Better to best

The newly launched once-daily dispersible oral iron chelator is billed to provide much needed relief to thalassaemia patients. But patients still need to monitor kidney functions, among other parameters. Suja Nair finds out details

Is it possible to live a normal life with thalassaemia, a genetic blood disorder? The answer is an emphatic no, because as of today, there is no definitive therapy for this disease, and as far as treatment is concerned, it is a lifelong process. The only permanent cure for thalassaemia is a bone marrow transplant from a matching donor. The incidence of thalassaemic is also rising steadily. It is estimated that there are about 65,000-67,000 beta-thalassaemia patients in India with around 9,000-10,000 cases being added every year. The carrier rate for beta-thalassaemia gene varies from one to three percent in Southern India to three to 15 percent in Northern India. There are about 30 million carriers of beta-thalassaemia in India, with a mean prevalence of 3.3 percent.

History

Thalassaemia is an inherited disorder characterised by defective production of the oxygen-binding blood pigment, haemoglobin. According to Dr V P Choudhry, Director, SunFlag Pahuja Centre for Blood Disorders, "When two thalassaemia carriers marry, their children have 25 percent chance of inheriting the thalassaemia gene from both parents. These children are called thalassaemia major/intermedia and require treatment from early childhood." It has been estimated that 10-12000 children with thalassaemia major are born every year in India and the numbers are expected to increase by over one lakh.

The current therapeutic method of managing thalassaemia is by chronic hypertransfusion or three weekly filtered packed red blood cell (RBC) transfusions to maintain a hematocrit of at least 27-30 percent. The only way by which patients can survive are by lifelong blood transfusions to keep haemoglobin up and they often require one to two transfusions at 15-20 days interval, depending upon their weight from the first year of life.

However even blood transfusion comes with many additional responsibilities and complications. After each transfusion, the RBCs in the new blood are broken down slowly over the next four months. This leads to increased iron deposition in body tissues. The iron in the blood stays in the body and it can lead to clinical deterioration of certain body organs if it is not removed. It can also lead to death in patients with severe forms of thalassaemia. Thus management of complications of iron overload and transfusions, like, osteoporosis, cardiac dysfunction, endocrine problem, infections are very essential. Chelation therapy is used to counter iron overload and if annual transfusion requirement increases by more than 50 percent, then a splenectomy is considered.

Chelation therapy

"Iron chelators like Asunra help in removing the excess iron from the body. Thus iron chelators form an integral part of thalassaemia management even though they do not treat the disease they do prevent complications arising out of iron overload arising due to repeated blood transfusions" - Ranjit Shahani Vice Chairman and Managing Director Novartis India

The process of removal of excess iron from the patient's body by iron-binding drugs called chelators, is called chelation therapy. The therapy gets its name from the Latin word 'CHELE', meaning 'claw of a crab'. This is an apt graphic description of the way the chelation process works by wrapping itself like a 'crab claw' around heavy metal molecules like lead, mercury, aluminum, arsenic, cadmium, and nickel. Thalassaemia patients thus need to be treated with iron chelators which combine with excess iron in the body, forming a complex which is then carried out through the urine.

The first iron chelators were administered via a subcutaneous (SC) or intravenous (IV) infusion (generic desferrioxamine, Novartis' brand name Desferal,). Though iron chelators work, SC or IV infusions are a painful cycle for patients, especially since most of them are children. Besides compliance issues, previous chelation therapies had an added disvantage in that the chelation process was non-specific, ie, other essential metal molecules like copper, zinc, magnesium were also excreted in the process. Also despite the use of parenteral iron chelator desferrioxamine for more than 30 years ago, 50 percent of patients with thalassaemia major died before the age of 35 years, predominantly from iron-induced heart failure as pareneral chelators could not chelate iron form myocardial (heart) tissues. Oral deferiprone was found to be more effective on this count. Therefore the thrice daily capsule Kelfer, made available for the first time in India by Cipla in 1995, was welcome both from the compliance as well as efficiency point of view. Although Kelfer is not painful, it has certain toxicities.

But now there has been a landmark discovery in which pharmaceutical companies have a found a way to administer this drug orally just once a day as a dispersible tablet. Developed in 2006 by Novartis, Asunra aka Exjade, (Deferasirox) has been a major breakthrough for removing iron from the body of multi-transfused thalassaemia major patients as it needs to be taken only once a day and has negligible toxicity and high efficacy.

Stressing the importance of iron chelators Ranjit Shahani, Vice Chairman and Managing Director, Novartis India, says, "Iron chelators like Asunra help in removing the excess iron from the body. Thus iron chelators form an integral part of thalassemia management even though they do not treat the disease they do prevent complications arising out of iron overload arising due to repeated blood transfusions."

Asunra excretes excess iron via faeces. Nearly 30,000 patients suffering from thalassemia on MDS, aplastic anemia etc. with iron overload have been given this drug. This drug is able to remove iron from heart, liver, endocrine glands and other parts of the body very effectively. Webposts on Thalforum, a community forum of thalassemia patients and family members, refer to web material stating that Exjade is technically ‘expected’ to work better for chelating heart tissues because it is a smaller molecule as compared to desferal.

The lesser pain

The generic version of Deferasirox is called as Desirox manufactured by Cipla. Speaking on the benefits of Desirox, Dr Jaideep Gogtay, Cipla, says, "The development of deferasirox is an important development since it can be given once a day as compared to Kelfer which needs to be given three-four times a day. This itself should improve the quality of life of some patients. In addition, the tablet is dispersible in water which can make it convenient for children." Further, Gogtay adds that studies have shown that Desirox is as effective as desferrioxamine which is to be administered by SC infusion over eight hours every night. There is as yet no direct comparison between deferiprone and deferasirox, but at the recommended dose there should not be a difference in the efficacy. Elaborating further, Shahani said that Asunra is found to be equally efficacious to Desferal in clinical studies at half the dose of Desferal. There is no direct comparison between Deferiprone and Asunra since the earlier is approved only as a second line iron chelator in most countries.

One notch higher

"Though it has similar efficacy to desferrioxamine it is not associated with any significant complications. More over its iron binding capacity is 2:1 unlike that of Desferrioxamine, which has 1:1. Moreover there are no comparative studies with Deferasirox to comment for it is placed as the best treatment for a person with severe thalassaemia" - Dr Narendra Malhotra President Federation of Obstetric and Gynaecological Societies of India (FOGSI) 2008

Children who are provided adequate safe blood transfusion and chelation therapy can expect to live as near a normal life as expected, under constant supervision and monitoring by medical experts. These individuals can marry and can have normal children, provided the spouse does not have the same condition. Stating the advantages of Deferasirox, Dr Narendra Malhotra, President Federation of Obstetric and Gynaecological Societies of India (FOGSI) 2008, states, "Though it has similar efficacy to desferrioxamine it is not associated with any significant complications. Moreover, its iron binding capacity is 2:1 unlike that of Desferrioxamine, which has 1:1. There are no comparative studies with Deferasirox to comment for it is placed as the best treatment for a person with severe thalassaemia."

However nothing in this world comes without a hitch and Deferasirox too comes with certain disadvantages tagged to it. What is causing concern, however, is Exjade's effect on kidneys, as Novartis has released an advisory containing reports on hepatic failure with Exjade. However, to date, this therapy seems to be the best bet for thalassemia patients.

Malhotra concurs, adding that it can cause fatal, acute, irreversible renal failure and cytopenias (reduction in number of blood cells), including agranulocytosis and thrombocytopenia. Thus there is a need to monitor renal (kidney) function of the patients. Moreover there is limited long-term data available and apart from that, it may not achieve negative iron balance in all patients at highest recommended dose. Also toxicity, inability to clear cardiac iron and high cost may compromise its place in therapy. The most frequently occurring adverse events in the therapeutic studies of deferasirox were diarrhoea (11.8 percent), vomiting (10.1 percent), nausea (10.5 percent), headache (15.9 percent), abdominal pain (7.8 to 13.9 percent), pyrexia (0.1 to 18.9 percent), cough (13.9 percent), and increases in serum cretonne (11.1 percent). Deferasirox should not be combined with other iron chelator therapies, as safety of such combinations has not been established. However, combinations have been suggested with caution on safety issues, but studies are not available. Gogtay clarifies that currently there is no information about combining deferasirox with either desferrioxamine or deferiprone

Prevention is the only cure

Thalassaemia is a disease that is very hard to treat the only way by which this can be controlled is by preventing the birth of thalassaemic children by increasing awareness of the disease and advocating/promoting pre-natal screening. Explaining the strategies, Choudhry says that the person should know their thalassaemia status before marriage, so that marriages between two thalassaemia carriers could (at least theoretically) be avoided. Thalassaemia status need to be identified either soon after marriage or during early pregnancy. If the lady is a thalassaemia carrier then it is important to know the thalassaemia status of the spouse too. If both of them are carriers, then there is 25 percent possibility that their children will be thalassaemia major. There is need to identify whether baby in the womb is a thalassaemia major (ie. has the baby inherited the thalassemic gene from both the parents?). This is possible by doing a DNA analysis on samples drawn from the womb between 10-12 weeks of pregnancy (CVS). The facility for these tests is available in metros and major cities of the country (nearly 10 centers). Obviously, this facility is very limited and cannot meet the needs of the country at present.

Several countries in the world have initiated thalassaemia screening and control programmes. Cyprus, Sardinia, Greece etc. have thus controlled the birth of thalassaemic children while countries like UK, Iran, Iraq have been successful to a greater extent. In contrast, no national program has been initiated in India till date. Several non-Governmental Organisations (NGOs) are doing their best to increase awareness of the disease and provide information and help on screening and control of thalassaemia.

Need of the hour

Thalassemia is a disease that cannot be cured, thus making it an expensive disease to treat and live with. The current need of the hour is providing affordable medication to patients in time. Speaking on the same lines Shahani says, "Novartis is committed to enhancing access to deferasirox through an integrated support and treatment program for select countries in Africa and the Indian subcontinent. The program includes education for patients, training for physicians, coordination of patient monitoring with institutions, and the availability of deferasirox, under the Asunra trademark, as part of a controlled distribution system."

Choudhry feels that the cost of drug can be reduced further if the government removes import duty on the drug and raw materials. In addition, the government can also remove all local taxes to facilitate patients. Moreover they could also provide free chelation therapy as it does for patients for tuberculosis, HIV etc on humanitarian grounds. The government could use its good offices and request companies to reduce cost of these drugs. Apart from these measures, NGOs should also rise to the occasion and put moral pressure on the government and pharma companies to reduce cost of such therapy. It will need many minds and hands to make this burden lighter.

suja.nair@expressindia.com