Novartis drug Exjade® first treatment approved by FDA

Novartis announced today that the US Food and Drug Administration (FDA) has approved Exjade® (deferasirox) for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration of at least 5 mg of iron per gram dry weight and a serum ferritin measurement greater than 300 micrograms per liter. Exjade is the first treatment indicated for patients with these types of thalassemia in the United States.

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].

“Patients with NTDT can suffer severe and life-changing complications from chronic iron overload,” said Elliott Vichinsky, MD, Medical Director, Hematology/Oncology, Children’s Hospital and Research Center, Oakland, California. “In these thalassemia patients, excess iron starts to accumulate at birth yet is often undetected until serious symptoms appear in early adulthood. With this approval of Exjade, physicians will be able to offer NTDT patients a treatment option, helping fulfill a critical unmet need.”

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 require 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],[7].

“For years, Exjade has effectively treated chronic iron overload in transfused thalassemia patients,” said Alessandro Riva, Global Head, Oncology Development and Medical Affairs, Novartis Oncology. “Now, for the first time, thalassemia patients who do not receive regular transfusions but suffer the same debilitating effects from chronic iron overload, have an approved treatment option.”

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[6]. 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[6],[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 5% in any Exjade or placebo group) were nausea, skin rash, diarrhea and headache[1].

About Exjade

In the US, Exjade is now indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 mg of iron per gram dry weight (mg Fe/g dw) and a serum ferritin measurement greater than 300 micrograms per liter. The basis of this indication is data showing achievement of an LIC less than 5 mg Fe/g dw after treatment with Exjade. An improvement in survival or disease-related symptoms has not been established. Since 2005, Exjade has been approved in the US for the treatment of chronic iron overload due to blood transfusions in adult and pediatric patients (aged 2 years and over).

In the European Union (EU), 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.

Exjade is approved in over 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, non-progressive increases in serum creatinine, increased transaminases, abdominal distension, constipation, dyspepsia, proteinuria and headache. Please visit www.exjade.com for more information.

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 E. 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. Thalassaemia International Federation. The Thalassaemia International Federation’s 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.
7. 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 B thalassemia intermedia. Haematologica. 2011 Nov;96(11):1605-12.
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 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.