Exjade, For Patients With Transfusional Iron Overload, Gains European Union Approval

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BlankExjade, For Patients With Transfusional Iron Overload, Gains European Union

Approval

02 Sep 2006

The European Commission (EC) has granted approval for Exjade (deferasirox) as a

new treatment to help patients with transfusional iron overload in all 25 member

states of the European Union (EU).

The approval brings to children and adults with a broad range of

transfusion-dependent anemias the only oral iron chelator to provide continuous

chelation coverage with a single daily dose[1]. The current standard of care is

a cumbersome infusion via pump that often lasts eight to 12 hours and must often

be done daily.

Exjade is the first oral iron chelator approved in the EU for use in patients

with transfusional iron overload who have a wide range of underlying diseases.

Exjade is approved in the EU for the treatment of chronic iron overload due to

frequent blood transfusions in patients age six and older with beta thalassemia

major.

It is also indicated in the EU for the treatment of chronic iron overload when

the medicine deferoxamine is contraindicated or considered inadequate in

patients with other anemias, children age two to five years and patients with

beta thalassemia major with iron overload due to infrequent blood

transfusions[1].

Iron chelation is often necessary to prevent potentially life-threatening

complications of excess iron[3] in patients who receive regular blood

transfusions for diseases such as thalassemia, myelodysplastic syndromes, sickle

cell disease and other anemias.

Tens of thousands of children and adults around the world have these

diseases[5],[6],[8]. For many, the need for transfusions and chelation are

life-long. A single dose of Exjade works throughout the entire day, removing

excess iron - including highly toxic labile plasma (unbound) iron - from key

organs such as the liver and heart.

A breakthrough in iron chelation therapy, Exjade is administered once-daily as a

drink. Exjade was developed specifically to meet the high unmet medical need for

iron chelation despite the availability of deferoxamine, the standard iron

chelator used around the world.

While effective, deferoxamine requires nightly infusions by needle and pump,

often lasting eight to 12 hours per night for five to seven nights a week as

long as the patient continues to receive blood transfusions or has excess iron

within the body. As a result, many patients may have stopped or avoided iron

chelation therapy, thus risking the toxic effects of iron overload.

" The approval of Exjade is fantastic news for people like me who need regular

blood transfusions, " said Anand Ghattaura, who lives in London, England. " I've

always found chelation with a pump and needle difficult to keep up with. I often

used to worry all day about my infusion in the evening. Now I can take Exjade in

the morning with a glass of juice and can forget about it until the next day. "

Due to the burdensome administration of deferoxamine, compliance with standard

chelation therapy is poor[2]. Previous studies of patients with thalassemia have

shown that good compliance with deferoxamine improves survival and quality of

life[3].

" The approval of Exjade in the Europe Union as a new therapy for transfusional

iron overload is most welcome. This allows for the first time an effective, once

daily oral monotherapy for transfusional iron overload, " said Prof. B.

Porter, MA, MD, FRCP, FRCPath at Department of Haematology at the University

College London. " This is also the first oral treatment available for

transfusional iron overload where the dose response effect on iron balance has

been systematically studied on a scale not previously undertaken with iron

chelation therapy. "

About iron overload and iron chelation

Iron overload is a cumulative, potentially life-threatening, consequence of

frequent blood transfusions. Iron starts to build up in the body after as few as

10 transfusions[3] because the body cannot remove it on its own[4]. Iron

chelation is the only effective drug treatment for transfusion-related iron

overload. In iron chelation, an agent binds to iron in the body and tissues and

helps remove it through the urine and/or feces.

Filing data[1]

The clinical trials for Exjade were part of the largest prospective global

clinical trials program ever implemented for an investigational iron chelator.

Data involving more than 1,000 patients with a broad range of underlying

diseases demonstrated that Exjade is effective at managing and reducing body

iron burden, particularly in patients with moderate to severe iron overload, as

measured by liver iron content (LIC). LIC, a measure of iron accumulation in the

liver, is an indicator for body iron content in patients receiving blood

transfusions. The main Phase III study showed that when dosed appropriately,

Exjade was as effective as deferoxamine (Desferal) in reducing iron burden. A

sub-study also indicated that Exjade is effective at managing and reducing the

content of iron in the heart, as measured by magnetic resonance imaging (MRI

T2*).

" The approval of Exjade starts a new era in treating iron overload by providing

effective continuous chelation coverage that is easy for patients to use, " said

Epstein, CEO and President, Novartis Oncology. " The introduction of this

innovative product continues the decades-long support and leadership Novartis

has brought to the iron chelation community. "

Safety data followed patients for up to 2.5 years. In the clinical studies,

Exjade was generally well tolerated, with the most frequently reported adverse

events being nausea, vomiting, diarrhea, abdominal pain, skin rash and increases

in serum creatinine. In patients who develop diarrhea, care should be given to

maintain adequate hydration, especially in patients who have experienced an

increase in serum creatinine. As with deferoxamine, cases of ocular and auditory

disturbances have uncommonly been reported.

Mild, non-progressive increases in serum creatinine, mostly within the normal

range, occur in about one-third of Exjade-treated patients. These are

dose-dependent, often resolve spontaneously and can sometimes be alleviated by

reducing the dose. Serum creatinine, creatinine clearance and/or plasma cystatin

C levels should be assessed in duplicate before initiating therapy and should be

monitored weekly during the first month of treatment and monthly thereafter to

determine if dose modification, interruption, or discontinuation is necessary.

Proteinuria should be monitored monthly. Exjade is contraindicated in patients

with creatinine clearance less than 60 ml/min. Liver function should be assessed

prior to initiating therapy and then monitored monthly. If there is an

unexplained, persistent, or progressive increase in serum transaminase levels,

Exjade should be interrupted or discontinued. Hearing and eye exams should be

performed yearly[1].

Already approved in 29 countries, Exjade was granted approval after the

Committee for Medicinal Products for Human Use (CHMP) of the European Medicines

Agency (EMEA) issued a positive opinion recommending marketing authorization.

Designated an orphan drug in the EU, US, Switzerland and Australia, additional

regulatory submissions for Exjade have been made around the world.

Disclaimer

The foregoing release contains forward-looking statements that can be identified

by terminology such as " breakthrough, " " only, " " first, " " significant advance, "

" should help, " " showed, " " new era, " or similar expressions, or by express or

implied discussions regarding potential additional marketing approvals or future

sales of Exjade. Such forward-looking statements 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 receive any additional marketing approvals in any other countries, or that

it will reach any particular sales levels. In particular, management's

expectations regarding commercialization of Exjade could be affected by, among

other things, additional analysis of Exjade clinical data; new clinical data;

unexpected clinical trial results; unexpected regulatory actions or delays or

government regulation generally; the company's ability to obtain or maintain

patent or other proprietary intellectual property protection; competition in

general; increased government, industry, and general public pricing pressures;

and other risks and factors referred to in the Company's current Form 20-F on

file with the U.S. 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.

For prescribing information on deferoxamine (Desferal) please contact your local

Novartis affiliate.

More information for health care providers:

Some clinical trials with Exjade are ongoing. To learn more about Exjade

clinical trials, health care providers can call +44 (0) 1506 814899.

References

[1]. Exjade Summary of Product Characteristics (DATE)

[2]. Nisbet-Brown E. Effectiveness and safety of ICL670 in iron loaded patients

with thalassemia: a randomised, double-blind, placebo-controlled,

dose-escalation trial. The Lancet. 2003. 361.

[3]. Gabutti V, Piga A. Results of Long-Term Iron-Chelating Therapy. Acta

Haematologica. 1996. 95:26-36.

[4]. Centers for Disease Control and Prevention. Hemochromatosis for Health Care

Professionals: Pathophysiology: Iron Overload. Available at:

http://www.cdc.gov/hemochromatosis/training/pathophysiology/iron_overload.htm.

[5]. Siddiqui AK, et al. Pulmonary manifestations of sickle cell disease.

Postgraduate Medical Journal. 2003. 79:384-390.

[6]. National Human Genome Research Institute at the National Institutes of

Health. Learning about thalassemia. Available at: www.genome.gov/10001221.

[7]. Porter JP. A risk-benefit assessment of iron-chelation therapy. Drug Saf.

1997 Dec; 17(6):407-21

[8]. Novartis data on file. E-mail correspondence from Alice Berringer, dated

May 1, 2006

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