Novartis drug pasireotide LAR shows superior efficacy compared to Sandostatin® LAR® in Phase III trial of patients with acromegaly
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Novartis drug pasireotide LAR shows superior efficacy compared to Sandostatin®
LAR® in Phase III trial of patients with acromegaly
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* Patients on pasireotide (SOM230) LAR were 63% more likely to achieve full
biochemical control than those on Sandostatin LAR, the current standard of
care[1]
* Acromegaly, a rare endocrine disorder caused by excess growth hormone, can
result in enlarged hands, feet and internal organs, and increased risk of
death[2],[3]
* Presently only 20-25% of acromegaly patients naïve to previous somatostatin
analog treatment achieve full control with current somatostatin analogs[1]
Basel, May 7, 2012 - Results of the largest Phase III study of acromegaly
patients show the novel therapy pasireotide (SOM230) long-acting release (LAR),
was significantly more effective at inducing full biochemical control compared
to the current standard medical therapy, Sandostatin(®) LAR(®) (octreotide/IM
injection). These data were presented at the 2012 joint 15(th) International
Congress of Endocrinology and 14(th) European Congress of Endocrinology meeting
(ICE/ECE) in Florence, Italy[1].
Acromegaly is a rare endocrine disorder characterized by enlargement of the
hands, feet and internal organs, as well as changes in facial structure[2],[3].
The majority of acromegaly cases are caused by a non-cancerous tumor in the
pituitary gland that secretes excess growth hormone (GH), leading to elevated
levels of insulin like growth factor (IGF-1)[4].
The study met its primary endpoint, with significantly more patients treated
with pasireotide LAR (31.3%) experiencing full control of their disease (defined
as the combination of both GH <2.5µg/L and age- and sex-matched normalized IGF-
1 levels) than those taking octreotide LAR (19.2%) (p=0.007). Patients treated
with pasireotide LAR were 63% more likely to achieve control of their disease
than those on octreotide LAR. The safety profile of pasireotide LAR was similar
to that of octreotide LAR with the exception of a higher degree of
hyperglycemia[1].
Growth hormone and IGF-1 levels are typically used to determine control of the
disease with the most commonly used standard medical therapy, somatostatin
analogs[4]. Currently, only 20-25% of acromegaly patients naïve to previous
somatostatin analog treatment achieve full control over their disease when
treated with current somatostatin analogs, as measured by these two levels[1].
"While Sandostatin LAR is an effective treatment, inadequate control of GH and
IGF-1 remains an issue for many patients with acromegaly and new therapeutic
approaches are needed for these patients to better control their disease," said
Annamaria Colao, MD, lead study investigator and Professor of Endocrinology,
Chief of the Neuroendocrine Unit at the Department of Molecular and Clinical
Endocrinology and Oncology, Federico II University of Naples. "We are very
encouraged by the findings of this study, the largest ever in this population,
which found that pasireotide LAR provided full control in nearly a third of
study participants."
Investigators also presented data from a 6-month extension study, where
paftients who did not achieve full biochemical control after 12 months on
therapy could switch to the other treatment. After an additional 6 months of
treatment, 21% of the 81 patients who switched to pasireotide LAR achieved full
control of their disease. By contrast, of the 38 patients who switched to
octreotide LAR, 2.6% achieved full control[5].
"The positive results seen in the Phase III trial point to the potential role of
pasireotide LAR in treating patients with acromegaly, a condition for which
there remains an unmet need," said Hervé Hoppenot, President, Novartis Oncology.
"These findings are welcome news as we continue our research efforts to discover
treatments for patients with pituitary-related conditions."
In addition to acromegaly, Novartis is committed to studying other pituitary-
related conditions including continued study in Cushing's disease. Data also
presented at this meeting include long-term follow-up results from the Phase III
registrational trial which led to the recent EU approval of Signifor(®)
(pasireotide) for the treatment of Cushing's disease. Additionally, researchers
presented data from a Phase I proof-of-concept trial for the investigational
11β-hydroxylase inhibitor, LCI699, in Cushing's disease[6],[7].
About the Study
This study, known as PASPORT-ACROMEGALY (PASireotide clinical trial PORTfolio -
ACROMEGALY), is a randomized, double-blind, Phase III study evaluating the
efficacy and safety of pasireotide LAR compared to the current standard medical
therapy, octreotide LAR, in 358 patients with active acromegaly, who were de
novo with a visible adenoma on MRI or medically-naïve (no previous medical
therapy, but prior pituitary surgery). Patients were randomized to receive
intramuscular injections of pasireotide LAR 40mg (n=176) or octreotide LAR 20mg
(n=182) every 28 days for 12 months. At months three and seven, dose titration
to pasireotide LAR 60mg or octreotide30mg was permitted if patients had GH
/>=2.5µg/L and/or IGF-1 > upper limit of normal (ULN). The primary endpoint was
to compare the proportion of patients in the pasireotide LAR and octreotide
LARtreatment arms with GH <2.5µg/L and normal IGF-1 at 12 months. Key secondary
endpoints included comparison of the effect of pasireotide LAR and octreotide
LAR on reduction of GH to <2.5µg/L alone and normalization of IGF-1 alone.
Reductions of tumor volume, symptoms and prolactin levels were also assessed[1].
The 12-month study was completed by 80.1% (141/176) and 85.7% (156/182) of
pasireotide LAR and octreotide LAR recipients, respectively, with dose up-
titration performed in 50.6% and 67.6% of pasireotide LAR and octreotide LAR
recipients[1].
At baseline, mean GH was 21.9 µg/L and 18.8µg/L in the pasireotide LAR and
octreotide LAR arms, respectively; mean IGF-1 was 2.6xULN and 2.8xULN. The
primary endpoint was achieved by 31.3% of pasireotide LAR recipients and 19.2%
of octreotide LAR recipients (p=0.007). Mean GH and IGF-1 decreased by month
three and remained suppressed. At month 12, 48.3% of patients receiving
pasireotide LAR had mean GH<2.5µg/L compared to 51.6% of those on octreotide LAR
(p=0.536), while normal IGF-1 was achieved by 38.6% of patients receiving
pasireotide LAR and 23.6% of patients receiving octreotide LAR (p=0.002).
Additionally, investigators reported that both pasireotide LAR and octreotide
LAR were effective in reducing GH levels and tumor volume, and improving health-
related quality of life and signs/symptoms of the disease[1].
Most adverse events (AEs) were mild or moderate. The most common AEs reported by
investigators with pasireotide LAR versus octreotide LAR were diarrhea (39.3%
vs. 45%), cholelithiasis (25.8% vs. 35.6%), headache (18.5% vs. 26.1%) and
hyperglycemia (28.7% vs. 8.3%)[1].
Study Extension
At the end of the 12-month study, eligible patients could enroll in an optional,
double-blind, 6-month extension phase. In this phase of the study, patients that
did not achieve full biochemical control could switch treatment at month 13 to
either pasireotide LAR 40mg every 28 days (n=81) or octreotide LAR 20mg every
28 days (n=38), with dose titration allowed at 3-month intervals. Patients with
GH <2.5µg/L and normal IGF-1 at month 12 could continue on their randomized
therapy[5].
Most AEs observed through the end of the study extension were mild or moderate.
The most common AEs during the 19 month treatment period with pasireotide LAR
versus octreotide LAR were hyperglycemia (25.9% vs. 7.9%), diarrhea (21.0% vs.
15.8%), nasopharyngitis (16.0% vs. 18.4%) and headache (18.5% vs. 10.5%)[5].
About acromegaly
Acromegaly is a chronic hormonal disorder that occurs when excess growth hormone
is produced. Commonly, acromegaly presents in middle-aged men and women and can
result in changes in metabolism and an increased risk of mortality. People with
acromegaly may also suffer from changes to facial structure, such as enlargement
of forehead and jaw with pronounced under- or overbite, spreading teeth and
enlarged tongue[3]. More serious problems may include accelerated cardiovascular
disease, hypertension, diabetes mellitus and possibly an increased risk of colon
cancer[2]. Worldwide, the estimated annual prevalence of acromegaly is 60 people
per million and the estimated incidence is three to four people per million[3].
About pasireotide
Pasireotide (SOM230) is an investigational multireceptor targeting somatostatin
analog (SSA) that binds with high affinity to four of the five somatostatin
receptor subtypes (sst 1, 2, 3 and 5). Pasireotide is approved in the EU as
Signifor(®) for the treatment of adult patients with Cushing's disease for whom
surgery is not an option or for whom surgery has failed. Additional regulatory
submissions for pasireotide for the treatment of Cushing's disease are under way
worldwide.
Information about Novartis clinical trials for pasireotide can be obtained by
healthcare professionals at www.pasporttrials.com.
Important Safety Information about Signifor (pasireotide)
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.
About Sandostatin LAR
Sandostatin(®) LAR(®) is a long-acting, injectable depot formulation of
octreotide acetate that is indicated for the treatment of patients who are
adequately controlled on s.c. treatment with Sandostatin; in patients in whom
surgery or radiotherapy is inappropriate or ineffective; in the interim period
until radiotherapy becomes fully effective. Treatment of patients with symptoms
associated with functional gastro-entero-pancreatic endocrine tumors: carcinoid
tumors with features of the carcinoid syndrome, VIPomas, glucagonomas,
gastrinomas/Zollinger-Ellison syndrome, insulinomas, GRFomas. Treatment of
patients with advanced neuroendocrine tumors of the midgut or unknown primary
tumor location.
Sandostatin LAR was first approved in France in June 1995 and is currently
approved in 95 countries. For more than a decade, Sandostatin LAR has achieved a
long-standing track record of sustained efficacy with a well-established safety
profile.
Not all indications are approved in every country.
Important Safety Information about Sandostatin LAR (octreotide/IM injection)
Patients who have a known hypersensitivity to octreotide or to any of the
excipients should not take Sandostatin LAR. Dose adjustments of drugs, such as
beta-blockers, calcium channel blockers or agents to control fluid and
electrolyte balance may be necessary. Caution should be used in patients with
insulinomas; patients with diabetes mellitus. Thyroid function should be
monitored if receiving prolonged treatment with octreotide. Patients receiving
Sandostatin LAR should receive periodic examination of the gallbladder; and
patients who have a history of vitamin B12 deprivation should have their vitamin
B12 levels monitored. Caution should be used in patients who are pregnant;
patients should be advised to use adequate contraception, if necessary. Patients
should not breast-feed during Sandostatin LAR treatment. The use of Sandostatin
LAR may increase the bioavailability of bromocriptine, impair intestinal
absorption of cyclosporin and delay that of cimetidine. Drugs mainly metabolized
by CYP3A4 and which have a low therapeutic index should be used with caution.
Very common (>=1/10) adverse drug reactions in clinical studies with Sandostatin
LAR were diarrhea, abdominal pain, nausea, constipation, flatulence, headache,
cholelithiasis, hyperglycemia and injection-site localized pain. Common
(>=1/100, <1/10) adverse drug reactions were dyspepsia, vomiting, abdominal
bloating, steatorrhea, loose stools, discoloration of feces, dizziness,
hypothyroidism, thyroid dysfunction (e.g., decreased thyroid stimulating
hormone, decreased Total T4 and decreased Free T4), cholecystitis, biliary
sludge, hyperbilirubinemia, hypoglycemia, impairment of glucose tolerance,
anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnea and
bradycardia.
The uncommon (>=1/1000, <1/100) adverse drug reactions were dehydration and
tachycardia. The following adverse reactions have been reported postmarketing:
anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis,
acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis,
jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphatase
levels and increased gamma glutamyl transferase levels.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "encouraged," "potential," "committed," or similar
expressions, or by express or implied discussions regarding potential new
indications or labeling for pasireotide, potential future marketing approvals
for LCI699, or regarding potential future revenues from these medicines. 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 pasireotide to be materially different from any future
results, performance or achievements expressed or implied by such statements.
There can be no guarantee that pasireotide will be approved for any additional
indications or labeling in any market, or that LCI699 will be submitted or
approved for sale in any market. Nor can there be any guarantee that either
pasireotide or LCI699 will achieve any particular levels of revenue in the
future. In particular, management's expectations could be affected by, among
other things, unexpected clinical trial results, including unexpected new
clinical data and unexpected additional analysis of existing clinical data;
unexpected regulatory actions or delays or government regulation generally;
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 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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References
[1] Colao, A. et al. Pasireotide LAR is Significantly More Effective Than
Octreotide LAR at Inducing Biochemical Control in Patients with Acromegaly:
Results of a 12-Month Randomized, Double-Blind, Multicenter, Phase III Study.
Abstract #OC1.1. 2012 Joint 15th International Congress of Endocrinology and
14th European Congress of Endocrinology.
[2] Colao, A. et al. Systemic Complications of Acromegaly: Epidemiology,
Pathogenesis, and Management. Endocrine Reviews. 2004;25(1):102-152.
[3] Ayuk, J. and Sheppard, M. C. Growth Hormone and Its Disorders. Postgrad Med
J. 2006;82:24-30.
[4] National Endocrine and Metabolic Diseases Information Service. Acromegaly.
Available at: http://www.endocrine.niddk.nih.gov/pubs/acro/Acromegaly_508.pdf.
Accessed April 2012.
[5] Fleseriu, M. et al. Pasireotide LAR Versus Octreotide LAR in Patients with
Acromegaly: Double-Blind, Crossover, Extension Period to a Randomized, Double-
blind, Multicenter, Phase III Study. Abstract #P1404. 2012 Joint 15th
International Congress of Endocrinology and 14th European Congress of
Endocrinology.
[6] Schopohl, J. et al. Long-Term Pasireotide Use Leads to Improvements in the
Biochemical Parameters of Cushing's Disease: 24-Month Results from a Randomized
Phase III Study. Abstract #P1410. 2012 Joint 15th International Congress of
Endocrinology and 14th European Congress of Endocrinology.
[7] Bertagna, X. et al. Patients with Cushing's Disease Achieve Normal Urinary
Cortisol with LCI699, a Potent 11β-Hydroxylase Inhibitor: Preliminary
Results from a Multicenter, Proof-of-Concept Study. Abstract #OC1.2. 2012 Joint
15th International Congress of Endocrinology and 14th European Congress of
Endocrinology.
# # #
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