`1 of 30
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1022
`
`

`

`THE PEDIATRIC
`CLINICS OF
`NORTH AMERICA
`
`New Frontiers in Pediatric Drug
`Therapy
`
`BENOIT BAILEY, MD, MSc, FRCPC, and
`GIDEON KOREN, MD, ABMT, FRCPC, GUEST EDITORS
`
`VOLUME 44
`
`•
`
`NUMBER 1
`
`•
`
`FEBRUARY 1997
`
`W.B. SAUNDERS COMPANY
`A Division of Harcourt Brace & Company
`PHILADELPHIA
`LONOON
`TORONTO MONTREAL SYDNEY
`
`TOKYO
`
`
`2 of 30
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1022
`
`

`

`W.B. SAU DERS COMPA Y
`I\ Vn•isio11 of Hnrco11rl Brace & Co111pn11y
`
`The Curtis Center • Independence Square West • Ph1ladl'lphi.i, Penn.'>yhama 19106
`
`T H E PED IATRIC C LINICS OF O RT H A MERICA
`February 1997
`Edi tor: Carin Baniewicz
`
`Volume 44, umb er 1
`ISSN 0031- 3955
`Production Editor: Carrie Schaller
`
`Copyrigh t © 1997 by W. B. Saunders Company. All rights reserved No part or this
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`each drug to be administe red to \•erif} the dosage, the method and duration of administra(cid:173)
`tion, or contraindications. It is the responsibility of the tre,1ting physician or o ther health
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`
`Printed in the United States of America
`
`
`3 of 30
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1022
`
`

`

`l
`
`NEW FRONTIERS IN PEDIATRIC DRUG THERAPY
`
`GUEST EDITORS
`
`BEN OIT BAILEY, MD, MSc, FRCPC, Fellow, Division of Clinical Pharmacology and
`Toxicology, Department of Pediatrics, The Hospital for Sick Child ren, Toronto,
`Ontario, Canada
`
`GID EON KOREN, MD, ABMT, FRCPC, Professor, Division of Clinical Pharmacology
`and Toxicology, Department of Pediatrics, and Research Institute, The Hospital for
`Sick Child ren; and the Departments of Pediatrics, Pharmacology, and Medicine,
`University of Toronto, Toronto, Ontario, Canada
`
`CONTRIBUTORS
`
`MICHAEL R. ANDERSON, MD, Fellow, Division of Pediatric Critical Care, Department
`of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies
`and Childrens Hospital, Cleveland, Ohio
`
`BENOIT BAILEY, MD, MSc, FRCPC, Fellow, Division of Clinical Pharmacology and
`Toxicology, Department of Pediatrics, The Hospital for Sick Children, Toronto,
`Onta rio, Canada
`
`JEFFREY L. BLUMER, PhD, MD, Professor, Departments of Pediatrics and
`Pharmacology, Case Western Reserve University School of Medicine; and Chief,
`Division of Pediatric Pharmacology and Critical Care, Department of Pediatrics,
`Rainbow Babies and Childrens Hospital, Cleveland, Ohio
`
`SYLVAIN CH EMTOB, MD, PhD, Departments of Pediatrics, Ophthalmology, and
`Pharmacology, Research Center of Hopital Sainte-Justine, University of Montreal,
`Montreal, Quebec, Canada
`
`ORNA DIAV-CITRIN, MD, Fellow, Division of Clinical Pharmacology and Toxicology,
`Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
`
`THO MAS W. FERKOL, MD, Assistant Professor, Division of Pediatric Pulmonology,
`Department of Pediatrics, Case Western Reserve University School of Medicine,
`Rainbow Babies and Childrens Hospital, Cleveland, Ohio
`
`TERENCE R. FLOTTE, MD, Assistant Professor, Department of Pediatrics, and Assistant
`Professor, Department of Molecular Genetics and Microbiology, and Co-Director,
`Gene Therapy Center, University of Florida School of Medicine, Gainesville, Florida
`
`iii
`
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`4 of 30
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`Exhibit 1022
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`NEW FROt\TIERS IN PEDIATRIC DRUG THERAPY
`
`0031-3955/97 $0.00 + .20
`
`ORAL IRON CHELATION
`WITH DEFERIPRONE
`
`Oma Diav-Citrin, MD, and Gideon Koren, MD, ABMT, FRCPC
`
`Patients with refractory anemias, such as tha lassemia major, who require
`regular red blood cell transfusions progressively accumulate iron. Each unit of
`red blood cells contains 200 to 250 mg of elemental iron and thus, patients on
`chronic transfusion programs accumulate approximately 0.5 mg/ kg/day of iron.
`Tissue iron accumulation results in progressive organ dysfunction, leading to
`death if no iron-chelating therapy is initiated. Although transfusions sustain
`normal growth and development and improve the life expectancy of patients,
`they are complicated by the harmful consequences of iron overload because
`humans lack a physiologic mechanism for excreting excess iron.
`Lron-chelating therapy for the management of transfus iona l iron overload
`was first introduced in the early 1960s.'"· ~1 • 63• 7• It is only since 1974, after the
`demonstration that it was possible to reduce the concentration of hepatic iron
`and arrest the progression of hepatic fibrosis in thalassemic patients with its
`long-term use, 1• that desferrioxamine gained acceptance as the standard form of
`therapy. Unfortunately, desferrioxamine is only effective when administered
`parenterally. Subcutaneous doses of 20 to 40 mg/kg/day for 8 to 12 hours
`resulted in iron excretion sufficient to produce a negative iron balance.37· '111
`Over the pilst two decades, several studies have demonstrated that regular
`desferrioxamine therapy ameliorntes hepatic, cardiac, and endocrine dysfunc(cid:173)
`tion, improves growth and sexual maturation, and prolongs survival in iron(cid:173)
`loaded patients.1u 1
`Because of its high cost (approximately $40 US/2 g vial), desferrioxamine
`is not available in many countries where it is most needed. Even where it is
`available, many patients fail to comply with a regimen of prolonged subcutane(cid:173)
`ous infusions, especially during adolescence. Other problems with desferrioxa(cid:173)
`rnine therapy include its serious adverse effects. Intensive therapy in young
`
`This work was s upported by an MRC-lndustry grant and by Apotex, Inc, Toronto.
`
`From the Division of Clinical Pharmacology and Toxicology, Department of Pediatrics
`(ODC, GK), and Research Institute (GK), The Hospital for Sick Children; and the
`Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto, To(cid:173)
`ronto, Ontario, Canada
`
`PEDIATRIC CLINICS OF NORTH AMERICA
`
`VOLUME 44 • NUMBFR 1 • FEBRUARY 1997
`
`235
`
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`236
`
`OIAV-CITRIN & KOREN
`
`Figure 1. Chemical structure of desferrioxamine.
`
`patients with low body-iron stores may result in serious neurotoxicity (audi(cid:173)
`tory and visual), abnormalities of cartilage formation, and stunted linear
`growth.5s-5!o. M
`ln the last decade we have witnessed the emergence of interest in oral
`iron chelation for transfusional iron-loaded patients in thalassemia and other
`refractory anemias. Currently, the orally active iron chelator with the broadest
`cUnical experience is deferiprone (l,2-dimethyl-3-hyd roxypyrid-4-one, or L1).
`The agent is a member of the hydroxypyridones of bidentate (two binding sites)
`iron chelators patented by Hider et al33 in 1982 as an alternative to desferrioxa(cid:173)
`mine in the treatment of chronic iron overload.
`This article summarizes the experience with this new, orally active iron
`chelator, deferiprone. In addition, it reviews novel uses of iron chelation and
`potential new applications in acute iron poisoning.
`
`STRUCTURAL COMPARISON BETWEEN
`DESFERRIOXAMINE AND DEFERIPRONE
`
`Desferrioxamine (Fig. 1), a trihydroxamate siderophore derived from Strep(cid:173)
`tomyces pilosus, is a hexadentate chelator.30 It is capable of combining with
`ferric iron at a 1:1 molar ratio because of its six binding sites with a high stability
`constant (Hl31). The desferrioxamine molecule is wrapped around the iron nu(cid:173)
`cleus, encasing it in an envelope of organic material. Because of its high molecu(cid:173)
`lar weight, desferrioxamine is poorly absorbed from the gastrointestinal tract,
`and is therefore administered parenterally.
`Deferiprone (Fig. 2) is a bidentate ligand. Therefore, three chelator molecules
`are required to form a neutral complex with a single iron a tom.
`The hexadentate chelators are inherently more stable kinetically than biden(cid:173)
`tate chelators. The greater stability of the hexadentate molecules minimizes the
`risk of iron redistribution or the participation of unstable iron-chelate complexes
`
`Figure 2. Chemical structure of deferiprone.
`
`
`6 of 30
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`

`ORAL IROl\ CHELATION WITH DEFERlPRONE
`
`237
`
`in the generation of harmful free radicals; they also have the ability to scavenge
`iron at low concentrations. On the other hand, bidentate compounds have a
`lower molecular weight and are usually easily absorbed from the gut. Because
`of this, however, they are able to penetrate other cells more quickly with the
`potential risk of cellular toxicity resulting from their interaction with iron(cid:173)
`requiring enzymes.65
`
`ORAL IRON CHELATION WITH DEFERIPRONE
`
`Chemistry and Pharmacology of Deferiprone
`
`Deferiprone is a white solid compound with a molecular weight of 139
`kD.44 It is water-soluble with a partition coefficient (K part, the ratio of the
`concentrations of the compound between an organic phase and water at a pH
`of 7.4) close to one.67 Deferiprone is highly stable at pH values ranging from 1
`to 1244 and it is resistant to cleavage by digestive enzymes.67 It generally forms
`a 1:3 complex with iron with a stability constant of 36.4° At low concentrations
`of chelator, however, partially dissociated deferiprone-iron complexes (2:1, 1:1)
`can form and may, in turn, generate hydroxyl radicals.67 Deferiprone binds ferric
`iron with a high affinity (binding constant log J3 = 37).
`Deferiprone is rapidly absorbed from the upper part of the gastrointestinal
`tract. Jt is excreted in the urine mostly as a glucuronide or unchanged, bound
`to iron or bound to trace metals such as zinc and aluminum.<• Glucuronidation
`abolishes the ability of deferiprone to chelate iron, because the hydroxyl group
`of deferiprone needed for iron binding is involved in the conjugation. The
`excretion of deferiprone-glucuronide is slower than that of free deferiprone. In
`patients with impaired renal function, the glucuronide derivative may accumu(cid:173)
`late in the plasma.q The pharmacokinetic characteristics of deferiprone are sum(cid:173)
`marized in Table 1.
`The efficacy of the drug in heavily iron-loaded patients, assessed by the
`amount of the drug excreted in urine bound to iron in 24 hours compared with
`the size of a single oral dose, has been estimated to be approximately 4%.9 The
`urinary iron excretion in heavily iron-loaded patients following a single dose is
`related to the area under the concentration-time curve for plasma deferiprone.
`Whether deferiprone is excreted in the stools and whether or not it increases
`fecal iron excretion in humans remain controversial. There are reports of iron
`excretion in the stool of iron-loaded patients following oral administration of
`deferiprone amounting to up to 30% of the total iron excreted.23•57 Another study9
`indirectly suggested that approximately 20% of an oral dose of deferiprone may
`be excreted in the stools. Kontoghiorghes et al,44 however, reported no increase
`
`Table 1. A SUMMARY OF DEFERIPRONE PHARMACOKINETICS
`
`Study
`
`Dose
`
`No. of
`Patients
`
`t'h..
`(minutes)
`
`Cmax
`(11g/ml )
`
`t'h,,
`(minutes)
`
`AUC
`(11g•minute/ml)
`
`Kontoghiorghes 3000 mg
`et al"
`Matsui et a1••
`25 mgll<g
`AJ-Refaie et al• 50 mgll<g
`
`7
`
`14
`24
`
`7.1 :!: 11.3
`
`NA
`
`74.3 :!: 28.7
`
`NA
`
`NA
`17.49 :!: 2.08
`22.2 :t 17.7 20.1 :!: 11 .5
`
`159.6 :!: 20.5
`91 .1 :t 33.1
`
`1635 :!: 174.97
`3020 :t 1199
`
`t'h e half·lite. " s absorption: II e elimination: Cmax - maximum concentration: AUG = area under the plasma
`serum concentrabon·bme CtJrve lrom time zero to inlinity; NA - not available
`
`
`7 of 30
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`

`238
`
`DIAV-CITRll'\ & KORF.>'J
`
`in iron excretion and no evidence of deferiprone in the stools of two patients
`with iron overload given deferiprone.
`Several factors may influence deferiprone pharrnacokinetics and efficacy.
`Food prolongs the rate of absorption of deieriprone but it does not signifi(cid:173)
`cantly affect the extent of absorption measured by the area under the plasma
`concentration-time curve. Thus, food docs not change the chelation capacity of
`the drug.~q
`Vitamin C was found to have no effect on urinary iron excretion in two
`small trials.72 The exact effect of vitamin C therapy, however, both in vitamin C
`replete and deficient patients is yet to be determined.
`No increase in the urinary iron excretion was found in two normal volun(cid:173)
`teers when deferiprone complexed to iron was administered oral ly.' 7
`There has been some evidence tha t long-term treatment with defcriprone
`may be associated with a fall in the defcriprone trough concentrations.'" The
`findings suggest self-induction of deferiprone metabolism or decreased absorp(cid:173)
`tion during long-term therapy. The former is supported by the results of an in
`vitro study that has shown that deferiprone induces its own metabolism by
`human hepa tocytes in culture. 5i
`The sites from which defcriprone chelates iron are not fully established.
`Anima l studies have shown that deferiprone concentrates main ly in the liver.'-'
`Because free deferiprone readily enters cells, it is likely that both parenchymal
`and reticuloendolhelial cells are sources of chelated iron. Unlike desferrioxa(cid:173)
`mine, deferiprone can also chelate iron from transferrin•· 27 and, based on studies
`of iron-loaded patients, it is estimated that up to 20% of iron excreted in the
`uri ne following a single oral dose may be derived from iron bound to trans(cid:173)
`ferrin.q Deferiprone also chelates iron from intact red cells that may be important
`in the therapeutic response to dcfcripronc in thalassernia intermcdia.71
`
`Clinical Trials of Deferiprone
`
`•
`
`12
`
`The results of the fi rst clinical studies on the efficacy of deferiprone in
`patients with myelodysplasia and thalassernia major were reported in 1987. 11
`They showed tha t deferiprone could induce urinary iron excretion comparable
`to that achieved with desferrioxamine. Iron excretion correlated to the iron
`burden. Subsequent short-term clinical trials have confirmed those preliminary
`fin di ngs.~· n Dose-response studies have shown that 75 mg/kg body weight was
`the minimal daily dose required to achieve a negative iron balance (> 0.5 mg/
`kg/ day) in most patients with thalassemia major.57 These findings, confirmed in
`a later comparison study between deferipronc and desferrioxam ine~' in sickle(cid:173)
`cell d isease, provide evidence that short-term efficacy of defcriprone is inferior
`to that of desfcrrioxamine. Long-term trials of deferiprone have shown long(cid:173)
`term effectiveness of deferiprone in the majority of patients with transfusional
`iron overload.'· 17 43• ><. n These studies have a lso provided information on a
`n umber of adverse effects that were not apparent in the initial short-term trials.
`
`Changes in Serum Ferritin Concentrations
`
`Significant decreases in serum fcrritin were reported in most of the long(cid:173)
`term clinical studies~· 51160 but not in all of them.2u 3.n Those trials were d ifferent
`in their design in many aspects: the duration of deferiprone treatment before
`repeated scrum ferritin assays were conducted; different adm inistered doses of
`
`
`8 of 30
`
`Taro Pharmaceuticals, Ltd.
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`
`

`

`ORAL IRON Cl IF.LA TlON WIT!-! DF.FF.Rll'RONE
`
`239
`
`deferiprone; the number of patients entering the studies after being poorly
`compliant with desferrioxamine and, thus, starting with high serum ferritin
`levels; and the degree of compliance with deferiprone therapy. One prospective
`trial>i showed a reduction in the mean serum ferritin level from approximately
`4000 µ.g/L to approximately 2500 µ.g/L, whereas in all patients with initial
`ferritin levels below 2500 µ.g/L there was no change. This may suggest that
`deferiprone can reduce serum ferritin to the range associated with cardiac
`disease-free survival in desferrioxamine-treated patients or maintain it in that
`range.22
`Reduction in serum ferritin concentration suggests a decline in body iron
`burden d uring long-term oral chelation with deferiprone. Serum ferritin levels
`may be misleading in the assessment of iron burden in individua l patients,21
`however, because serum ferritin is a lso influenced by other factors such as
`hemolysis, ineffective erythropoiesis, vitamin C deficiency, inflammation, and
`liver disease, all of which are common in iron-loaded patients.
`
`Changes in Hepatic Iron Concentration
`
`Initial evidence that therapy with deferiprone may reduce tissue iron stores
`was provided by a study of an iron-loaded patient with thalassernia intermedia
`in whom stores were reduced to normal over a period of 9 months.-w
`This was subsequently followed by a report of a significant decrease in
`hepatic iron concentrations in heavily iron-loaded, previously poorly chelated
`patients.~ The patients in that cohort were given deferiprone therapy at a dose
`of 75 mg/kg/day for a mean of 3.1 ± 0.3 years. in 10 patients in whom previous
`chelation therapy with desferrioxamine had been ineffective, initial hepatic iron
`concentrations decreased from a mean of 125.3 :!: 11.5 to 60.3 :!: 9.6 µ.mol/g
`wet weight (P < 0.005). Jn the remaining 11 patients, previously effectively
`chelated and with initial liver iron less than 80 µ.mol/g wet weight, the liver
`iron remained below this level. Hepatic iron concentrations below 80 µ.mol/g
`wet weight are associated with prolonged survival free of clinical complications
`from iron overload in thalassemia patients treated with desferrioxamine.22
`
`Improvement in Organ Function
`
`Lightening of skin color occurring within a few months of initiating chela(cid:173)
`tion with deferiprone was observed in heavily pigmented, previously inade(cid:173)
`quately chelated patients.J. 1~
`Improvement in cardiac function assessed by radionuclide angiography was
`observed in one patient with an established iron-related cardiomyopathy. This
`was associated over a 1-year period of study with a decrease in cardiac iron
`measured by MR imaging.;.i Jn the prospective study of deferiprone in 21
`patients with thalassemia,si a reduction in card iac stores has been observed 53 by
`cardiac MR imaging eva luation. ln other studiesJ~ no overall change in cardiac
`function assessed by multiple gated acquisition (MUGA) scanning occurred
`among 31 patients treated for a year (Al-Refaie et al, unpublished data). Because
`the leading cause of death in iron-loaded patients2' is cardiac iron loading, the
`ability to prevent and reverse cardiac iron loading is crucial for any iron chelator.
`In two patients with thalassemia treated with deferiprone, changes consis(cid:173)
`tent with the reduction of anterior pituitary iron were demonstrated by MR
`imaging.53
`
`
`9 of 30
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`

`

`240
`
`DIA V-CITRL'J & KOREN
`
`Progressive decline in serum aspartate aminotransferase level has been
`reported in some patients d uring long-term deferiprone treatment. 1·•.n
`
`Changes in Non-Transferrin Bound Iron
`
`Non-transferrin bound iron (NTBI) is a form of iron present in the serum
`of heavily iron-loaded patients.30 It is believed to be involved in free-radical
`formation and hence tissue toxicity.31 The concentration of NTBI has been found
`to correlate with the degree of organ damage in thalassemia major. Serum NTBI
`dropped significantly after 6 months of deferiprone therapy. TB! was sug(cid:173)
`gested as an independent parameter to measure the effectiveness of chelation.'°
`
`Adverse Effects
`
`Deferiprone is generally well tolerated with no significant acute toxic effects
`at doses up to 150 mg/kg daily. Excellent compliance with the treatment has
`been reported in most patients.54
`62 There have been several reports of side
`•
`effects, however, the most important of which are agranu locytosis and arthropa(cid:173)
`thy.
`
`Neutropenia and Agranulocytosis
`
`The first reported toxic effect of deferiprone was agranulocytosis in a
`woman with Blackfan-Diamond anemia.36 To date, there have been 13 patients
`in whom neutropenia or agranulocytosis has been reported (11 of whom had
`neutrophil counts of 0.5 x 10• /Lor less at the time of diagnosis).2· 11 n 2'1." The
`overall incidence of agranulocytosis has been estimated at approximately 2% of
`long-term treated patients. 13 Agranulocytosis has been observed as early as 6
`weeks, and up to 21 months, after initiating therapy with deferiprone. The
`periods of neutropenia and of total agranulocytosis have ranged from 7 to 124
`days and up to 7 weeks, respectively. Three patients have received at least one
`course of granulocyte colony-stimulating factor during their course of neutro(cid:173)
`penia:i.; in an attempt to accelerate recovery. The dose of deferiprone in these
`patients has ranged from 50 to 105 mg/kg. The patients suffered from thalas(cid:173)
`semia major, Blackfan-Diamond anemia, and myelodysplasia. Females tended
`to predominate (9/13) and, in general, the patients have been heavily iron(cid:173)
`loaded. Rechallenge has invariably led to a second episode of neutropcnia and
`should be avoided.
`The mechanism for the neutropenia or agranulocytosis associa ted with
`deferiprone administration remains obscure. 12- 13 It seems most likely that the
`patients affected have an idiosyncratic sensitivity to a toxic effect of deferiprone
`or one of its metabolites. Deferiprone-associated neutropenia or agranulocytosis
`appears to be fully reversible to date.
`
`Arthropathy
`
`The second most important adverse effect and the most common clinical
`problem associated with deferiprone treatment is joint toxicity, first described
`by Bartlett et al.1' Studies have reported an incidence in up to 38°0 of patients.'
`14 The reported incidence of arthropathy from the International Collaborative
`3• 14•
`
`
`10 of 30
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`Exhibit 1022
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`

`

`ORAL IRON CHELATION WITH OEFl:.RIPRONE
`
`241
`
`Study Group, however, was 21 %.• The arthropathy or lesser degree of joint pain
`may occur within a few weeks after initiation of therapy with deferiprone. The
`syndrome consists of musculoskeletal stiffness, joint pain, and, in severe cases,
`joint effusions. The large joints are primarily affected. In the Indian trial, the
`incidence was greatest in the most iron-loaded patients receiving the largest
`dose of the drug (100 mg/kg/day).1' In most patients, the symptoms and
`signs resolved spontaneously on discontinuation of the drug or following dose
`reduction. In a minority of patients who developed severe arthropathy the drug
`had to be permanently discontinued. Arthroscopy in seven affected patients in
`Bombay revealed excess iron in the synovium, cartilage, and joint fluid but no
`deferiprone, implying that iron may be involved in the cause of the problem.•
`In the Canadian study, aspiration of synoviaJ fluid in three patients revealed a
`sterile transudate without inflammatory celJs; arthroscopy showed mild synovial
`hypertrophy and hyperplasia with iron staining; and synovial biopsy revealed
`lining-cell proliferation and extensive iron deposition without evidence of an
`inflammatory or allergic react1on. 1q In two patients, symptoms resolved d uring
`continued drug administration whereas the third has continued therapy without
`worsening of the symptoms.'~
`The cause of the deferiprone-associated arthropathy is still not fully known.
`The arthritis seems to be due to a toxic effect of deferiprone, possibly mediated
`by free radicals, caused by formation of 1:1 or 1:2 deferiprone-iron complexes
`rather than the usual inert 1:3 complexes. It has been hypothesized that as iron
`is shifted into the synovium and incompletely complexed with deferiprone,
`increased production of free radicals may result in the peroxidation of synovial
`membranes. No relation to the presence of antinuclear factor antibody, rheuma(cid:173)
`toid factor, antihistone antibody, or antiDNA antibody in the patient's plasma
`before or during deferiprone treatment has been consistently detected. The
`overall incidence of a positive rheumatoid factor test in patients with deferiprone
`long-term treatment has been estimated to increase from 13.9% to 16.2% and the
`incidence of antinuclear factor from 9.8% to 11.9%; minor fluctuations in the
`titer of these antibodies were observed.7· ~
`
`Other Adverse Effects Reported with Deferiprone
`
`A decrease in the concentration of zinc in plasma and increased urinary
`zinc excretion in patients receiving long-term deferiprone therapy were first
`reported by Al-Refaie et al. 14 In 8 of 10 patients on deferiprone treatment,
`increased urinary zinc excretion was found associated with a decrease in the
`serum zinc concentration to subnormal levels in four patients. One patient
`developed dry, scaling skin lesions tha t were ascribed to zinc deficiency and
`responded to zinc therapy. A few cases with zinc depletion have been reported
`by others.•· ici. 33 Al-Refaie et all~ have shown that deferiprone causes increased
`urinary zinc excretion, particularly in patients with diabetes meUitus and to a
`lesser extent in patients with glucose intolerance. Decreased serum zinc levels
`were found in 7 of 39 patients treated with deferiprone for at least 6 months. In
`other studies no changes in serum zinc status have been reported. The observed
`difference may be partly due to the absence of diabetic patients from some trial
`groups. Serum zinc estimation has limited value in assessing zinc deficiency.
`Patients with normal zinc concentrations may be zinc deficient and subnormal
`
`serum zinc is only suggestive of zinc deficiency. 1"' The reported incidence of
`zinc deficiency from the International Collaborative Study Group was 14'Yo.1'
`
`
`11 of 30
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1022
`
`

`

`242
`
`DIAV-CrrRIN & KOREN
`
`Zinc deficiency is not a major adverse effect of deferiprone therapy. It can be
`readily detected and easily treated.
`Gastrointestinal symptoms have been reported with deferiprone therapy.
`· " · 14 '~ In some patients the
`Symptoms include anorexia, nausea, and vomiting.1
`gastrointestinal symptoms were a cause of discontinuing therapy. The reported
`incidence of nausea from the International Collaborative Study Group on oral
`iron chelation was 8% of patients.•
`Fluctuations in liver function during dcferiprone treatment were first re(cid:173)
`ported by Barllctt.17 Elevated liver function tests <1ppeared to be more frequent
`in patients infected with hepatitis C. In all cases the ra ised serum transaminase
`levels gradually settled to pretreatment levels or lower after 3 months of therapy.
`More recently, the incidence of abnormal liver er1zymes, defined as an increase
`of more than twice the upper limit of normal serum alanine aminotransferase
`(ALT) at any time during the observation period, was SO of 84 patients (60%) in
`combined data from four centers.0 Nine of the SO had hepatitis C and three had
`raised scrum ALr before initiating defcriprone therapy. ln 37 of the remaining
`38, liver abnormalities were mild and transient, resolving spontaneously without
`reducing or discontinuing defcriprone therapy. In one patient abnormal liver
`enzymes were considered to be related to defcriprone and they fell to pre(cid:173)
`dcfcriprone levels on cessation of deferiprone therapy.
`
`ACUTE IRON POISONING
`
`iron intoxication remains a common and serious form of accidental poison(cid:173)
`ing, especially in children. Recently, there has been an increased number of
`reported iron intoxications;~ as well as increa!>ed mortality related to acute iron
`poisoning.~'
`Dcsfcrrioxamine has been used as a potent chclator in the context of acute
`iron poisoning . ..,· 71 It is currently the most effective agent in eliminating excess
`iron after its absorption.~• Dcsfcrrioxaminc, however, is limited to use in coun(cid:173)
`tries that can afford it. For use in the treatment of acute iron poisoning, it is
`further limited to use in a hospital setting. Defcriprone may have a potential
`use in the treatment of acute iron intoxication in remote areas, far away from a
`medical center, as well as in countries where dcsfcrrioxamine is unavailable.
`Deferiprone was shown to be efficacious in the treatment of acute iron intoxica(cid:173)
`tion in an animal model.28
`Desfcrrioxamine has been reported to have adverse effects, such as hypoten(cid:173)
`sion in the context of acute iron intoxication. Desfcrrioxamine covillcntly
`attached to high- molecular weight carbohydrates s uch as dcxtran and hydroxy(cid:173)
`ethyl starch prevented the decrease in blood pressure that may occur with large
`desferrioxamine doses in experimental animals.•1 It was generally less toxic than
`the free desferrioxamine when given intravenously.
`
`NOVEL USES OF IRON CHELATION
`
`Protection from acute and chronic iron toxicity is only one aspect of the
`clinical potential of iron chelation therapy. 1 here are three categories of diseases
`unrelated to iron toxicity in which chelation therapy may be considered poten(cid:173)
`tially useful by interfering with iron dependent reactions.
`
`
`12 of 30
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1022
`
`

`

`ORAL IRON Cl IELA rlOI\ WITH DEfERIPRO'JE
`
`243
`
`Diseases in Which Iron May Be Essential for the Production
`of Free Radicals Involved in Tissue Damage
`
`The number of diseases known to be associated with oxygen radical damage
`in which treatment with iron chelators may be beneficial is increasing each year.
`The diseases