L1 - Journey through the years

Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) alias L1, Kelfer, Ferriprox

Professor George J. Kontoghiorghes
Postgraduate Research Institute Science, Technology, Environment and Medicine
Ammochostou 3, CY 3021 Limassol, Cyprus. Tel: ++3575734615, e mail: pri_gjk@cylink.com.cy

Deferiprone is the first oral iron chelator used clinically, mainly in thalassaemia patients, where the annual birth rate worldwide is estimated to be 100000. Deferiprone belongs to the family of the alpha - ketohydroxpyridines, a relatively new class of chelating agents, some of which are naturally occurring. These have high affinity for binding iron and are able to remove it from proteins that are transporting and storing it in the body, largely sparing other biologically important metals. These chelators are stable in conditions that exist in the human digestive system and are readily absorbed.

Deferiprone has undergone extensive trials in hundreds of patients all over the world and has proved to be orally effective in removing excess iron from the body. Studies show that deferiprone is rapidly absorbed from the stomach. It appears in the blood minutes after the capsules are swallowed. In each patient, removal and excretion of iron depends on the dose and frequency of administration of the drug and the amount of iron overload. The major adverse effects, which have been observed in overall about 10% of the patients during worldwide clinical trials over a period of ten years, have been transient musculoskeletal and joint pains, neutropenia and agranulocytosis , gastric intolerance and zinc deficiency. Of these, perhaps the most disturbing is agranulocytosis, affecting less than 0.6% of the patients. In patients with agranulocytosis a substantial reduction or total absence of a group of white cells called granulocytes is observed, which amounts to rendering the body's immune system fatally weak.

This is the reason the focus of the mandatory monitoring procedure is primarily on levels of white blood cells and platelets. The monitoring not only helps to safeguard the well being of the patient but yields valuable data that can contribute to the development of a diagnostic method for agranulocytosis, its prevention and general improvement of the therapy with Deferiprone.

The Journey across the years:

1981.Discovery, design, synthesis and physicochemical characterization.

1981-82. Iron binding, protein and cell studies in-vitro. Animal studies.
1982. Naming of L1 and other alpha - ketohydroxpyridines.
1983. Patented in the UK. Later patented in the USA, EEC and some other countries.
1982-86. Intensive chemical, biochemical, cell and animal studies.
1986. DHSS grants permission for clinical trials in UK.
1987. Simple, cheap synthesis of L1. First ever clinical trials in London.
1988. Multicenter clinical trials begin worldwide.
1989. First publications on joint/musculoskeletal toxicity and agranulocytosis ( London ).
1990. Pharmacokinetic and metabolic properties characterisation of L1 in patients.
1992. Approved BAN and INN name for L1: Deferiprone.
1994. Registration of L1 in India, where now more patients are using L1 than desferal.
1995. Clinical use and multicentre clinical studies continue.
1998. Over 5000 patients in 35 countries have been using L1, some daily for over 10 years.
1999. Registration of L1 in European, South American and Asian countries.
2000. 10th International Conference in Oral Chelators for the treatment of Thalassaemia and other Diseases. 22nd-26th March, 2000. Limassol , Cyprus.

For more information contact Professor George J. Kontoghiorghes at the above address.

Reproduced from : UKTS Website

PS: The above does not mention 1987 : 400 Thals in India put on the largest trial for L1 the in the world.

Deferiprone Provides Significantly Greater Cardiac Protection

New Hope For Patients Afflicted with Rare Genetic Blood Disease: Study Finds Deferiprone Provides Significantly Greater Cardiac Protection

TORONTO, May 7 /CNW/ - Iron-induced heart disease is the major cause of death in patients with the genetic blood disorder, thalassemia. Now, a new published study in the journal Haematologica, reveals that long-term therapy with deferiprone (Ferriprox(TM)) provides greater protection of the heart from iron overload than standard therapy. The article, Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis, is the first study to examine the frequency of heart complications and survival in patients treated with Ferriprox in comparison with those treated with the standard therapy, deferoxamine (Desferal(TM)). The data revealed that Ferriprox had a major advantage in preventing iron-induced heart disease. The probability of worsening heart function over 5 years was five times more likely in the patients treated with deferoxamine than in those treated with Ferriprox.

The study coordinated by Dr. Antonio Piga of the Department of Pediatric Hematology, University of Turin, followed 129 patients with thalassemia major:
54 patients treated with Ferriprox and 75 patients treated with deferoxamine for an average of 6 years. At the initiation of the study, there was no significant difference in the percentage of patients with heart disease between the two treatment groups. At the end of the study, heart dysfunction, expressed as a worsening of pre-existing cardiac abnormality or development of new cardiac disease, was diagnosed in 2 (4%) of the Ferriprox-treated patients and in 15 (20%) of the deferoxamine-treated patients. None of the patients treated with Ferriprox died, while 3 of the patients treated with deferoxamine died because of irreversible worsening of their cardiac condition during the study period.

"Removal of iron from the body is important for transfusion-dependent patients, but the real benefit of an iron chelator is whether or not that effect translates into less morbidity and mortality. We have followed, very closely, hundreds of patients in our thalassemia center for decades. A few years after deferiprone was introduced, we began to suspect patients on this treatment were experiencing an advantage to the heart. On this basis, we conducted this retrospective examination of all of our patients who had been on continuous therapy with either chelator. The results are very encouraging for the patients.", stated Dr. Antonio Piga, lead author of the study.

Thalassemia major is a rare inherited anemia and affected children require blood transfusions every 2-4 weeks to survive. While the repeated transfusions extend survival to the 2nd or 3rd decade of life, iron in the transfused blood leads to a build up of toxic levels in the body, causing organ damage and premature death, primarily due to heart disease. Prior to the development of deferiprone, treatment for patients with iron overload was limited to deferoxamine, a drug that requires daily injections for 8-12 hours. Despite 30 years of use of deferoxamine, cardiac disease remains responsible for 70% of deaths in thalassemia patients. To provide an alternative medicine, Apotex initiated clinical trials of Ferriprox, an orally active iron chelator, in 1993. Presently, Ferriprox is approved as a life-saving alternative for patients in 25 countries including those of the European Union.

"There has been accumulating evidence from both animal and human studies
over the past decade that there might possibly be a cardioprotective effect with Ferriprox, but Dr. Piga's study is the first to demonstrate that Ferriprox reduces the toxicity of iron in the heart of patients with thalassemia and can extend survival", stated Dr. Fernando Tricta, Medical Director Apotex Inc. and a coauthor of the publication. "We look forward to further data that will add to these findings from a prospective and randomized study that is currently underway", concluded Tricta.

The really good news is for the patients. "We are excited about the hope the study provides to our patients. This is the fifth new study in the last year revealing important positive findings about deferiprone, and this one, about its benefits on the heart, is the most important. We anxiously await the availability of deferiprone as an option for treating our patients with thalassemia in the US.", stated Frank Somma, National President of the organization.

Ferriprox(TM) is the trademark of Apotex Inc. for deferiprone, an orally
active iron chelator.
Desferal(TM) is the trademark of Novartis AG for deferoxamine, an
injectable iron chelator.

RE: The Status of Ferriprox at the Time of this Press Release:
Ferriprox is on the market in 25 countries where the medicine is approved as a second line indication in transfusion-dependent thalassemia. Agranulocytosis (a decline in white blood cells that fight infection, down to a level that may not protect against invading microorganisms) is a reversible, but serious adverse reaction to Ferriprox that has been reported in about 1% of patients on chronic treatment. Country-specific prescribing information is available from Apotex. Applications for approval of Ferriprox in the US, Canada and several other countries are expected to be filed in 2003 and 2004.

RE: The Claims Referred to in this Press Release:
While the scientific statements about the cardiac benefits of deferiprone described in this Press Release are based upon the studies that have been conducted, Apotex advocates the use of Ferriprox according to the specific indications in each of the respective countries in which it is sold.

Prescribing information is available from Apotex.

Article reproduced from Newswire Canada