clinically indicated. Therapy should be discontinued if the
patient develops jaundice, other clinical signs of significant liver
dysfunctions, sustained AST (aminotransferases) or ALT (alanine
aminotransferase) increase five times the upper limit of normal (ULN) or
greater, or if ALT or AST increase three times ULN with concurrent bilirubin
elevation greater than two times ULN.
Patients with cardiac disease and/or risk factors for bradycardia need to be
closely monitored. Caution is to be exercised in patients who have or may
develop QT prolongation. Hypokalemia or hypomagnesemia must be corrected prior
to initiating therapy and monitored thereafter. Electrocardiography should be
performed prior to the start of Signifor therapy and as clinically indicated
thereafter.
Treatment with Signifor leads to rapid suppression of adrenocorticotropic
hormone (ACTH) secretion in Cushing's disease patients. 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.
Monitoring of gallbladder and pituitary hormones is recommended prior to
initiating treatment and periodically thereafter.
Signifor should not be used during pregnancy unless clearly 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 is to be exercised with the concomitant use of drugs
with low therapeutic index mainly metabolized by CYP3A4, bromocriptine,
cyclosporine, anti-arrhythmic medicines or drugs that may lead to QT
prolongation.
The most frequently reported adverse events (AE) (>10%) by investigators for
Signifor 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 tolerability profile
of Signifor was similar to that of other somatostatin analogs with the exception
of the greater degree of hyperglycemia[1].
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "potential," "under way," or similar expressions, or by
express or implied discussions regarding potential future 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, or its LAR version, will be approved for sale, or
for any additional indications, in any market, 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; government, industry and general public pricing
pressures; the company's ability to obtain or maintain patent or other
proprietary intellectual property protection; competition in general; unexpected
manufacturing issues; 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 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 124,000 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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http://twitter.com/novartis.
References
[1] Signifor® (pasireotide) Summary of Product Characteristics. Basel,
Switzerland: Novartis; April 2012.
[2] 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
March 2012.
[3] Pedroncelli, A. Medical Treatment of Cushing's Disease: Somatostatin
Analogues and Pasireotide. Neuroendocrinology. 2010;92(suppl1):120-124.
[4] Colao, A. A 12-Month Phase III Study of Pasireotide in Cushing's Disease.
New Engl J Med. 2012; 366:32-42.
[5] Tritos N., Biller, B. Advances in Medical Therapies for Cushing's Syndrome.
Discovery Medicine. 2012:13(69):171-179.
[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] European Commission. The Centralised Procedure. Available at:
http://ec.europa.eu/health/authorisation-procedures-centralised_en.htm. Accessed
March 2012.
[9] European Medicines Agency. Committee for Orphan Medicinal Products. Public
Summary of Positive Opinion for Orphan Designation of Pasireotide for the
treatment of Cushing's Disease. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/
WC500006176.pdf. Accessed March 2012.
[10] 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.
[11] 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 March 2012.
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