Novartis drug Exjade® approved by European Commission for iron overload in patients with non-transfusion-dependent thalassemia

• Exjade is the first oral treatment approved in the EU for chronic iron overload in patients with non-transfusion-dependent thalassemia (NTDT) syndromes
   
• Pivotal placebo-controlled study data show Exjade significantly decreases iron burden in NTDT patients versus placebo, with similar overall adverse event rate[1]
   
• At least three quarters of a million people worldwide have NTDT, which can lead to severe and life-altering complications due to excess iron accumulation[2-5]
  

Basel, December 21, 2012 - Novartis announced today that the European Commission has approved Exjade^® (deferasirox) for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients aged 10 years and older with non-transfusion-dependent thalassemia (NTDT) syndromes. Exjade is the first oral treatment approved in the European Union (EU) specifically indicated for the treatment of chronic iron overload in patients with these types of thalassemia.

The approval is based on results from the first prospective placebo-controlled study of iron chelation in NTDT patients, THALASSA, which showed a significant dose-dependent decrease in iron burden compared to placebo (p<0.001)[1]. In this pivotal study, Exjade significantly reduced the concentration of iron in the liver, known as liver iron concentration (LIC), as well as the amount of iron anywhere in the body, measured by serum ferritin[1]. The overall adverse event rate for Exjade was similar to the placebo arm[1].

"NTDT syndromes can be complicated to manage. Without proper treatment, patients with NTDT can suffer severe and life-changing complications from chronic iron overload," said Professor Maria Domenica Cappellini, MD, Department of Internal Medicine, University of Milan. "The THALASSA data show that these patients now have an effective oral treatment option to help reduce iron concentration in the body."

Thalassemia refers to a diverse group of genetic disorders that affect red blood cell production, causing anemia. Unlike patients with other types of thalassemia, those with NTDT syndromes don't receive regular transfusions, a significant cause of chronic iron overload. However, even without transfusions, NTDT patients still accumulate excess iron through intestinal absorption, leading to debilitating health complications like liver fibrosis and cirrhosis, blood clots, bone disease, pulmonary hypertension, and vascular and endocrine diseases[2],[6].

"This approval is a critical milestone for patients with NTDT syndromes," said Hervé Hoppenot, President, Novartis Oncology. "For the first time, Exjade will be available to thalassemia patients who are not regularly transfused but still suffer from the life-altering effects of excess iron."

According to published studies, at least three quarters of a million people worldwide have NTDT syndromes, although as understanding of the disease increases, it is probable the number will grow[3-5]. Because NTDT patients are not symptomatic at birth, when most thalassemias are diagnosed, they are often underdiagnosed and undertreated[7]. Many complications associated with chronic iron overload begin to appear as early as age 10 and become increasingly common as patients reach their 20s or 30s[8]. Most NTDT patients are of South and Southeast Asian, Mediterranean or Middle Eastern origin, with immigration broadening the global prevalence[7],[9].

About the THALASSA study
The THALASSA trial showed that Exjade at a 10 mg/kg per day starting dose significantly reduced LIC from baseline by 3.8 mg of iron per gram of liver dry weight (Fe/g dw) compared to an increase of 0.38 mg Fe/g dw in patients receiving placebo after 52 weeks of treatment (p<0.001)[1]. The study also determined that a 10 mg/kg per day dose was superior to a 5 mg/kg per day dose (p=0.009)[1]. Additional research has also demonstrated Exjade continues to provide benefit over the longer term, with LIC levels reduced by 7.14 mg Fe/g dw from baseline after 24 months of treatment[10]. The most common reported adverse events (at least 10% in any Exjade or placebo group) were headache, upper respiratory tract infection, oropharyngeal pain, pyrexia, rash and diarrhea[1].

About Exjade
Exjade is an oral iron chelation therapy indicated for the treatment of chronic iron overload due to frequent blood transfusions (>=7 ml/kg/month of packed red blood cells) in patients with beta-thalassemia aged 6 years and older). It is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: patients with beta-thalassemia major with iron overload due to frequent blood transfusions (>=7 ml/kg/month of packed red blood cells) aged 2 to 5 years; patients with beta-thalassemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older; and patients with other anemias aged 2 years and older. Exjade is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassemia syndromes aged 10 years and older.

It is approved in more than 100 countries including the US, Switzerland, Japan and countries comprising the EU. The approved indication may vary depending upon the individual country.

Exjade important safety information
Exjade is contraindicated in patients with an estimated creatinine clearance <60 mL/min, with hypersensitivity to the active substance or any of the excipients, or in combination with other iron chelator therapies. Exjade is not recommended in patients with severe hepatic impairment.

There have been postmarketing reports of acute renal failure, hepatic failure and cytopenias. Renal failure requiring temporary or permanent dialysis, renal tubulopathy and interstitial nephritis have been reported. Upper gastrointestinal ulceration and hemorrhage, sometimes fatal, have been reported. Caution should be used in elderly patients due to a higher frequency of adverse reactions. Exjade is not recommended in patients with a short life expectancy (e.g., high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events.

Skin rashes, serious hypersensitivity reactions, decreased hearing and lens opacities have been reported. The most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain, rash, pruritus, non-progressive increases in serum creatinine, increased transaminases, abdominal distension, constipation, dyspepsia, proteinuria and headache.

Please visit www.exjade.com for more information.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "will," or similar expressions, or by express or implied discussions regarding potential future revenues from Exjade. 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 Exjade to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Exjade will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Exjade 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 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 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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References

[1] Taher A, Porter J, Viprakasit V, et al. Deferasirox significantly reduces iron overload in non-transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012. Published online before print May 15, 2012.
[2] Musallam KM, Cappellini MD, Wood JC, et al. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Reviews. 2012:26S:S16-S19.
[3] Vichinsky EP. Hemoglobin E syndromes. Hematology Am Soc Hematol Educ Program. 2007;79-83.
[4] Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Reviews. 2012:26S:S3-S6.
[5] Vichinsky EP. Changing patterns of thalassemia worldwide. Ann NY Acad Sci. 2005;1054:18-24.
[6] Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamin H, Taher AT. Elevated liver iron concentration is a marker of increased morbidity in patients with ß thalassemia intermedia. Haematologica. 2011 Nov;96(11):1605-12.
[7] Thalassaemia International Federation. The Thalassaemia International Federation's (TIF) New Focus: Addressing the Management of Non-Transfusion-Dependent Thalassaemias (NTDT). Position Paper 5.2. March 20, 2012. Accessed at: http://www.thalassaemia.org.cy/pdf/NTDT_Position_Paper_Final.pdf.
[8] Taher AT. Age-related complications in treatment-naïve patients with thalassemia intermedia. Brit J Haematol. 2010;150:486-489.
[9] Taher A, Cappellini MD, Musallam KM. Recent advances and treatment challenges in patients with non-transfusion-dependent thalassemia. Blood. 2012;26S:S1-2.
[10] Taher AT, Porter JB, Viprakasit V et al. Deferasirox continues to reduce iron overload in non-transfusion-dependent thalassemia: a one-year, open-label extension to a one-year, randomized double-blind, placebo-controlled study (THALASSA). Poster presented at the 54^th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.

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