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`Fabron Jr., A., ct al., Rev. bras. hematol. hemotcr. 2003;25(3):177-188
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`1 of 14
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`Taro Pharmaceuticals, Ltd.
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`
`Fabron Jr. A et al
`
`Rev. bras. hematol. Hen1oter. 2003;25(3):177-188
`
`[bilingual text:]/Review
`
`[bilingual text:]
`Oral iron chelation therapy 'vith deferiprone in patients \Vith iron overload
`
`Antonio Fabron Jr. 1
`Fernando Tricta2
`
`\Vith
`iron chelation
`introduction of parenteral
`the
`Despite
`desferrioxainine over thirty years ago, 50% of patients \vith
`thalassemia 1najor die before the age of 35, mostly due to heait
`failure secondary to iron overload. Although desferrioxan1ine can
`reduce or stabilize iron load, many patients do not receive adequate
`therapy \Vith this chelator, 1nainly due to intolerance to a regin1en
`that requires parenteral ad111inistration for an extended period of
`th11e, five to seven days per \Veek. For these patients, deferiprone,
`an orally active chelator, is a treat111ent alternative to control iron
`overload. 1'he safety and efficacy of deferiprone have been
`demonstrated in a large nu111ber of clinical trials. It is estimated that
`over six thousands patients \Vith iron overload have already been
`treated \Vith this chelator, and some of the111 have been taking the
`drug for over I 0 years. Deferiprone-induced iron excretion is
`directly affected by the dose of deferiprone and the patient's iron
`overload. Recently, it has been demonstrated that desferrioxamine
`and deferiprone have different chelating capabilities and that their
`concon1itant or sequential use promote an additive or synergistic
`iron excretion \Vith a rapid reduction in the body's iron load. It is
`nO\V possible to consider tailor-made chelation regimens based on
`individual patient needs. Rev. bras. hematol. hen1oter. [Brazilian
`Journal of Hematology and 1-lemotherapy] 2003;25(3): 177-188.
`
`Key "'ords: Deferiprone; desferrioxan1ine; thalassemia; chelation.
`
`Introduction
`
`Iron chelation therapy is essential for the survival of
`patients \Vith he1nosiderosis secondary to red blood
`cell transfusions. 1
`3 Until recently, only one iron
`•
`chelator, desferrioxamine (DFO) \Vas available for
`the clinical treat111ent of these patients.
`the
`tolerate
`1-Io\vever, many patients do not
`subcutaneous and intravenous infusions of DFO, for
`
`The efficacy and safety of the use of DFO, as \veil as
`its efficacy in increasing the survival of patients \Vi th
`iron overload, have been \veil docu1nented in the last
`6
`l\vo decades. 4
`-
`
`Clinical studies have sho\vn that the fecal excretion
`of iron corresponds to an average of 20o/o of the total
`
`1
`
`MD, PhD in Hematology and Hcmotherapy ofFaculdade de Medicina de Marilia-SP [Marilia Medical School- Sao
`Paulo} Brazil.
`2
`MD, Director, Apotex Research Inc. -Toronto -Canada
`
`Mail to: Fernando Tricta
`Apotcx Research Inc.
`150 Signet Drive
`Weston, ON
`Canada- M9L I T9
`Phone/FAX: (416) 407-0332 - E-1nail: ftricta 1@apotcx.com
`
`177
`
`rcvie\V- chelation therapy.p65 177
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`0912512003, 2: 19 p.111.
`
`2 of 14
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
`
`
`
`Rev. bras. he1nalol. Hcmoter. 2003;25(3): 177-188
`
`Fabron Jr. A et al
`
`8 to 12 hours for at least five days per \\'eek. 7·9
`Additionally, in many patients, DFO causes irritation
`in the infusion site, and as \Veil as bone abnormalities
`and stunted gro\vth, in addition to neurotoxic, visual
`[adverse] effects. 7·9
`and hearing
`Intolerance
`to
`chelation therapy is considered to be the main cause
`of death in patients \Vith iron overload, especially in
`6'7'10 In the last fe\v
`patients \Vith thalasse1nia niajor. 1
`'
`decades an intense search for less aggressive11·13
`chelation therapies and for oral chelators has been in
`progress. 1-Iundreds of chelators \Vere developed, but
`only deferiprone demonstrated acceptable results for
`its use in clinical practice.
`Deferiprone (1.2 dimethyl-3-hydroxypyrid-
`4-one, LI) is a synthetic chelator developed at King's
`College of London in 1984. It is estimated that over
`six thousand patients \vith iron overload, most of
`then1
`\Vith
`thalassemia, have already
`received
`treatment \Vith deferiprone and some patients have
`been taking the drug for ten years or more. 10·15·25 This
`article is a revie\v of recent clinical studies conducted
`\Vith deferiprone and of its ne\v potential use in
`clinical practice.
`
`Pharrnacokinetics
`Deferiprone is an orally active iron chelation
`agent that preferentially chelates the trivalent iron
`cation (Fe3+) creating a deferiprone/iron complex in
`a 1nolar ratio of 3:1 (3 deferiprone: I iron), \vhich is
`excreted
`together
`\Vith
`the
`free drug. Studies
`conducted in anin1als have demonstrated that 92% to
`99o/o of the dose of deferiprone adn1inistered orally is
`rapidly absorbed by the gastrointestinal tract.26 These
`findings \Vere confirmed in patients \vith thalasse1nia
`1najor \\'here the peak plas1na concentration of the
`drug \Vas reached \Vithin 45 to 60 1ninutes after
`ingestion and over 90% of the dose \Vas elin1inated as
`\Vithin
`five
`to six hours after
`its
`free drug
`ad1ninistration.21·29 The conco1nitant
`ingestion of
`food reduces the absorption speed but does not
`reduce the amount of absorbed drug.30·31 ln patients
`\Vi th iron overload, approximately 85o/o of the dose of
`deferiprone ingested is metabolized in an inactive
`g\ucuronide conjugate, \Vhich is excreted in urine
`together \Vith the deferiprone: iron coinplexes.28-29
`
`eliminated. varying fiu1n 0%
`patients. 32-34
`
`to 60%
`
`in so1ne
`
`Efficacy
`The efficacy of deferiprone has been
`evaluated in patients \Vith secondary he111osiderosis,
`especially in those \Vith thalassemia 1najor, due to its
`capacity to boost iron excretion, its effect on the
`levels of seru1n ferritin and on iron overload in the
`liver and heart.
`
`Iron excretion
`the
`Clinical studies have den1onstrated
`efficacy of deferiprone in inducing the excretion of
`\Vith he1nosiderosis. 15-i 7,35·37 The
`iron
`in patients
`amount of iron eli1ninated is, generally, directly
`influenced by the dose of deferiprone and by the
`•36-39 Metabolic studies
`patient's iron overload level. 15
`that 25 1ng of
`of iron balance have sho\vn
`deferiprone, three ti1nes a day, causes iron excretion
`similar
`to
`the excretion caused by 40 mg of
`7·41·43
`desferrioxamine.22,3
`5 This dosage causes an
`-4
`iron excretion that neutralizes the iron introduced by
`transfusions in most patients undergoing chronic
`transfusion
`regi1nens.
`Iron urine excretion
`in
`response to the use of deferiprone is not affected by
`the concomitant ad1ninistration of vitan1in C or
`food.1s.21
`
`Serum ferritin
`nlagnetic
`as
`such
`procedures,
`Ne\v
`1nagnetic
`resonance
`i1naging
`(MRI)
`and
`susceptometry (SQUID) have been developed for the
`evaluation of iron concentration in several organs.
`Ho\vever,
`the measuren1ent of seru1n
`ferritin
`continues to be the 111ost co1n1nonly used diagnostic
`1nethod in clinical practice for the assessn1ent of iron
`overload. Due to the variability of its results, a single
`measurement of seru1n ferritin has li1nited diagnostic
`value in the assess1nent of the efficacy of a chelation
`therapy.46 I-lo\vever, serial measure1nents of ferritin
`generally
`reflect
`the
`changes
`in
`liver
`iron
`concentration and provide a
`relatively precise
`indication of the efficacy of the chelation therapy,
`indicating if the iron overload is static, increased or
`decreased.40·42 Moreover,
`serum
`ferritin
`level
`continues
`to be considered
`the 1nost
`important
`prognostic factor in patients \Vith iron overload. 43·44
`
`178
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
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`
`
`Fabron Jr. A et al
`
`Rev. bras. hematol. Heinoter. 2003;25(3):177-188
`
`Liver iron concentration
`iron
`liver
`of
`The
`determination
`concentration (LIC) has the advantage of nieasuring
`the amount of iron in the organ that presents the
`highest overload of
`this mineral,
`and
`its
`concentration provides a relatively precise estimate
`of the total level of iron in the body. 51 LIC can be
`detern1ined by biochemical measure1nent of liver
`fragments obtained through biopsies or through
`magnetic biosuscepto1netry (SQUID). 1--Jo,vever due
`to the inconvenience of repeated liver biopsies and
`the
`limited availability of SQUID (only
`four
`niachines, t\vo in the USA and 1\VO in Europe, are
`currently active in clinical use), only a fe\v studies
`have used sequential LIC detern1ination to evaluate
`the effect of chelation therapy \Vith desferrioxamine
`\Vith deferiprone. Moreover,
`\Vhen LIC
`is
`or
`evaluated in biopsy fragments, it can present a large
`variability, \Vhich can make it difficult to interpret
`the chelation effects
`in
`son1e patients. This
`variability can be explained by factors such as
`inadequate size of the samples obtained through the
`biopsies and heterogeneous distribution of iron in
`the liver parenchy1na, especially in the presence of
`55 Recently_, there have
`severe fibrosis or cirrhosis.52
`"
`been attempts to evaluate LIC through magnetic
`resonance imaging (MRI).
`The studies that evaluated UC during
`treatment \Vith deferiprone have produced results
`similar to those of serun1 ferritin. \vith its decrease
`or stabilization, despite continuous
`transfusion(cid:173)
`57 In one of
`56
`induced iron overload (Table 1). 24.4 1.42
`·
`·
`the studies, the authors co1npared the efficacy of
`deferiprone and of DFO on LIC alterations,
`evaluated through liver biopsies, in patients \Vith
`thalassemia major. 42 The authors have sho\vn that
`deferiprone and DFO \Vere equally effective in
`decreasing liver iron concentration.
`
`Heart iron concentration
`Since heart disease is responsible for most
`of the deaths of patients \Vith thalasse1nia major
`(78o/o) a decrease in heart iron load is the 1nost
`important ele1nent of a chelation therapy. 58
`
`\vith deferiprone have
`studies
`Clinical
`demonstrated that its use decreases or stabilizes serum
`ferritin
`levels
`in
`patients undergoing
`chronic
`47
`(Figure 1 ).42.45
`transfusion
`treatment
`regimens
`•
`Co1nparative studies have sho\vn that deferiprone has
`8 Similarly to
`an efficacy si1nilar to that of DF0. 42
`.4
`\vhat is found \Vith DF0,49 the intensity of the response
`to defe1·iprone is directly proportional to the dose used
`and to the level of iron overload at the beginning of the
`treatment. Patients \Vith a higher level of iron overload
`at the beginning of the treatment have the highest
`decrease during treatment \Vith deferiprone, \Vhile
`patients \Vith a lov.:er level of iron overload at the
`beginning of the treatment have steady or slightly
`47 While
`ferritin. 16
`45
`increased
`levels of seru1n
`•
`•
`studying 532 patients \Vho \Vere taking deferiprone,
`Ceci et al. found that patients \Vho started treatment
`\Vith serum
`ferritin
`levels >4,000 mg/L had a
`significant and steady decrease in serum ferritin, \Vhile
`patients \Vho started treatment \Vith ferritin
`levels
`<2,000 mg/L did not present with
`significant
`changes.47 Moreover, Wonke et al. have demonstrated
`in a study \Vith nine patients considered
`to be
`inadequately chelated at a dose of 75mg/kg/day of
`deferiprone that a slight increase in the dose, to 83-
`100 mg/kg/day, or
`its combination
`\Vith DFO,
`produced a significant decrease in ferritin level and in
`liver iron concentration \Vithin a fe,v 1nonths of
`treatment and \Vithout any ne\v side-effects. 50
`
`('Jl':W>~ 1t'W
`
`ft1¥!:>1'1""'1Jl~M
`
`l\4¥f"~'xir
`'1?:1;xo
`
`'"'
`
`Fig. I - Serum ferritin levels in patients undergoing chronic
`transfusion treatment regimen treated with deferiprone.
`Each line represents the mean iron ferritin level at the
`begin11i11g and al tile end of treatment with deferiprone in
`patients participating in each of tile studies above.
`
`179
`
`revie\v ~chelation therapy.p65 179
`
`09/25/2003, 2: 19 p.m.
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`4 of 14
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
`
`
`
`Rev. bras. hcmatol. Hcmotcr. 2003;25(3):177-188
`
`Fabron Jr. A et al
`
`Several 1nagnetic resonance 111ethods have been used
`to evaluate heart iron load. These studies demonstrate
`that deferiprone is as effective as, or superior to,
`DFO in the clearance of heart iron, as sho\vn in the
`studies on table 2. Maggio et al. have con1pared heart
`iron concentration using MRI in 145 patients treated
`\Vith deferiprone or DF0.42 After one year of the
`study, the use of both chelators produced a similar
`increase in the intensity of the magnetic resonance
`signal. compatible \Vith a decrease in heart iron.
`Studies conducted for
`longer periods and
`\Vith
`magnetic 1·esonance techniques that are considered to
`be nlore precise have sho\vn a higher efficacy of
`deferiprone in the re1noval of heart iron than the use
`of subcutaneous DFO. Another randomized study,
`\Vhich evaluated patients treated \Vith deferiprone for
`an average period of 22 nlonths, has sho\vn a
`in T2 relaxation
`tin1e,
`significant
`in1provement
`co111patible \Vith a reduction in heart iron, in patients
`treated \Vith deferiprone (initial T2 = 23.9±6.4 ms;
`final ~ 32.4±9.3 ms; p <0.0005), which remained
`unaltered in patients treated \Vith DFO (initial =
`21.4±7.9; final ~ 21.7± 6.9 ms; p >0.67).59 Jn an
`evaluation of another group of patients receiving
`deferiprone for a longer period (2.9±1.3 years), the
`saine authors have also
`found
`a significant
`iinprove111ent in heart T2 rela"Xation time (initial T2 =
`26.6±8.4 ms; final~ 30.5±6.7 ms; p <0.005).60
`More recently, a study has demonstrated
`that the evaluation of T2* (T2-star) is a promising
`111ethod for the early diagnosis of 111yocardial iron
`overload.
`
`The authors evaluated heart iron concentration and
`heart function in patients treated for at least three
`years \Vith deferiprone or DFO. Deferiprone \Vas not
`only 1nore effective than DFO in the re111oval of heart
`iron but also in the improven1ent of heart function.61
`Pennel & Bland den1onstrated that T2* has a better
`than
`predictive effect of ventricular dysfunction
`serum ferritin or liver iron concentration.62
`Another indication of the higher efficacy of
`deferiprone in relation to DFO in the reduction of
`heart iron \Vas demonstrated in a retrospective study
`that co111pared the occurrence of cardio1nyopathy and
`survival in patients \Vith thalassemia major treated
`\Vith defcriprone or DFO, for a minimun1 period of
`four years in a single treat111ent site. At the end of the
`study period, the rate of cardio111yopathy in patients
`treated \Vi th deferiprone \Vas four tin1es lo\ver than in
`patients treated with DFO (p ~ 0.007). The three
`patients \vho died due to heart failure during the
`study period had been treated only \Vi th DFO. 63
`The mechanism of the apparently better
`cardioprotective effect of deferiprone can be
`attributed
`to
`its higher
`lipophilicity and
`lo\ver
`111olecular \Veight than DFO, \Vhich facilitates its
`the cell n1en1brane and a n1ore
`transit through
`effective chelation of the intracellular iron.64
`Despite
`the
`fact
`that
`the global data
`currently available de1nonstrates that the efficacy of
`deferiprone is con1parable, if not superior, to that of
`DFO in the elin1ination of heart iron, the efficacy of
`deferiprone in patients \Vi th heart failure secondary to
`iron overload is not yet kno\Vn.
`
`Table 1
`Mean liver iron concentration at the beginning and at the end of chelation therapy "'ith deferiprone in
`patients underEoing chronic transfusion treatn1ent re imen
`
`Author
`
`Mazza et al t221
`Olivieri et al am
`Olivieri et al 1~ 5 i
`
`Mannio et al Hl)
`
`I l\'lcasuremcnt 1\lethod
`
`Biopsy
`SQUID or biopsy
`SQUID or biopsy
`NMR
`Bionsv
`
`patients
`
`(mg/kg/day)
`
`No. of I Dose
`
`20
`21
`18
`71
`20
`
`70
`75
`75
`75
`75
`
`I Duration
`
`(years)
`
`>1
`3.1
`4.6
`1.0
`2.5
`
`Liver iron
`
`Initial
`16.2 mg/g
`80.7 µmol/g
`88. 7 µmol/g
`0.83 llSR]
`4.4 lllP/P
`
`Final
`21.0 mg
`46.8 ~unol/g
`65.5 µmol/g
`0.89 [JSRJ
`2.3 Ill!!/!!
`
`SQUIB [sic: SQUID]= Superconducting Quantum Interference Device Biosusceptometer
`
`I 80
`
`5 of 14
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
`
`
`
`Fabron Jr. A ct al
`
`Rev. bras. hematol. Hemotcr. 2003;25(3): l 77-188
`
`Table2
`Heart iron concentration, evaluated through Magnetic Resonance, in patients "'ith thalassen1ia major
`durini! chelation theranv "'ith deferiorone or desferrioxamine (DFO)
`Heart l\1RI (mean)
`Chelator
`
`Author
`
`I
`
`Initial
`J.06 [JSR]
`
`Final
`1.18 [JSR]
`
`p
`<0.05
`
`Meomcmcnt Method I Duration of I
`I
`
`Maggio et al (42)
`
`NMR
`Rate of signal intensity
`
`chelation
`therapy
`I year
`
`Deferiprone 75
`mg/kg/day
`
`Olivieri et al
`(J08)
`
`MRIT2
`Relaxation time
`(Norma!> 32 ms)
`
`18-23 months
`
`DFO
`
`0.98 [ISR]
`
`1.12 [JSR]
`
`<0.0!
`
`Defcriprone 75
`mg/kg/day
`
`DFO 50 mg/kg
`5 days per week
`
`23.9 ms
`
`32.4 ms
`
`<0.0005
`
`21.4 ms
`
`21.7
`
`>0.67
`
`Olivieri ct al
`( J09)
`
`Anderson ct al
`(6 J)
`
`MRIT2
`Relaxation time
`(Nonna\> 32 ms)
`MRIT2*
`(Nonna]> 20 ms)
`
`2.9 years
`
`75
`
`26.6 ms
`
`30.5 ms
`
`<0.005
`
`> 3ycars
`
`Deferiprone 80
`mg/kg/day
`
`DFO 37 mg/kg
`5 da\'S ner week
`
`Not available
`
`34.0 ms
`
`0.02
`
`Not available
`
`11.4 ms
`
`treatn1ent
`recommended
`the
`these patients
`For
`continues to be continuous intravenous infusion \Vith
`DFO. Ho\vever,
`since
`continuous
`intravenous
`66
`infusion \Vith DFO is not effective in all patients,65
`•
`prospective studies are required to evaluate \Vhether
`deferiprone alone or in co1nbination \Vith DFO could
`increase the recovery rate of patients \vith heart
`failure.
`
`Quality oflife
`In
`terms of quality of life, the use of
`deferiprone has been associated \Vith a significant
`i1np1·ovement in the quality of life of patients \Vith
`thalasse1nia. The replacetnent of daily subcutaneous
`infusions of DFO
`\Vith oral deferiprone
`\Vas
`associated \Vith a decrease in Disease Impact Profile
`from 5.2±7.0 to 2.2±2.3 (p<0.05). which is consistent
`in quality of life.67 The
`\Vith an
`improvement
`ilnprovement in quality of life \.Vith the replace1nent
`of parenteral chelation therapy v-.'ith oral therapy \Vas
`also de1nonstrated by Zahed et al.68
`
`Clinical safety
`Clinical safety in the use of the deferiprone
`\Vas evaluated in approxhnately one thousand
`patients, some of\vhom \Vere treated \Vith this
`24
`21
`chelator for over 10 ycars. 16
`20
`42
`57
`69
`•
`•
`•
`·
`·
`•
`
`The clinical studies found agranulocytosis, arlhralgia,
`gastrointestinal symptoms and fluctuations
`in the
`serum level of liver enzy1nes to be the main side
`effects of therapy \Vith deferiprone.
`
`Agranulocytosis and neutropenia
`Transient agranulocytosis (neutrophils from
`0 to 0.5 x 109/L) is the 1nost serious adverse reaction
`associated \.Vith the use of deferiprone, occurring in
`approximately 1 % of the patients.20
`42 The cause of
`21
`•
`•
`agranulocytosis during treat1nent \Vith deferiprone is
`unknown. 70 Studies in animals \Vithout iron overload
`have sho\vn that deteriprone has a dose-dependent
`effect on bone n1arro\v production, 71 but, in hu1nans,
`agranulocytosis
`seen1s
`to be an
`idiosyncratic
`73
`occurrence. 72
`In a clinical
`study developed
`•
`specifically to establish the rate of agranulocytosis,
`blood tests \Vere carried out \Veekly and, if an
`absolute neutrophil count belo\V 1.5 x 109/L \Vas
`confirmed, the drug \Vas discontinued. In this study,
`agranulocytosis \vas diagnosed in one (0.5o/o) out 187
`patients studied, corresponding to a rate of 0.6 per
`I 00 patients/years of therapy. 21 Other
`studies
`confirmed the lo\v rate of agranulocytosis and its
`resolution after the discontinuation of deferiprone or
`\Vith the use of granulocyte gro\vth factor (0-CSF) in
`some patients.20
`74
`42
`•
`•
`
`181
`
`revie\v- chelation therapy.p65 181
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`09/25/2003, 2: J 9 p.m.
`
`6 of 14
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
`
`
`
`Rev. bras. hematol. Hemoter. 2003;25(3):177-188
`
`Fabron Jr. A et al
`
`l-lo\vever, l\VO fatal repo1is of agranulocytosis during
`treat1nent
`\Vith deferiprone are described
`in the
`literature,75
`76 reinforcing the need for the \Veekly
`•
`follo\v-up of neutrophil count in all patients treated
`\Vith deferiprone until the agranulocytosis risk factors
`arc identified.
`that nlild,
`Cohen et al. have reported
`the use of
`\Vith
`transient types of neutropenia
`deferiprone see1n
`to be more associated
`\Vith
`hypersplenis1n and intercu1Tent infections than \Vith
`the use of the chelator.21 Similar results
`\Vere
`described by Ceci et ai. 20
`Although the number of agranulocytosis and
`neutropenia cases is small. the analysis of these
`events indicates that the spleen, \Vhen in a state of
`hypersplenism,
`plays
`an
`important
`role
`in
`detennining the probability of the occurrence of
`neutropenia
`in patients. During
`four years of
`evaluation, n1ild agranulocytosis or neutropenia \Vas
`found
`in
`t\vo (2.7%) out of 74 splenectomized
`in 15
`(13.3%) out of 113 non(cid:173)
`patients and
`splenecto1nized patients (p = 0.014).77 Neutropenia
`has also occurred in patients treated \Vith DF0. 7s In a
`rando1nized study \Vith DFO, 20°/o out of 36 patients
`treated \Vith DFO presented \Vith neutrophil count
`\o\ver than 1.5 x 109/L. 79 In another study that
`compared the use of DFO \Vith the alternate use of
`deferiprone and DFO, neutropenia events occurred
`only in patients treated \vith DFO alone.so
`Despite the possibility that so111e factors
`1nay interfere in the development of a lo\V neutrophil
`count in patients \Vith thalassemia, the reintroduction
`of deferiprone
`in
`patients
`\\1ho
`developed
`is
`not
`recommended.
`The
`agranulocytosis
`reintroduction of deferiprone in patients \Vith mild
`neutropenia should be considered \Vith caution.
`
`Liver toxicity
`So111e patients present \Vith fluctuations in
`the levels of liver enzymes, especially in the first fe\v
`1nonths of treatn1ent
`\Vith deferiprone.
`In an
`international, cooperative study, 50 out of 84 (59.5%)
`patients presented \Vith at least one serum ALT value
`t\VO times higher than the upper limit of normal
`during the first six nlonths oftreatment. 16
`
`The abnon11alities in liver enzy1nes \Vere, in general,
`mild and te1nporary, \Vith persistent elevation in only
`one patient, \Vho \Vent back to pretreat1nent levels
`after the discontinuation of deferiprone. Other studies
`have not found any significant alteration in liver
`enzy1ne levels during up to three years of therapy
`20
`\Vith deferiprone. 17
`,
`One study considered that deferiprone could
`be associated \Vith the progression of liver fibrosis. 45
`By using serial liver biopsies, five out of 14 patients
`\Vere considered
`to have
`receiving deferiprone
`progression of the fibrosis compared to zero patients
`in a group of 12 patients treated \Vith DFO. 1--Jo\vever,
`an
`editorial
`that 1nonitored
`this publication
`questioned this conclusion, by mentioning some
`differences bet\veen the patients receiving the l\vo
`chelators, such as higher LIC and average age in the
`deferiprone ann, different size of the biopsies
`collected and presence of hepatitis C in 4/5 patients
`receiving deferiprone and vvith fibrosis progression.s 1
`Progression of liver fibrosis is a co1n1non finding in
`patients \Vith high LIC, especially if the patient also
`has hepatitis C, and had already been found in 25o/o-
`35% of patients
`\Vith
`thalasse1nia
`treated
`\Vith
`DF0. 82
`83 Recently, a study carried out by Wanless et
`•
`al. using serial liver biopsies in 58 patients \Vith
`thalasse1nia major, after an average of 3.1 years of
`treatment \Vith deferiprone, has not de1nonstrated any
`evidence of the progression of liver fibrosis induced
`by
`the chelator, even
`for patients
`\vho
`\Vere
`seropositive for hepatitis C, 84 confirming other
`smaller studies
`that have also evaluated
`liver
`histology in patients treated \Vith deferiprone. 18
`85-s9
`•
`
`Other adverse effects
`In one of the larger, multicenter studies
`designed to evaluate the safety profile of deferiprone,
`Cohen et al. have evaluated, every \Veek, for up to
`four years, 187 patients \Vith thalassen1ia major and
`have found
`that the most frequent side effects
`associated \Vith its use are gastrointestinal syn1pto111s,
`90
`such as nausea, vomiting and abdo1ninal pain. 21
`•
`These symptoms, reported in 24% of the patients,
`have occurred more frequently in the first \Veeks of
`therapy, \Vere ofmild/inoderate intensity and, in most
`cases, disappeared \Vithin a fe\v days, \Vithout the
`need to discontinue the use of deferiprone or to
`reduce its dosage.
`
`182
`
`7 of 14
`
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`Exhibit 1064
`
`
`
`Fabron Jr. A et al
`
`Rev. bras. hen1atol. Hemoter. 2003;25(3): 177-188
`
`Joint sympto1ns, especially arthralgia in the large
`joints \Vere found in 13% of the patients, a rate
`similar to the one reported \Vith the use of DF0.91
`Arthralgia usually disappears after the temporary
`discontinuation of the drug or the reduction of its
`dosage, \Vith an average duration of 12 days.20 The
`cause of the joint symptoms during therapy \Vith
`deferiprone re1nains unkno\vn, and no
`laboratory
`abnormality indicative of autoimmune etiology or
`related to the severity of the iron overload has been
`found.21,14
`\Vhether
`evaluated
`studies have
`Fe\v
`deferiprone causes hearing loss in patients \vith
`normal hearing. A progression of hearing ability \Vas
`found during therapy \Vith deferiprone in five out of
`nine patients \vho had started therapy \vith this
`chelator due to hearing loss caused previously by
`DF0.92
`
`In contrast to DFO, \vhich is a microbial
`siderophore that can be used by Y. enterocolitica for
`iron acquisition for its multiplication, deferiprone
`uses a synthetic iron chelator that does not cause
`septicemia through Y. enterocolitica.93 The increased
`rate of infection caused by Y. enterocolitica in
`patients
`\Vith
`iron overload
`is
`\Veil
`recognized,
`especially in patients receiving DFO as a chelation
`therapy.94·95 Contrary to DFO, synthetic chelators,
`such as deferiprone can inhibit bacterial gro\vth
`through siderophore iron removal, or by blocking
`siderophore-n1ediated iron uptake.96 Consistent \Vith
`in vitro studies and
`\Vith studies conducted
`in
`animals,
`rare
`cases of
`infection
`caused by
`Y. enterocolitica have been reported in the last nine
`years of clinical use of deferiprone in over six
`thousand
`patients,
`despite
`the
`increased
`predisposition of these patients to infection due to
`iron overload.
`
`Alternative therapies
`The recognition that deferiprone and DFO
`have different characteristics for iron chelation of
`several organs in the body provides, for the first time,
`the opportunity to use chelation regimens \Vith the
`conco1nitant or sequential use of both drugs.
`Available data indicates that, in conventional doses,
`deferiprone has preferential access to heart iron and
`DFO has preferential access to liver iron.61
`
`Metabolic studies \Vith the use of both chelators have
`demonstrated that their combined use has an additive
`and, probably, a synergistic effect on the excretion of
`iron.34·97 Based on the above, combined treatment
`regin1ens \Vith DFO and deferiprone are currently
`being investigated to optimize chelation therapy in
`patients \Vith iron overload.34·50
`97·100
`•
`Combined chelation
`therapy has been
`investigated as an attractive option for patients \vith
`heavy iron overload or for those \Vho do not achieve
`an adequate reduction in iron overload \Vith the use
`of deferiprone or DFO alone. Several studies have
`demonstrated that con1bined therapy is associated
`\vith a significant reduction in the levels of iron in the
`body, \Vi th no apparent increase in the frequency or
`99·103
`intensity of the side effects of both chelators.50
`•
`The alternate use of both chelators \Vas
`published initially by Aydinok et al., who used a
`\veekly regimen of oral deferiprone, 75 mg/kg for
`four days,
`followed
`by DFO 40-50 mg/kg,
`subcutaneously, for t\VO days, in the treatment of
`seven children \Vith thalassen1ia major. 104 Intravenous
`DFO, 40-50 mg/kg, was added every three-four
`\veeks at the time of the blood transfusions. The
`acceptance of this therapy \Vas excellent and \Vithin
`six months it led to a reduction in the levels of scrum
`ferritin from 5,536 1ng/L to 3,7781ng/L, and of liver
`iron from 26.5 mg/g to 21.1 nig/g. Another clinical
`study compared the efficacy and safety of the
`alternate use of deferiprone, 75 1ng/kg for five days,
`followed by two days of DFO 33 ±6 mg/kg in thirty
`patients, with the use of DFO 38± 9 mg/kg, five to
`seven days per \Veek in another thirty patients during
`one year.80 Both regin1ens \Vere equally effective, and
`the alternate use of the chelators \Vas not associated
`\Vith an increase in the rate of side effects.
`
`Discussion
`A large nun1ber of clinical studies have been
`conducted in recent years to evaluate the safety and
`efficacy of deferiprone as an iron chelation agent.
`The large nun1ber of patients and the longer period of
`intense monitoring of these patients provide a
`detailed and \Veil-documented profile of the safety
`and efficacy of the extended use of deferiprone.
`In the dosage of 75 mg/kg/day, deferiprone
`has been sho\Vn to be effective in stabilizing or
`reducing iron overload in patients subject to chronic
`blood transfusion trcat1nent regimens.
`
`183
`
`revie\v- chelation thcrapy.p65 183
`
`09/25/2003, 2: 19 p.m.
`
`8 of 14
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1064
`
`
`
`Rev. bras. he1natol. He1noter. 2003;25(3):177-188
`
`Fabron Jr. A ct al
`
`Higher dosages, of up to I 00 mg/kg per day of
`deferiprone pro1note higher iron clin1ination and
`should be considered for those patients undergoing a
`heavier transfusion regin1en or those \Vho do not
`respond adequately to a dose of 75 mg/kg/day,
`it
`\Vas demonstrated
`that DFO and
`Recently,
`deferiprone have different capabilities
`for
`the
`chelation and eli1nination of iron in different organs
`of the body, 106
`107 and
`that
`\Vhen adn1inistered
`•
`conco1nitantly, the effect on the excretion of iron is
`additive, or even synergistic, in sonic patients, \vith a
`rapid
`reduction
`in
`the
`body
`iron
`overload. 3<1,so,97,99, 100, 102
`These 1nechanis1ns can include the concon1itant use
`of both chelators to promote a rapid decrease in body
`iron overload, particularly in patients \Vith severe
`iron overload; or the alternate use of the chelators,
`increasing or decreasing the frequency and the dose
`of each chelator according to the organ targeted for
`the reduction of iron overload.
`
`Conclusions
`iron overload secondary to
`Patients \Vith
`\Vho
`respond adequately
`to
`transfusions
`blood
`treatment
`\Vith DFO should be encouraged
`to
`continue \Vith this treatment regime. 1-lo\vever, the
`difficulty in maintaining chelation therapy \Vith DFO
`is \videly recognized.
`Deferiprone has been sho\vn to be a drug
`that presents an efficacy comparable, if not superior,
`to that of subcutaneous DFO infusions, particularly
`in the reduction of heart iron overload. Its use has
`been associated \Vith an i1nprove1nent in the quality
`of life of patients and its side effects are known,
`predictable, reversible and controllable. It is nO\V
`possible to consider tailor-made chelation treatn1ent
`regimens, based on the patients' individual needs.
`
`Abstract
`
`Despite the introduction of t/Je parenteral iron ctwlator
`desferrioxBrnine 1nore tf1an 30 years ago, 5096 of
`patients lVith thalassemia nnyor die before t/Je age of
`35 years, predotninant/y due to lron-induced lleart
`failure. Alt/wugh desferrioxa111ine can reduce or
`stabilize t11e iron load, rnany patients still do not receive
`adequate clwlation rnainly due to its cu1nberso111e
`
`mode of administration Vlhic/J in1pairs the compliance
`with the reginw of repeatedly subcutan12ous infusions.
`For these patient~ the orally active iron c/1eiator
`deferiprone is an attractive alternative to control tlw
`overloaded iron. It has bea1 estin1ated that nlOfe tl1an
`six thousands patients have a/re..."ldybeen tre,1ted l