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`Vol. 332 No. 14
`
`EDITORIALS
`
`953
`
`AN ORALLY ACTIVE IRON CHELATOR
`
` is essential for all organisms from bacteria to
`I
`RON
`humans; but like excessive amounts of alcohol, which is
`so pleasant in moderation, a surfeit of iron is fatal. The
`lethal effects of iron overload can be immediate, as in
`an accidental or deliberate overdose of medicinal iron,
`or slow, as in congenital hemochromatosis and transfu-
`sional hemosiderosis. In the slowly developing condi-
`tions — the former due to hyperabsorption of iron in
`food and the latter to iatrogenic, as well as, in the case
`of thalassemia, hyperabsorptive factors — iron stores
`in the reticuloendothelial system are filled to the brim
`with nontoxic ferruginous granules. Spillage of iron
`into parenchyma and plasma is inevitable, and toxic ef-
`fects due to oxidation of membranes follow. The excess
`iron saturates the binding sites of transferrin, the “de-
`livery boy” of iron metabolism, allowing free iron to cir-
`culate and oxidize heart-muscle membranes
` until the
`1
`patient succumbs to heart failure and arrhythmia.
`Thalassemia is one of the most common diseases in
`regions of the world where malaria has long been ram-
`pant. This inherited disorder of hemoglobin synthesis is
`fatal in infancy without transfusions but is fatal in ado-
`lescence even with them. The advent of treatment with
`subcutaneous deferoxamine has changed this gloomy
`prognosis. Recent studies demonstrate that over 90
`percent of patients who comply with the difficult and
`expensive regimen of deferoxamine treatment survive
`without heart disease
` and with minimal toxic effects if
`2
`the dose is tailored to the iron burden.
`3
`Deferoxamine has a very high and selective affinity
`for iron that is independent of the iron concentration.
`4
`The required dose is relatively low (about 40 to 50 mg
`per kilogram of body weight administered in an over-
`night subcutaneous infusion). Serious side effects are
`rare. But the drug is not active orally, and nightly sub-
`cutaneous self-administration is onerous, leading to a
`high frequency of noncompliance, a uniformly fatal
`“complication” of therapy.
`There are only two alternatives to subcutaneous de-
`feroxamine: allogeneic bone marrow transplantation
`for the 25 percent of patients with histocompatible do-
`nors, and an orally active iron chelator. The former has
`received attention recently because of a report from a
`center in Italy, where patients with good chelation had
`more than a 90 percent likelihood of indefinite thalas-
`semia-free survival after bone marrow transplantation.
`5
`However, the investigators’ method of stratifying pa-
`tients is not readily reproducible, and experience with
`bone marrow transplantation in young patients with
`good chelation in the United Kingdom and the United
`States shows that the rate of disease-free survival is no
`higher than 75 percent and may be lower.
` Neverthe-
`6,7
`less, bone marrow transplantation can solve the thera-
`peutic problem once and for all and, until now, has
`been the only useful option if a patient cannot or will
`not use deferoxamine or if the blood supply is of uncer-
`tain safety and reliability.
`Journal,
`In this issue of the
` Olivieri and her colleagues
`report a clinical trial of the new, orally active agent
` De-
`deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one).
`8
`
`feriprone has a checkered history. It was originally
`synthesized by Robert Hider and his colleagues at Es-
`sex University, and the early biologic assessments were
`performed at University College Hospital in London.
`9
`The drug was used in the clinic of another London
`hospital without sufficient studies of toxic effects in an-
`imals and without Hider’s approval.
`Deferiprone has a much lower therapeutic ratio
`than deferoxamine, for two reasons. First, deferiprone
`is considerably more toxic and regularly depresses the
`granulocyte count in both normal and iron-overloaded
`animals
`; deferoxamine, in contrast, does not depress
`10
`the marrow. In clinical studies, deferiprone has caused
`both agranulocytosis and arthralgia or arthritis; the
`frequency of these complications is not yet known.
`Second, though Olivieri and her colleagues clearly
`demonstrate that deferiprone can reduce iron stores to
`lower, if still elevated, levels in patients with severe
`overload, the drug has a concentration-dependent af-
`finity for iron.
` Three molecules of deferiprone are re-
`4
`quired to bind one molecule of iron, whereas deferox-
`amine binds iron tightly in a 1:1 ratio. For this reason,
`deferiprone must be present at very high concentra-
`tions (close to toxic levels) to be effective. It dissociates
`from iron when the concentration of iron in body fluids
`falls to the level achieved just a few hours after oral ad-
` Hence, as demonstrated by Olivieri and
`ministration.
`4
`her colleagues, deferiprone does not readily reduce ex-
`cessive body iron stores below a certain level. It is
`therefore not clear that the drug will provide long-
`term protection from heart disease.
`Not enough is known about the pharmacologic
`properties of deferiprone. Will the low levels of drug
`that remain in the plasma continue to chelate free iron
`and thereby protect heart-muscle membranes, or will
`the small but highly toxic pool of free iron remain or
`return to high levels between doses to do its damage?
`Over time, will the drug’s ability to be absorbed prove
`to be a two-edged sword because it can also permeate
`the cell membranes of vital organs such as the kidney,
`with toxic effects? That has been the sad fate of an
`extremely active oral iron chelator called desferithio-
`cin.
` Finally, will adolescents really swallow enough
`11
`pills to amount to 75 mg per kilogram in three divided
`doses every day? For an adolescent of average weight,
`this represents 1 to 2 g of the drug three times daily.
`Such a burdensome regimen is itself an open invitation
`to noncompliance and the development of heart dis-
`ease. Ominously, 10 percent of the patients in the trial
`reported by Olivieri et al. did not comply with the
`regimen.
`Given these concerns, clinical studies of deferiprone
`that last for several years and enroll at least 100 pa-
`tients will be required before physicians can advise pa-
`tients with thalassemia to dispense with nightly subcu-
`taneous administration of deferoxamine and instead
`swallow a handful of capsules every eight hours. Pa-
`tients who are unable or unwilling to use deferoxamine
`and for whom there are histocompatible donors avail-
`able will have to weigh the unknown risks of defer-
`iprone against the more established risks of bone mar-
`row transplantation.
`
`The New England Journal of Medicine
`Downloaded from nejm.org at INFOTRIEVE on September 28, 2016. For personal use only. No other uses without permission.
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`1 of 2
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1020
`
`

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`954
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`April 6, 1995
`
`Despite questions about the long-term efficacy and
`safety of deferiprone in the management of thalasse-
`mia, Olivieri and her coworkers are to be congratulat-
`ed for rescuing the drug from a shaky start and for per-
`forming a careful initial study that moves the field
`forward. Whether deferiprone proves to be useful and
`safe will be known in the fullness of time. Whatever
`further studies of the drug reveal, it is comforting to
`know that the search for a better life for patients with
`thalassemia is in reliable hands.
`
`Children’s Hospital
`Boston, MA 02115
`
`D
`
`AVID
`
` G. N
`
`ATHAN
`
`, M.D.
`
`R
`
`EFERENCES
`
`1. Hershko C. Iron chelators in medicine. Mol Aspects Med 1992;13:113-65.
`2. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treat-
`b
`ed patients with homozygous
`-thalassemia. N Engl J Med 1994;331:574-
`8.
`
`3. Fosburg MT, Nathan DG. Treatment of Cooley’s anemia. Blood 1990;76:
`435-44.
`4. Motekaitis RJ, Martell AE. Stabilities of the iron (III) chelates of 1,2-
`dimethyl-3-hydroxy-4-pyridinone and related ligands. Inorg Chim Acta
`1991;183:71-80.
`5. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in
`patients with thalassemia. N Engl J Med 1990;322:417-21.
`6. Walters MC, Thomas ED. Bone marrow transplantation for thalassemia: the
`USA experience. Am J Pediatr Hematol Oncol 1994;16:11-7.
`7. Vellodi A, Picton S, Downie CJ, Eltumi M, Stevens R, Evans DI. Bone mar-
`row transplantation for thalassaemia: experience of two British centres.
`Bone Marrow Transplant 1994;13:559-62.
`8. Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with
`oral deferiprone in patients with thalassemia major. N Engl J Med 1995;332:
`918-22.
`9. Hider RC, Singh S, Porter JB, Huehns ER. The development of hydroxypy-
`ridin-4-ones as orally active iron chelators. Ann N Y Acad Sci 1990;612:
`327-38.
`10. Porter JB, Hoyes KP, Abeysinghe RD, Brooks PN, Huehns ER, Hider RC.
`Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4-one
`iron chelators in overloaded and nonoverloaded mice. Blood 1991;78:2727-
`34.
`11. Wolfe LC, Nicolosi RJ, Renaud MM, et al. A non-human primate model for
`the study of oral iron chelators. Br J Haematol 1989;72:456-61.
`
`The New England Journal of Medicine
`Downloaded from nejm.org at INFOTRIEVE on September 28, 2016. For personal use only. No other uses without permission.
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`2 of 2
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1020
`
`