Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1047
`
`

`
`Amtaéem So<::§i“*r es‘ Cmmt Grzeotooir {AEG}
`
`Mm’ i245? 2%“;
`
`fimxs ?R%‘i~@£E§£@ ~ we
`
`- Reference: Programl Proceedings American Society of Clinical Oncology,
`
`Vol. 20, Part 1 of 2, 2001
`
`Abstract no. 1595
`
`phase I trials, pk and safety, i.v. administration
`
`abstract and poster presentation
`
`CONFIDENTIAL
`
`HELSN0118295
`
`Exh. 1047
`
`

`
`A000
`
`1595
`
`Symptom Management
`
`GENERAL POSTER, SUN, 1:00 PM — 5:00 PM
`
`Pharmacokinetic Features of a Novel 5-HT3-Receptor-Antagonist: Palonose-
`tron (RS—25259~197). G. Plraccinl, R. Stolz, M. Tei, A. Macc/'occlii,-
`He/sinn Healthcare SA, Pa/nb/o~Noranco, Switzerland; GFI Pharmaceuti-
`cals, Evansville, IN,- University of Tokyo, Dep FBP, Tokyo, Japan
`
`Palonosetron is a novel, potent, selective 5—HT3—receptor antagonist with
`high degree of efficacy in animal models (1, 2).
`it acts by blocking a
`cascade of neuronal activation and performs its anti—emetic and anti-
`nausea activity at central and gastrointestinal sites. Therapy with palonose—
`tron is
`intended for patients receiving emetogenic chemotherapy or
`undergoing surgical procedures, who need acute or long-lastinganti—ernetic
`coverage. Two phase I doseascending clinical trials, performed in US and
`Japanese subjects, were aimed at assessing the pharmacokinetic proper-
`ties and the safety profile of palonosetron IV administered in a range of
`dosages from 0.1 to 90 mcg/kg. A third study was conducted on healthy
`volunteers in order to determine the metabolic and pharmacokinetic profile
`of [14C]—palonosetron in plasma and urine. The results of these studies
`indicate that palonosetron is moderately bound to plasma proteins (62%),
`is metabolized at hepatic level (50%), and part is found unchanged in urine
`(42%). A key element of the pharmacokinetic properties of palonosetron is
`a long elimination half~lite (t1/2) of over 40 hours (range 24.0~6-4.2). In
`general, palonosetron showed linear kinetics. The drug was well tolerated,
`no dose—related incidence of adverse events (AE5) and no unexpected or
`serious AEs were recorded. The most common AEs were headache and
`constipation that were generally mild or moderate. These findings in human
`volunteers suggest potential therapeutic benefits in terms of potency and
`longer duration of action with respect to available therapies. References 1.
`Wong E.H.F. et al., BritishJ Pharm, 114:851—~859, 1995. 2. Eglen R.M.
`et al., British J Pharm, 114660-866, 1995.
`
`CON Fl DENTIAL
`
`HELSN0118296
`
`Exh. 1047
`
`

`
`Pharmacokinetic Featur
`
`ABSTRACT
`
`MATERIALS AND METHODS
`
`Palonosetron is a novel, potent, selective 5—HT3-receptor
`antagonist with high degree of efficacy in animal models (I.
`2).
`It acts by blocking a cascade of neuronal activation and
`performs its anti-emetic and anti-nausea activity at central
`and gastrointestinal sites. Therapy with palonosetron is
`intended for patients receiving emetogenic chemotherapy
`or undergoing surgical procedures, who need acute or long-
`lasting anti-emetic coverage. Two phase I dose-ascending
`clinical trials, performed in US and Japanese subjects, were
`aimed at assessing the pharmacokinetic properties and the
`safety profile of palonosetron lV administered in a range of
`dosages from 0.1 to 90 mcg/Kg. A third study was conduct-
`ed on healthy volunteers in order to determine the metabol-
`ic and pharmacokinetic profile of [MC]-palonosetron in plas-
`ma and urine. The results of these studies indicate that
`palonosetron is moderately bound to plasma proteins
`(62%),
`is metabolized at hepatic level (50%), and part is
`found unchanged in urine (42%). A key element of the phar-
`macokinetic properties of palonosetron is a long elimination
`half-life (t 1/2) of over 40 hours (range 24.0-64.2). ln gener-
`al, palonosetron showed linear kinetics. The drug was well
`tolerated, no dose-related incidence of adverse events
`(AEs) and no unexpected or serious AEs were recorded.
`The most common AEs were headache and constipation
`that were generally mild or moderate. These findings in
`human volunteers suggest potential therapeutic benefits in
`terms of potency and longer duration of action with respect
`to available therapies.
`
`INTRODUCTION
`
`Palonosetron hydrochloride is a potent selective 5-HT3-
`receptor antagonist. Palonosetron prevents activation of the
`vomiting reflex by blocking the binding of serotonin to the 5-
`HT3 receptors in a manner similar to that of ondansetron,
`granisetron and dolasetron.
`in pre-clinical studies,
`palonosetron exhibited significant activity in the prevention
`of nausea and vomiting induced by both highly and moder-
`ately emetogenic chemotherapy <12). This positive pre-clin-
`ical activity of palonosetron warranted further investigation.
`
`Paltmosetron Izydroc/zloride
`(3a§-2-[C§]1-zabicycl0[2.2.2]oc1-
`3~yl]-2,3, 351,4, 5, 6-hexahydr0~1-
`oxo-Jfl-bmx] j’Q/isoquirtolirie
`hydrorr/i.[nrI'rle}
`
`M. W:332.87
`
`1 Wong E}-.F. et al,, British J Pharm, 114:851-859, 1995
`2 Eglen R.M. er at, British JPnarm, 114:860-366, 1905
`
`Three phase I studies were performed to assess the safety, tolerat
`pharmacokinetic, metabolic and excretion profile of palonosetron
`the studies were randomized, double-blind, placebo-controlled ,
`formed in healthy volunteers with administration of single ascer
`doses or‘ palonosetron (Study 1 & 2). The third study performed or
`subjects administered l”C]~palonosetron, was carried out in order
`acterize the metabolic profile in plasma and urine, the pharma
`parameters of total radioactivity and the excretion profile of 1
`(Study 3).
`Study 1: 80 male US subjects were randomized (311 ratio) tr
`either study drug or placebo. Palonosetron was administered a
`towing doses: 0.3, 1, 3, 10, 20, 30, 45, 60 and 90 mcg/Kg. Study
`tion was administered by a single 5-minute l.V. infusion.
`
`32 male Japanese subjects were randomized (3:1
`Study 2:
`receive either study drug or placebo. Palonosetron doses were:(
`and 90 mcg/Kg. Study medication was administered by a single SC
`l.V. bolus injection.
`In both trials, the higher dose was administered after assessme
`safety data of the preceding group. Subjects undenrvent physical 9
`tion, ECG and Hotter (study 1) and routine laboratory tests before»
`entering the study. Blood and urine samples were collected forl
`macokinetic analysis before and after dose administration.
`remained in the unit for 72 hrs after dosing and the last control
`performed 1 week later. Adverse events (AEs) were monitored d:
`72 hrs of the study period and any reports otAEs occurring therear
`captured from patient diary entries.
`.
`Among the pharmacokinetic parameters evaluated for palonosetlt:
`N—oxide metabolite (MD), the following are reported in tables 2-4
`plasma half-life (t ‘/2),
`time to maximum observed plasma concentration (Truax).
`maximum observed plasma concentration (CW),
`area under plasma concentration-time curve from 0 to infir
`AUC).
`The following parameters were calculated only for palonosetron:
`— clearance (Cl) and
`e volume of distribution (Vdfl).
`Parent and metabolite identification in urine was made only in the?
`est dose groups in study 1 and on all grot ps in study 2.
`Statistical calculations were done using the SAS procedure PRO-
`Study 3: Three male and three female healthy volunteers were 6
`in an open-label, single—dose, metabolic-disposition study. The
`were administered a single l.V. dose (10 jig/Kg or 0.8 j;Ci/Kg)
`palonosetron. Blooo and urine samples were taken before and E‘
`ing. AEs were collected during the whole observation period (11 r‘
`The following pharmacokinetic parameters were evaluated:
`total
`radioactivity in all blood samples for palonosetroi
`metabolites
`total radioactivity in all urine samples for palonosetron and
`lites
`the metabolic profile in plasma and urine,
`qualitative tests for j3~g|ucuronide and sulfate conjugates in L
`structural characterization of the metabolites in urine.
`The calculated pharmacokinetic parameters were T\'laX» Cmax, t ‘/2,
`plasma ratio for total radioactivity, AUC0-95. AUCC-last, AUCO-cc, \
`t
`‘/2, total radioactivity in urine to last measurable Au (Au (Has
`radioactivity in urine from last measurable Au to infinity (Ar. last t-v
`lative radioactivity (Au 0-) and renal clearance (Cir).
`All adverse events were followed until the overall clinical outcé
`‘ ascertained.
`
`CON Fl DENTIAL
`
`HELSN0118297
`
`Exh. 1047
`
`

`
`ures of a Novel 5-HT3-Receptor-Antagonist: Paloii
`
`Gaia§Piraccinl*, Helsinn Healthcare SA, (Lugano, Swilzerlanil), Randajll Slolz, GFI Pharmaceutical Services, (Evansville, IN r USA);
`netelsulei, School of Medicine, University 01 Tokyo, (Tokyo, Japan); and, Alberto Macciocchi, Helsinn Heallhcare SA, (Lugano, Switzerland)4
`I
`
`Study 1
`N=8O
`
`Study 2
`N=32
`
`Study 3
`N___5
`
`'
`
`Variable
`
`0 3 meg/Kg
`n=6
`
`10 meg/Kg
`n=6
`
`2ty,toIerab1Iity, and
`Jnoselron Two of
`ontrolleol and per-
`gle ascending l V
`rimmed 0" healthy
`“‘ '" °’‘‘‘’' ‘D W"
`3 pharmacokinetic
`rofile of the drug
`
`ratio) to receive
`1
`Esteétiddeii th&afO|-
`9
`U 3 me ma"
`
`ratio) to
`Ized (3 1
`es were 3. 10, 30
`3 S'“9'e 3°'5'3°°"d
`assessment of all
`physical examina-
`.13 before and after
`acted for the pha.-.
`tration
`Subjects
`at control visit was
`mitored during the
`mg fhereafler were
`alonosetron and its
`ables 2-4
`
`23 7
`
`63 3
`
`I71 8
`
`_
`
`,,
`
`T
`
`-
`
`V
`
`AGE
`(years)
`WEIGHT
`K 1
`( g)
`HEIGHT
`(gm)
`
`RACE
`Asian
`Black
`Caucasian
`
`25 5
`
`80
`
`I73 4
`
`-
`
`3 8%
`5 3%
`90 0%
`
`V
`Table I Deinogmphzc data of subjects enrolled in studzes
`1 2 and 3
`
`CMAX (ng/mL)
`Palonosetron
`N-Oxide (M9)
`TMAX (hr)
`Palonosetron
`N‘OXld6 (M9)
`HALF-LIFE (hr)
`Palonosetron
`_
`_
`N-Oxide (M9)
`T0TAL AUG mg hr/mL)
`Palonosetron
`N~0xide (ll/I9)
`CLEARANCE (mL/min/Kg)
`-
`VOLUIVIE OF
`9 85:1 90
`8 81:1 33
`DISTRIBUTION (L/Kg)
`Table 3 Plzarmacolmzerzc data ofpalonosetron and Its metczbolzte (M9)fr
`
`4 53:4 53
`0 0933:0 0545
`0 692:1 62
`42 7167
`
`30 8:9 22
`no
`
`_
`
`15 2:4 50
`n0
`3 50:0 817
`
`7 79:3 31
`0 170:0 0559
`0 016710
`5 6714 33
`
`34113 75
`37 4:19 2
`
`51 2:9 44
`5 70:2 70
`3 37:0 747
`
`Variable
`
`CMAX (ng/mL)
`Palonusetron
`
`0 3 mcg/Kg
`n=6
`
`1 mcg/Kg
`n=6
`
`3 mcg/Kg
`n=6
`
`10 mcg/Kg
`n=l2
`
`20 mcg/Kg
`n=6
`
`30 mcg/Kg
`n=6
`
`0114:0053
`
`0349:0205
`
`0918:0250
`
`353:1/l/I
`
`571:293
`
`115:s7i
`
`45
`
`21
`
`04
`
`N—Oxide(M9)
`Tl1IlA>'(hr)
`Palonosetron
`N—0><ide(M9)TMAX(hr)
`HALF-LIFE (hr)
`Palunoselron
`N Oxide (M9)
`
`0736:100
`0
`
`54 1:36 6
`0
`
`0
`
`T
`
`0
`
`0
`
`0102:00183
`
`015e:00414
`
`0443:0201
`
`0225:1235
`0
`
`00033:000
`0
`
`00903:00241
`357:151_
`
`0550:0732
`500:125
`
`0403:0752
`53s:242__Z_
`
`03
`5
`
`33 7:16 8
`U
`
`47 24:14 7
`D
`
`35 0:8 77
`0
`
`37 01615
`19 6:0 394
`
`37 8:6 60
`19 3:15 4
`
`150:56 1
`10 3:4 47
`390:1a1
`12 0:5 52
`
`(Tm
`
`10to lrlflnily (rota;
`
`”°3e"°“
`
`my in the two high
`lure PROC GLM
`
`’;§y“VeT'§ee‘;<”:‘Jll;*J:*Ci‘g
`0 ).lCl/Kg) of [I40]
`We and 3719" CI05
`fggd (11 days)
`I°n°5e“'0“ and/°I'
`eiron and metabo
`
`Jgaies in urine and
`me
`31.1» 11/2 blood to
`LUCO-m Vdu urine
`(Al, 0-last t)
`total
`A0 last 1-co) curiiu
`iical outcome was
`
`__
`
`5 80:3 46
`0
`4311:0652
`3 8510 645
`
`L
`
`9 35:2 59
`0
`159:0455
`,
`5 31:2 35
`
`__
`
`TOTAL AUC (rig hr/ml)
`Palonoselrori
`N-Oxide rivi9)
`CLEARANCE
`ImU”1l“/K9)
`VOLUME 01:
`DISTRIBUTION (L/Kg)
`Table 2 1’/mrmacokznelzc dam qfpalonosetrmi and 77s m.etaZ;i0Iz2‘2 (M9) from subjects of study I (mean ::SD)
`
`29 8:9 02
`0
`15120 547
`6 88:0 374
`
`__
`
`65 7:14 5
`0
`2135:0005
`,
`7 83:1 81
`
`,,
`
`1531441
`5 51:1 29
`2s0:07e5
`727:1 19
`
`Study 1 Palonosetron Plasma Concentrations
`
`Smdy 2 Pa'°“°39‘“'°I" PI55"“a C°”°5““’a“°“5
`
`/
`
`1:‘;
`
`I
`
`Time (hrs)
`
`1
`
`;
`
`4:
`
`Cl 3 meg/mt
`-1 mcg/ml.
`3 mcg/mL
`1D rricg/mL
`—2D ircg/i'iL I
`—C«D meg/mL I
`«:45 rrcg/ml.
`--60 rrcg/ml.
`90 rrcg/ml. 1
`
`' "
`‘I0 meg/ml.;
`i — 30 meg/rr1L
`90 mtg/mL
`
`CONFIDENTIAL
`
`HELSN0118298
`
`Exh. 1047
`
`

`
`30 mcg/Kg
`n=6
`
`23.31323
`0.31910.115
`
`013110.134
`3.3412.06
`
`31.31355
`24312.30
`
`208168.13
`11,112.54
`2.5810667
`
`6.9511.75
`
`90 mcg/Kg
`n=6
`
`52.61367
`077710.137
`
`0.0s9410.0452
`23311.33
`
`3618:4172
`3413.15
`
`5611129
`33.31505
`
`2.fi7810.549W
`
`8.7011.24
`
`halite (M9) from subjects of study 2 (mean :SD)
`
`45 mcg/Kg
`n=6
`
`60 meg/Kg
`n=6
`
`90 meg/Kg
`n=6
`
`g/Kg
`5
`
`»8.71
`
`26.0123.7
`
`17,114.37
`
`0201
`
`046910.274
`
`052510.206’
`
`0.782
`
`033310.573
`
`008331000
`
`2.42
`
`6.60
`
`5. 114.01
`
`41,217.33
`54.31508
`
`3._4212.25
`
`41 .819.55
`39.6117]
`
`3431137
`‘ 23.3122
`2.3910717
`
`3701701
`20-411.63
`27810488
`
`23913.87
`070310.143
`
`1_40,3_23
`46712.42
`
`40,216.63
`33.31977
`
`7501271
`
`2517.04
`2.1710578
`
`0.327
`0.012
`
`0537
`0.366
`
`0287
`0.265
`
`<0.001
`
`0.441
`<0.001
`
`Variable
`
`CMF0( (09/mL1
`Males
`Females
`All
`HALF-LIFE (hr)
`
`mfges
`A"
`CLEARANCE (mljmin/Kg)
`Males
`Females
`All
`
`3.941056
`23310.38
`3.131038
`
`28315.5
`46.01159
`37.41142
`
`100132
`140129
`160135
`
`TMAX (HR)
`Males
`?emales
`All
`TOTAL AUC (ng.hr/mL)
`Males
`Females
`All
`
`0.083310.00
`008331000
`008331000
`
`555”-3
`73.31134
`65113.8
`
`VOLUME or D|STRlBUT|ON (L/Kg)
`Males
`7.661237
`Females
`90212.33
`All
`33412.45
`
`Table 4. Plrcirmacokirzetic damfivm healthy volunteers ofsmdy 3 (mean 15D)
`
`ADVERSE EVENT
`
`Constipatmn
`Headache
`Vasodilatation
`Contact Dermatitis
`Sinusitis
`SGOT inc
`Diarrhea
`SGPT inc
`
`PLAC EBO
`N=23
`0.0%
`28.6%
`3.6%
`7.1%
`3.6%
`7.1%
`10.7%
`25.0%
`
`PALONOSETRON PALONOSETHON
`N=90
`MINUS PLACEBO
`11.1%
`11.1%
`34.4%
`5.9%
`7.8%
`4.2%
`11.1%
`4.0%
`5.6%
`2.0%
`6.7%
`0.5%
`6.7%
`-4.0%
`18.9%
`-6.1%
`
`Table 5. Incidclrcc Rate 0fMosI Common Adverse Events in Studies I, Z and 3
`
`DISCUSSION AND CONCLUSIONS
`The demonstration of pre-clinical activity by palonosetron warranted further elu-
`cidation oi the characteristics of the drug, including pharmaookinetics. The three
`studies reported here have identified at least one attribute of palonosetron, a
`long half—life, that has the potential to provide additional clinical valuetor patients
`receiving emetogenic cheniotherapy.
`Plasma concentrations of palonosetron after infusion were measurable at all
`dose levels in all studies.
`in both studies 1 and 2, t 1/2 was higher than 30 hours
`at all tested doses.
`in study 1. Cflax ranged from 0.114 to 26.0 nglmL. The plasma concentrations of
`. palonosetron generally increased with increase of dose, although a lull dose-
`proportionality could not be demonstrated in this study. No increasing or
`decreasing trend in clearance or volume of distribution was seen with increases
`of dose.
`In study 2 the pharmacoklnetics of the drug was dose-proportional over the test-
`ed range (3-9O mcg/Kg) with Crnax ranging from 4.68 to 52.8 ng/mL.
`Study 3 confirmed the long ha|f»lite of the drug (37 hrs), the distribution profile
`Into tissues, with an extensive distribution and a low hepatic transformation.
`Binding to plasma proteins was about 52%. The major route of excretion was
`urine, and the most important metabolite was the N—oxide of palonoselron.
`Palonosetron was well tolerated during the course of all the studies, with no seri-
`ous or unexpected adverse events (AEs). The most frequent reported AEs were
`constipation and headache. All reported AEs were transient, of mild or moderate
`intensity, and did not require treatment. No dose-related increase in the inci-
`dence or severity of AEs was seen. ECG and Hotter data for all subjects were
`normal.
`Therefore, the first data from phase 1 trials with |.V. palonosetron indicate a phar-
`macokinetic protile not similar to the currently available 5-HTS-receptor antago-
`nists. The clinical value of the evidenced long hal1—life, which may extend the
`duration of action of a single dose, will be iurthei‘ studied In Phase it and Phase
`
`[ill clmical trials.
`
`072311.00
`
`9.7811 .17
`
`7.501225
`
`720.001 7
`
`Study3 Palonosetron Plasma Concentrations
`
`1
`
`mcg/mL
`
`
`
`concentration(ng/mL)
`
`CONFIDENTIAL
`
`HELSN0118299
`
`Exh. 1047