Novartis’ Signifor® (pasireotide) intramuscular injection to treat adult patients with acromegaly approved by the European Commission

• Acromegaly is a rare pituitary disorder, which requires normalization of hormonal levels to help prevent the serious consequences of the disease[1],[2],[3],[4]
• Approval based on two large phase III trials showing superior efficacy of new formulation of Signifor over current SSAs in patients with acromegaly[5]
• Additional regulatory filings of this new long acting release formulation of Signifor currently under review by health authorities worldwide

BASEL, 24-11-2014 — /EuropaWire/ — Novartis announced today that the European Commission has approved Signifor® (pasireotide) as a new long acting release formulation for once monthly intramuscular injection to treat adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with a first-generation somatostatin analogue (SSA). Next-generation SSA Signifor offers the first alternative treatment option directly targeting the pituitary tumor for patients whose acromegaly remains inadequately controlled on currently available SSAs[5].

Acromegaly affects an estimated one to two in every 10,000 people in the EU[6]. In the majority of acromegaly cases, a non-cancerous tumor in the pituitary gland leads to excess production of growth hormone (GH) and, ultimately, insulin-like growth factor-1 (IGF-1) in the body[3]. Prolonged exposure to excess GH and IGF-1 may cause patients to experience significant physical changes including the enlargement of hands, feet, facial features, and internal organs[3]. Moreover, acromegaly patients who do not achieve biochemical control of their disease, as measured by GH and IGF-1 levels, may face serious health consequences such as heart disease, hypertension, diabetes, arthritis, colon cancer leading to an increased risk of death[3]. According to recent research, 45% of acromegaly patients fail to achieve the recommended levels of GH or normalized IGF-1 on current therapies[2].

“Acromegaly that is not properly controlled can have a devastating impact on the long-term health of patients living with this serious pituitary disorder,” said Bruno Strigini, President, Novartis Oncology. “This first approval of Signifor in acromegaly marks a much needed advance in the treatment of this rare disease and we are working hard to bring this therapy to this underserved patient population worldwide in the near future.”

The approval is based on data from two multicenter Phase III studies, C2402 and C2305, which respectively evaluated patients with inadequately controlled acromegaly on first-generation SSAs, and medically naïve patients who were post-surgery, or newly diagnosed patients for whom surgery is contraindicated. Both studies showed Signifor to have superior efficacy in providing biochemical control, as measured by both GH and IGF-1 levels, compared to a first-generation SSA[5].

The EU approval follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in September 2014 for Signifor for the treatment of acromegaly and applies to all 27 EU member states, plus Iceland and Norway[7]. Additional regulatory applications for the new long acting release formulation of Signifor have been filed worldwide for the treatment of acromegaly, including an application currently filed in the United States. In the EU, Signifor has orphan drug designation for acromegaly[8]. Orphan drugs are those that treat a condition which affects no more than five in 10,000 people in the EU[9].

About study C2402
The Phase III multicenter, randomized, three-arm, parallel-group study C2402 evaluated the efficacy and safety of double-blind Signifor intramuscular injection 40 mg and 60 mg versus maximal doses of Sandostatin LAR or Somatuline Autogel* in patients with inadequately controlled acromegaly treated for at least 6 months with first-generation SSAs. The primary efficacy objective was to compare the proportion of patients achieving biochemical control (defined as mean GH levels <2.5 Mu g/L and normalization of sex- and age-adjusted IGF-1) with Signifor 40 and 60 mg separately, versus active control represented by Sandostatin LAR and Somatuline Autogel. The primary endpoint was met in both Signifor dose groups with 15.4% (P=.0006) and 20.0% (P<.0001) of patients receiving Signifor 40 mg and 60 mg achieving biochemical control, respectively, compared with zero in the active control arm. In patients treated with Signifor in whom reductions in GH and IGF-1 were observed, these changes occurred during the first 3 months of treatment and were maintained at week 24[5]. Additionally, 24.6% (P<.0001) and 26.2% (P<.0001) of patients receiving Signifor 40 mg and 60 mg achieved normalization of IGF-1, respectively, compared with zero in the active control arm; 35.4% and 43.1% of patients receiving Signifor 40 mg and 60 mg achieved GH levels <2.5 Mu g/l, respectively, compared with 13.2% in the active control arm. A higher proportion of patients on Signifor (18.5% and 10.8% for 40 and 60 mg, respectively) achieved a reduction in tumor volume of at least 25% versus 1.5% on active control[5].

The most common adverse reactions observed (frequency >=20%) in either of the Signifor arms were hyperglycemia and diabetes mellitus. Common Toxicity Criteria (CTC) Grade 3 and 4 adverse reactions were mostly related to hyperglycemia[5].

About study C2305
In the Phase III multicenter, randomized and blinded study, medically naïve patients with active acromegaly received either Signifor intramuscular injection (starting dose of 40 mg with possibility to up titrate to 60 mg) or Sandostatin LAR (starting dose of 20 mg with possibility to up titrate to 30 mg) for 12 months. Medically naïve patients enrolled in the trial included those who were post-surgery, or newly diagnosed patients for whom surgery was contraindicated. The primary endpoint was met, showing superiority of Signifor over Sandostatin LAR in providing biochemical control, as defined by the proportion of patients with a reduction of mean GH level to <2.5 Mu g/l and the normalization of IGF-1 to within normal limits. Specifically, 31.3% and 19.2% of patients achieved biochemical control on Signifor and Sandostatin LAR, respectively, demonstrating a statistically significant superior result that favored Signifor (P=.007). In addition, 80.8% of patients achieved a tumor volume reduction greater than 20% with Signifor compared with 77.4% with Sandostatin LAR[5].

The most common adverse reactions observed (frequency >=20%) with Signifor were diarrhea, cholelithiasis, hyperglycemia and diabetes mellitus. Common Toxicity Criteria (CTC) Grade 3 and 4 adverse reactions were mostly related to hyperglycemia[5].

About acromegaly
Worldwide, the prevalence of acromegaly is estimated to be 60 cases per million, with an annual incidence of 3 to 4 new cases per million[3]. However, recent studies suggest that pituitary adenomas may be more prevalent than previously thought, and that the prevalence of acromegaly may be between 115 and 295 cases per million globally[10]. Acromegaly most commonly presents in middle-aged men and women[3]. This debilitating disease can be difficult to detect because it can develop gradually and/or individual symptoms may be mistaken for another medical condition, with the average delay from disease onset to diagnosis between 6 to 10 years[3],[10],[11]. Acromegaly is also associated with two- to three-fold increased mortality rates and serious health complications, including heart disease, hypertension, diabetes, arthritis and colon cancer[1],[3],[4]. In fact, heart disease is responsible for approximately 60% of deaths among people with acromegaly[12].

About Signifor
Signifor® (pasireotide) intramuscular injection is now approved in the EU to treat adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with a first-generation somatostatin analogue (SSA).

Signifor is available for patients with acromegaly through carefully controlled and monitored clinical trials which are designed to better understand the potential benefits and risks of the compound. For various reasons, including the uncertainty of clinical trials, there is no guarantee that Signifor will become commercially available for acromegaly or any other indication anywhere else in the world.

Important safety information about Signifor (pasireotide) intramuscular injection
Signifor is contraindicated in patients with severe hepatic impairment (Child Pugh C).

Hyperglycemia and diabetes occurs with initiation of Signifor therapy. Acromegaly patients with poor glycemic control (as defined by hemoglobin A1c (HbA1c) values >8% while receiving anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g., ketoacidosis. Intensive glucose monitoring is recommended and may require initiation or adjustment of anti-diabetic treatment.

Treatment with Signifor may lead to bradycardia and QT prolongation. Caution should be used in at-risk patients. ECG testing is recommended prior to dosing and during treatment. Hypokalemia and hypomagnesemia must be corrected prior to Signifor administration and should be monitored periodically during therapy.

Mild transient elevations in aminotransferases are commonly observed in patients treated with pasireotide. Liver tests are recommended prior to and after the first 2 to 3 weeks on treatment, then monthly for 3 months, and as clinically indicated thereafter.

Cholelithiasis is associated with Signifor. Gallbladder ultrasounds should be performed before and at 6- to 12- month intervals.

Inhibition of pituitary hormones may occur with Signifor treatment. Monitoring of pituitary function should occur prior to initiation of therapy and periodically during treatment with Signifor.

Treatment with Signifor may lead to a decrease in circulating levels of cortisol resulting in biochemical and/or clinical hypocortisolism. Signifor dose of reduction or interruption and/or adding low-dose short-term glucocorticoid therapy may be necessary.

Caution is required when co-administering Signifor with anti-arrhythmics and drugs that prolong QT. The following drugs may require monitoring and possible dose adjustments when used with Signifor: cyclosporine, bromocriptine.

The most common adverse reactions (>=10%) occurring in patients in acromegaly clinical trials are hyperglycemia, diabetes mellitus, diarrhea, abdominal pain, cholelithiasis and alopecia.

Please see full Prescribing Information at Signifor.com. More information is also available at NovartisOncology.com

About Sandostatin LAR
Sandostatin LAR, a long-acting, injectable depot formulation of octreotide acetate, is approved in the EU for Treatment of patients with acromegaly in whom surgery is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective as per recently finalized label harmonization. In the US, Sandostatin LAR is available as Sandostatin® LAR® Depot for long-term maintenance therapy in patients with acromegaly who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal. Outside the EU and US, acromegaly indications vary by country.

Sandostatin LAR is available from Novartis for different uses and not all indications are available in every country.

Important safety information about Sandostatin LAR (octreotide/intramuscular injection)
Treatment with Sandostatin LAR may affect gallbladder function, sugar metabolism, thyroid and heart function and nutritional absorption, which may require monitoring.

Caution is to be exercised for those with a history of heart disease or taking other medications, including cyclosporine, insulin, oral hypoglycemic agents, beta-blockers and bromocriptine.

Common side effects include diarrhea, gallstones, abdominal pain and flatulence.

Please see full Prescribing Information at Sandostatin.com.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as “under review,” “near future,” “suggest,” or similar terms, or by express or implied discussions regarding potential new indications or labeling for Signifor long acting release formulation, or regarding potential future revenues from Signifor long acting release formulation or Sandostatin LAR. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Signifor long acting release formulation will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Signifor long acting release formulation or Sandostatin LAR will be commercially successful in the future. In particular, management’s expectations regarding Signifor long acting release formulation and Sandostatin LAR could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. 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, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 133,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visithttp://www.novartis.com.

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References
[1]Holdaway M et al. Factors Influencing Mortality in Acromegaly. J Clin Endocrin Metab. 2004; 89(2): 667-674.
[2]Carmichael J.D. et al. Acromegaly Clinical Trial Methodology Impact on Reported Biochemical Efficacy Rates of Somatostatin Receptor Ligan Treatments – a Meta-analysis. J Clin Endocrin Metab. 2014; 99:1825-1833.
[3]Acromegaly. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. 2008 May; 8(3924): 1-10.
[4]Holdaway I.M. et al. A Meta-Analysis of the Effect of Lowering Serum Levels of GH and IGF-1 on Mortality in Acromegaly. European Journal of Endocrinology. 2009; 159: 89-95.
[5]Signifor® (pasireotide) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; September 2014.
[6]RI Health Solutions. “Epidemiology Report for an Orphan Drug Application in the European Union.” 2012: 1-17.
[7]European Medicines Agency. “Summary Opinion (Post Authorisation) for Signifor Pasireotide.”http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/002052/WC500173649.pdf. Accessed November 2014.
[8]European Medicines Agency. “Public Summary of Positive Opinion of Orphan Designation of Pasireotide for the Treatment of Acromegaly.” Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006177.pdf. Accessed November 2014.
[9]European Medicines Agency. “Orphan Designation.” Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp. Accessed November 2014.
[10]Rosario P.W. Frequency of Acromegaly in Adults with Diabetes or Glucose Intolerance and Estimated Prevalence in the General Population. Pituitary. 2011; 14: 217-221.
[11]Schneider H et al. A Novel Approach to the Detection of Acromegaly: Accuracy of Diagnosis by Automatic Face Classification. J Clin Endocrin Metab. 2011; 96: 2074-2080.
[12]Colao, et. al. Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management. Endocrine Reviews. 2004; 25:102-152.

* Lanreotide Autogel (Somatuline®Autogel®) is a registered trademark of Ipsen.

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