Exjade® benefits chronicaly transfused patients (Exjade removed iron from heart)

Published: 00:30 09.12.2008 GMT+1 /HUGIN /Source: Novartis International AG /SWX: NOVN /ISIN: CH0012005267

Exjade® benefits chronically transfused patients by significantly reducing toxic iron that can damage key organs, according to landmark trial


[bgcolor=#ffff00]First prospective, multicenter study to show Exjade removes iron from the heart in beta-thalassemia patients with mild to severe cardiac iron overload[/bgcolor]


In a subgroup analysis of 341 patients with myelodysplastic syndromes (MDS), Exjade significantly reduced levels of toxic iron


These results are part of the largest prospective trial in iron chelation, which includes more than 1,700 patients with various transfusion-dependent anemias

[bgcolor=#ffff00]Basel, December 9, 2008 - New data from the largest prospective trial in iron chelation demonstrate the efficacy and safety of Exjade® (deferasirox) in treating chronic transfusional iron overload, a potentially life-threatening condition for patients who have had multiple blood transfusions to treat underlying anemias, including beta-thalassemia and myelodysplastic syndromes (MDS).[/bgcolor]
 
Data from this landmark trial, known as EPIC, were presented today at the 50th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco, California.
 
[bgcolor=#ffff00]The EPIC cardiac substudy showed that Exjade removed iron from the heart in beta-thalassemia patients, based on a statistically significant improvement in T2* magnetic resonance imaging, a validated technique to assess cardiac iron content (P<0.0001).  The one-year substudy included 114 beta-thalassemia patients with cardiac iron overload, the leading cause of death in these patients.[/bgcolor]

[bgcolor=#ffff00]"These data clearly demonstrate that deferasirox significantly reduces cardiac iron in beta-thalassemia patients with iron overload, which is a critical goal of treatment for these patients," said Dudley Pennell, MD, Professor of Cardiology, Royal Brompton and Harefield NHS Trust and Imperial College, London. "Cardiac complications caused by the buildup of toxic iron in the heart can be life-threatening for people living with thalassemia."
 
A pre-planned analysis of 341 MDS patients enrolled in the study showed that Exjade significantly reduced levels of serum ferritin (SF), a key measure of iron in the body, by 253.0 ng/mL from baseline (P=0.0019).  Of the 171 MDS patients whose SF was measured at one year, the decrease from baseline was 606 ng/mL.
 
"Many MDS patients receive regular blood transfusions as part of their ongoing treatment, which puts them at risk for iron overload," said Norbert Gattermann, MD, PhD, Hematology, Oncology and Clinical Immunology, Heinrich Heine University Medical Center, Dusseldorf, Germany. "This study, which includes the largest number of MDS patients of any iron chelation study, shows deferasirox can effectively reduce iron burden and is generally well tolerated when used appropriately to treat these patients."
 
Iron toxicity can lead to permanent damage of the liver, heart and endocrine glands, leading to an increased risk of serious health problems and early death.  Previous studies of transfusion-dependent MDS patients have found that increased levels of SF are associated with shortened overall survival.

About the EPIC trial
The EPIC trial was a one-year, open-label, prospective, multicenter trial.  EPIC studied the efficacy and safety of a fixed starting dose of Exjade based on transfusional iron intake, with subsequent dose titration at 3-monthly intervals based on serum ferritin (SF) trends. With 1,744 patients, this trial is the largest ever conducted for an iron chelator and included the largest cohorts of underlying anemias in a single trial, including patients with beta-thalassemia, MDS and aplastic anemia. Twelve abstracts from EPIC are being presented at ASH[/bgcolor].
 
[bgcolor=#ffff00]Study details
The EPIC cardiac substudy evaluated the cardiac efficacy of Exjade in 114 beta-thalassemia patients with myocardial siderosis (T2* <20 ms). Baseline myocardial T2* was <10 milliseconds (ms) in 47 (41%) patients (considered severe cardiac iron overload) and 10-20 ms in 67 (59%) patients (considered mild to moderate). Mean baseline liver iron concentration (LIC) was 28.2±10.0 mg Fe/g dry weight (dw), median SF was 5235 ng/mL, and the mean amount of transfused blood in the year prior to study entry was 185 mL/kg.
 
Patients experienced a statistically significant increase in myocardial T2* indicating a decrease in myocardial iron content.  Based on a geometric mean ± coefficient of variation, change from baseline (11.2 ms ±40.5%) to 12.9 ms ±49.5% represents an increase by a factor of 1.16 from baseline (P<0.0001). Overall, 69.5% of patients taking Exjade had an improvement in T2* (>4% increase); there was no change in 14.3%; and worsening (>4% decrease) in 16.2% of patients. Left ventricular ejection fraction remained stable throughout the study.  Additionally, LIC and SF levels (both indicators of total body iron) were significantly reduced from baseline by -6.6±9.9 mg Fe/g dw and -1257 ng/mL, respectively (P<0.0001). Four patients discontinued treatment due to adverse events.  Most investigator-assessed drug-related adverse events were mild to moderate in severity; rash was the most common (13.2%). There is an ongoing one-year extension of this substudy.
 
The pre-planned subgroup analysis of the EPIC study included 341 patients with transfusion-dependent MDS and SF levels >=1000 ng/mL, or SF <1000 ng/mL, but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of red blood cells) and an R2 MRI-confirmed LIC >2 mg Fe/g dw.  Overall, mean actual dose of Exjade over one year of treatment was 19.2±5.4 mg/kg/day. Based on the last observation carried forward statistical method, at one year, there was a significant reduction in median SF from baseline (-253.0 ng/mL; P=0.0019, n=341).  Of the 171 MDS patients whose SF was measured at one year, the decrease from baseline was 606 ng/mL. Overall, 48.7% of pts (n=166) discontinued therapy. Most common investigator-assessed drug-related adverse events were mild to moderate in severity and included diarrhea (n=110, 32%), nausea (n=45, 13%), vomiting (n=26, 8%), abdominal pain (n=26, 8%), upper abdominal pain (n=25, 7%), rash (n=23, 7%) and constipation (n=21, 6%).[/bgcolor]
 
About Exjade
Exjade is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional haemosiderosis) in adult and paediatric patients (aged 2 years and over).  It is approved in 90 countries including the U.S., Switzerland, Japan, and the countries comprising the European Union.  The approved indication may vary depending upon the individual country.
 
Exjade is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
 
There have been postmarketing reports of acute renal failure, hepatic failure and cytopenias in patients treated with Exjade.  Monthly monitoring of serum creatinine, proteinuria, serum transaminases and blood counts is recommended, and the dose of Exjade should be modified or interrupted if necessary. More frequent creatinine monitoring is recommended in patients with an increased risk of renal complications. Upper gastrointestinal ulceration and hemorrhage have been reported and caution should be exercised when combined with drugs with ulcerogenic potential.  Skin rashes, including hypersensitivity reactions, have been reported.  Exjade should be interrupted if severe rash develops and discontinued if severe hypersensitivity reaction occurs. Auditory and ophthalmic testing should be conducted annually.
 
Exjade should not be taken with aluminium-containing antacids.  Caution should be exercised when Exjade is combined with drugs metabolized through CYP3A4. 
 
The most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain, rash, non-progressive increase in serum creatinine, increased transaminases, abdominal distension, constipation, dyspepsia, proteinuria and headache.
 
 

Please visit www.exjade.com for more information.

P.S : Andy , and all others please have your say on it , i think its a great news .....

Best Regards
Take Care
Umair

Umair,

This is great news!!  I think that if Exjade is well suited to a person then it can be better than desferal and L1.  I think this because it is easier to comply with then desferal, and it removes iron from key organs like the heart.  I think that it is better than L1 because you can take it once a day and receive the same benefits - and it is less likely to cause other symptoms like neutropenia and fluid in joints.  I hope that Exjade continues to give good results and that most people tolerate it well.

Sharmin

Sharmin ,
you're absolutely right , i was amazed and became very happy when i saw this new trial details in my e-mail box , now i m planing to send it to my doctor just after eid holidays ( bcoze i won't to disturb her in eid holidays ) .. i hope she wil like it ....  hope to get more good news within the end of this mont/year , ....

Best Regards
Umair

The abstract from the 2008 ASH conference on this topic can be seen at http://ash.confex.com/ash/2008/webprogram/Paper4328.html
There is some important information that is available in the abstract, specifically the dosing information. Doses were started at 30 mg/kg and adjusted from 5 to 10 mg more where needed, for a mean dose of 32.6 mg/kg. A one year extension of the study is underway.

This is very encouraging, as it had not yet been shown in a large group of humans that Exjade can remove a significant amount of iron from the heart. Hopefully, this will continue over the long term. It does have to be noted that a sizable percentage of subjects (16.2 %) saw an increase in heart iron while using Exjade. As we have heard from some members here, Exjade does not work for everyone, just as every other chelator does not work for everyone. This emphasizes the need for a variety of chelators, so that all patients have a safe effective chelator to use. Starch desferal is possibly the safest iron chelator yet, and I hope they can find the money to run the trials, because it would offer much hope to those who react to everything and also present another chelator that could be used in combination with oral chelators. It would also be helpful to see these results compared to results using other chelators and combinations of chelators.

http://ash.confex.com/ash/2008/webprogram/Paper4328.html

Last updated December 8, 2008. Please note that this site represents the latest program changes
and differs from the print version in some details.
Start | Author Index
3873 Efficacy and Safety of Deferasirox (Exjade®) in Reducing Cardiac Iron in Patients with β-Thalassemia Major: Results from the Cardiac Substudy of the EPIC Trial
Monday, December 8, 2008, 5:30 PM-7:30 PM
Hall A (Moscone Center)
Poster Board III-955

Dudley Pennell1*, John B Porter2*, Maria Domenica Cappellini3, Chi-Kong Li4*, Yesim Aydinok5, Chan Lee Lee6*, Antonis Kattamis7*, Gillian Smith1*, Dany Habr8*, Gabor Domokos9*, Abdel Hmissi9* and Ali Taher10

1Royal Brompton Hospital, London, United Kingdom
2University College London, London, United Kingdom
3Universitá di Milano, Policlinico Foundation IRCCS, Milan, Italy
4Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
5Ege University Medical Faculty, Izmir, Turkey
6University Malaya Medical Centre, Kuala Lumpar, Malaysia
7First Dept of Pediatrics, University of Athens, Athens, Greece
8Novartis, East Hanover, NJ
9Novartis, Basel, Switzerland
10American University Beirut, Beirut, Lebanon
Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis.
Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin (SF) >2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr.
Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%). Mean baseline LIC was 28.2±10.0 mg Fe/g dw, median SF 5235 ng/mL, and the mean amount of transfused blood in the previous yr 185 mL/kg. 68% of pts had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination therapy. Mean actual deferasirox dose over 1 yr was 32.6 mg/kg/d. At 1 yr, the myocardial T2* improved significantly from a (geometric mean ±coefficient of variation) baseline of 11.2 ms ±40.5% to 12.9 ms ±49.5% (P<0.0001), representing an increase by a factor of 1.16 from baseline. Significant increases from 7.4 ms ±19.4% to 8.2 ms ±25.6% (P=0.0002) and from 14.6 ms ±20.9% to 17.4 ms ±31.2% (P<0.0001) were also noted in pts with baseline T2* <10 and 10–20 ms, respectively. Improvement in T2* (>4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by –6.6±9.9 mg Fe/g dw and –1257 ng/mL (P<0.0001 for both).
Treatment was completed in 105 pts (92.1%) with 4 discontinuations due to AEs (3.5%) and 5 for other reasons (4.4%). No pts died during the study. Most investigator-assessed drug-related AEs (78.6%) were mild-to-moderate in severity; rash was the most common (n=15; 13.2%). Two drug-related serious AEs (one nephritis leading to acute renal failure and one renal tubular disorder) were reported which eventually resolved following drug discontinuation. In total, 5 pts (4.4%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10xULN on two consecutive visits; levels were already elevated in these pts.
Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.

Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Principle investigator of two Novartis studies (2409 and 2206), Research Funding; Siemens: Consultancy, Research Funding; Cardiovascular imaging solutions: Equity Ownership; Apopharma: Honoraria. Off Label Use: The specific use of chelation for cardiac siderosis is off-label. Porter: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Membership on an entity’s Board of Directors or advisory committees. Cappellini: Novartis: Speakers Bureau. Li: Novartis: Consultancy, Speakers Bureau. Aydinok: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lee: Novartis: Honoraria, Research Funding. Kattamis: Novartis: Consultancy, Honoraria, Speakers Bureau. Smith: Novartis: Consultancy. Habr: Novartis: Employment. Domokos: Novartis: Employment. Hmissi: Novartis: Employment. Taher: Novartis: Honoraria, Research Funding.

Thank You Andy , for explaining it clearly   and finding this article on internet ...

Umair