Transparency and Access to Full Information for the Fatal or Serious Toxicity Risks, Low Efficacy and High Price of Deferasirox, Could Increase the Prospect of Improved Iron Chelation Therapy Worldwide

Dear Sir,

The risks of using a drug causing fatalities and irreversible organ damage outweigh its benefits, especially if safer and more effective therapies are available. The toxicity and efficacy profile of deferasirox has been previously reviewed and additional toxic side effects of imminent concern for the safety of patients have recently been included from information based on the manufacturers' and regulatory authorities clinical trial and post marketing monitoring reports ([1–3]). Porter et al. have a different risk and benefit assessment on iron chelation therapy and especially deferasirox, which is not shared by others ([1],[2],[4–6]). In the conclusion of their letter, Porter et al. admit that there are unanswered questions about the tolerability, efficacy and safety of deferasirox, a view shared by the Food and Drug Administration (FDA) of the USA, and many others who require more clinical data demonstrating deferasirox's long term safety and efficacy ([6],[7]).

However, while deferasirox was provisionally approved pending further investigations and following fast-track orphan drug procedures by the FDA in November 2005, irreversible renal failure fatalities were reported in June 2006, the publication of which coincided immediately after its provisional approval by the European Union (EU) authorities. In the same report, pancytopenias including agranulocytosis were also reported. The report of fatalities from the cytopenias followed a few months later during clinical trials and post marketing monitoring. Subsequently, more fatalities from irreversible liver failure were reported in 2007, despite earlier warnings from one of the clinical studies of drug-induced hepatitis ([1],[3]). These events are alarming for patients and clinicians using deferasirox because no fatal toxicities were reported during the clinical trials and before the registration of deferiprone (L1) and deferoxamine (DFO). Furthermore, the occurrence of fatal toxicities was not identified or anticipated or reported from the animal studies in the pre-registration period for the development of deferasirox, so that prophylactic measures could be introduced to prevent or minimize them. This is in a sharp contrast to events during the developmental period of L1, where the case of agranulocytosis was immediately published and precautions were taken to minimize the risk of fatalities ([8]).

Marketing forces and indiscriminate use of deferasirox are now overtaking safety issues. Full information and transparency on the toxicity and efficacy of deferasirox are urgently needed, not only to avoid further fatalities but also to promote the use of deferasirox, especially for patients who cannot tolerate L1, DFO or their combination ([1],[2]). Porter et al. highlight a number of issues which not only are inaccurate but in many cases contradict statements made by the manufacturers and the regulatory authorities. Some of the issues are discussed with emphasis mostly on those affecting the morbidity and mortality of thalassemia and other transfusional iron loaded patients.

Fatal and Other Toxic Side Effects of Deferasirox

It is possible that renal, liver and cytopenia fatalities could have been avoided if monitoring and prophylactic measures were adhered to as described in the recent reviews and the toxicity statements on deferasirox by the regulatory authorities and the manufacturers ([1–3]). It is also worrying that no details of cases of renal and liver failure or cytopenia, including fatal outcomes or their reversal, have yet been published, despite that such episodes occurred during the clinical trials and the post marketing period of the use of deferasirox.

In most cases, clinical trials during drug development by pharmaceutical companies are strictly controlled by secrecy agreements with the investigators and their institutions. During this period, details of any event of a negative nature are not readily released and further information during post marketing monitoring is very limited.

Porter et al. and the manufacturers' warning sections refer to the following: “… most of the fatalities resulting from renal failure occurred in patients with multiple co-morbidities … ;” in the cytopenia fatalities: “… most of the patients had pre-existing hematological disorders … ;” and in the liver failure fatalities: “… most patients had significant co-morbidities …” ([3]). This reporting approach is not useful for those using, or likely to use, deferasirox. Porter et al. and the manufacturers should provide full information not only for the fatal incidences of patients with co-morbidities but most importantly for the minority of patients who have died of these toxic side effects and did not have any related co-morbidities.

Transparency and full details on the safety of deferasirox, and especially for the fatal incidences should urgently become available. Such information should include the incidence rate, the category of patients, necropsy findings and period of fatalities following the introduction of deferasirox in the patients affected. Explanation should also be provided why these fatal incidences were irreversible despite earlier warnings ([1–3]). Similarly, more details of the monitoring and possible prophylactic measures of these life-threatening toxic side effects should also be included. More information such as whether there have been any biopsies to assess the possible cause of the renal, liver, bone marrow and other toxicities observed should also be provided.

Porter et al. also show no interest in prophylaxis for other life-threatening toxicities regarding deferasirox and contradict statements made by the manufacturers and the regulatory authorities. In the deferasirox drug monograph of 2006 it was stated that “The concomitant administration of deferasirox and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, deferasirox should not be taken with aluminum-containing antacid preparations.” ([3]). Surely, the toxicity of aluminum to the brain not only from the increased absorption of aluminum from aluminum antacids, but also from aluminum in food by deferasirox, is a major toxicity issue ([1],[2],[9]). The prospect of increased aluminum and iron absorption by deferasirox needs to be urgently investigated. Increased accumulation of iron from food and iron-containing solutions was previously shown by 8-hydroxyquinoline and other lipophilic chelators like deferasirox ([10],[11]). In contrast, the hydrophilic L1 and DFO have been shown to decrease iron absorption and to increase aluminum excretion in normal volunteers and renal dialysis patients, respectively ([12],[13]).

In the case of copper (Cu) and zinc (Zn), Porter et al. contradict statements made by the manufacturers, where it was stated that “Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.” The toxicity implications of such findings should not be ignored and confused. Toxicity can be caused not only by the increased excretion of these essential metals but also from their decompartmentalization, an issue which also needs to be urgently investigated because many metabolic pathways are affected by Cu and Zn containing enzymes ([1],[2],[14]).

The indiscriminate use of deferasirox instead of L1 and DFO may increase mortality from cardiomyopathies because of the inability of deferasirox to remove iron from the heart. In contrast to L1, deferasirox has been shown not only to be insufficient in preventing iron-induced cardiotoxicity due to iron overload but also to be ineffective in a model of iron-related doxorubicin-induced cardiotoxicity ([15]).

Despite that ocular, e.g., lens, opacity and other toxic side effects such as bacterial infections by deferasirox are less frequent, these have also to be monitored and further investigated ([16]). No such toxicities have been observed during the use of L1, and its antibacterial effects, have been investigated before its registration ([17]). Overall, the lack of sufficient information from pre clinical and clinical studies and from post marketing reports related to safety, as well as for monitoring and prophylactic measures, increases the risk of using deferasirox.

Concerns on the Efficacy of Deferasirox

The ultimate aim of any form of iron chelation therapy is to reduce the excess iron load from transfusions and to maintain non toxic, normal iron levels. Effective chelators should also be able to prevent the major cause of death affecting more than 70% of transfused iron loaded patients, namely iron overload-induced cardiac failure ([1]). The removal of iron from other organs is also important but not as critical as iron removal from the heart for the long-term survival of transfused patients. Tolerance of the daily administration and costs are also contributory factors affecting iron removal.

Iron excretion increases using deferasirox, but at the approved doses of 10–30 mg/kg, the majority of regularly transfused patients cannot reach a negative iron balance ([18]). Similarly, although iron removal by deferasirox from the liver in some patients is a positive effect, this cannot be extrapolated to other organs, including the heart. Liver iron concentration and serum ferritin are not reliable parameters for measuring the efficacy of iron chelation, especially since iron is not uniformly distributed in the body and liver iron is only a part of it. This can be illustrated in the magnetic resonance imaging (MRI) scan in Figure 1, where the liver of a patient is cleared of excess iron but the heart is overloaded with iron ([19]). The effect of deferasirox on cardiac iron removal in transfused iron loaded patients is one of the clinical investigations requested by the FDA to confirm its suitability for iron chelation therapy ([6]). However, this study still remains a guarded mystery, and not only is avoided but there is no clear indication that deferasirox is at all effective in removing excess cardiac iron from iron loaded patients. This is in sharp contrast to the use of L1 and its combination with DFO and intravenous DFO, which have been shown in randomized clinical studies using MRI T2*, to be effective in reducing cardiac iron and in improving cardiac function within a year of treatment ([20],[21]). It should be noted that Porter is a co-author in the 1-year study with intravenous DFO ([21]).

FIGURE 1 Magnetic resonance imaging scan of a thalassemia patient indicating normal range T2* of iron deposition in the liver and of severe iron loading deposition in the heart. The figure was adapted from Figure 3 in ([19]); with permission.

The comparison of efficacy often made between deferasirox and DFO is misleading. The number of days during which DFO has been used by patients in comparative studies is not accurately reported. Usually, very few patients can tolerate DFO for more than 3–5 days per week, and despite the fact that many patients can tolerate deferasirox better, the overall excretion of iron is lower than that of DFO. The efficacy of deferasirox could have been improved but repeated administration is not feasible due to toxicity restrictions. Overall, deferasirox is not an effective iron chelating drug for most patients, and further studies are needed to confirm its suitability, especially for thalassemia and other transfused patients who cannot tolerate DFO, L1 and their combination ([4],[22]).

Cost/Benefit Assessment of Iron Chelation Therapy

The cost benefit assessment by Porter et al. and references therein, is irrelevant to the main issue, which is inaccessibility due to the high cost of chelating drugs and especially deferasirox, by the majority of thalassemia and other transfused patients who live in the developing countries ([1],[2]). The cost/benefit assessment by Porter et al. and references therein, is misleading in many ways. For example, incorrect assessments were made on the assumption that DFO is taken daily, that only one company is providing it, and that there are no additional costs for the toxicity monitoring of deferasirox such as serum and urine creatinine, liver enzymes, blood counts for cytopenias, ophthalmic and auditory effects, etc. ([1–3]). If we compare the approximate yearly EU cost of effective dose protocols for a 50 kg man at 45 mg/kg, 5 days per week on DFO, this is about 5,000 euros (excluding needles and pumps, etc.) and for L1 at 80 mg/kg/day, 8,000 euros. For deferasirox at 30 mg/kg/day, which is not an effective dose for reaching a negative iron balance in most patients, the cost is 33,000 euros. The cost of the L1/DFO combination, e.g., the ICOC L1/DFO combination protocol of using L1 during the day (80–100 mg/kg/day) and of subcutaneous DFO (40–50 mg/kg at least 3–4 days/week) is 11,000–14,000 euros. In the latter case, the iron stores could usually be normalized within about 1–2 years, and maintenance therapy at normal iron store levels could be achieved thereafter using L1 monotherapy ([23],[24]).

A major paradox with chelating, and possibly other drugs, is the set up and control of prices by pharmaceutical company monopolies. Deferasirox is to be sold in India at a 60-times cheaper price than in the EU and USA (Scrip 2008: S00990226), with no evidence that the preparation method or purity will be different. There is a major question on how the price of deferasirox was fixed in the EU and the USA, and why the regulatory authorities allowed it, especially since it is designated as an “orphan drug.” Deferiprone, which is now a generic drug and is sold in India at about 4-times cheaper than in Europe, can be sold at 50-times cheaper by non profit organizations in developing countries, but such initiatives are still lacking. Similarly, DFO is also a generic drug and is sold by competitive companies in some countries at slightly lower prices than before, but not at sufficiently low prices to benefit patients who need it in developing countries.

Porter et al. have raised some other issues, in part highlighting the marketing drive and indiscriminate use of deferasirox, which may endanger more lives. The authors appear to have access and to circulate information on the unconfirmed number of users of deferasirox but not on the number of fatalities or the discontinuation rates. They also highlight the toxicity aspects of L1 by referring to a group in Ceylon with a 50% rate of joint pains using L1, a rate which has not been reported by other groups. It is well established that L1 toxicities can be well monitored, managed and controlled ([1],[2]). This reminds me of another report a few years ago on liver cirrhosis with L1, which was not confirmed by other groups but set back the development of L1 for many years, and in the process, many patients in countries where it was not approved, e.g., the USA, could have lost their lives from iron overload-induced cardiomyopathies. In Cyprus, more than 50% of the patients have been using L1 since its EU approval in 1999, mainly in combination with DFO, resulting in a substantial drop in mortality from congestive cardiac failure ([25]). In contrast, deferasirox is used in Cyprus by less than 5% of patients who are not complying, or having toxic side effects with DFO, L1 or their combination. Similar policies have also been adopted elsewhere. For example, a recommendation on the use of deferasirox has recently been issued by a panel of the Italian Society of Hematology, who judged that “The evidence on long-term efficacy and safety of deferasirox was not sufficient to allow approval of its use as first-line therapy in practice. The use of the drug in registries of clinical trials seemed a more cautious recommendation” ([26]).

CONCLUSIONS

Iron chelation therapies using L1, DFO and their combination, are generally more effective, less toxic and less costly than deferasirox. More studies are needed to prove the efficacy and safety of deferasirox, which in the meantime may endanger the lives of more patients if is used indiscriminately, and without proper monitoring and prophylaxis for its toxicity and efficacy. The use of deferasirox could be considered as a third-line treatment, especially for patients not tolerating or responding to L1, DFO and their combination. Initiatives are needed for introducing changes in drug pricing to benefit patients in developing countries, who are not benefitting from old or new chelation therapies due to prohibitively high costs.

Declaration of Interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article.

Notes

3. Anonymous. Exjade (deferasirox) tablets for oral suspension. Prescribing information. Novartis Pharmaceutical Corporation USA (NDA 21–882). October, 2006; 1–12. Changes to the warnings and adverse reactions sections (www.fda.gov) 2006 and 2007.