AASLD
`61th Annual Meeting of the American
`Association for the Study of Liver Diseases
`Boston, MA, Hynes Convention Center
`October 30-November 3, 2010
`
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`Back
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`High Rapid Virologic Response (RVR) with PSI-7977 Daily Dosing plus PEG-IFN/RBV in a
`28-day Phase 2a Trial
`
`
`
`
`Reported by Jules Levin
`AASLD Nov 1 2010 Boston
`
`Lawitz E1, Lalezari J2, Rodriguez-Torres M3, Kowdley KV4, Nelson DR5, DeJesus E6, McHutchison JG7,
`Cornpropst MT8, Mader M8, Albanis E8, Symonds WT8, Berrey MM8 1Alamo Medical Research, San
`Antonio, TX, 2Quest Clinical Research, San Francisco, CA, 3Fundacion de Investigacion de Diego,
`Santurce, PR, 4 Virginia Mason Medical Center, Seattle, WA, 5 University of Florida, Gainesville, FL,
`6Orlando Immunology Center, Orlando, FL, 7 Duke Clinical Research Institute, Durham, NC,
`8Pharmasset, Inc., Princeton, NJ
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`Conclusions
`
`• RVR rates of 88--94% were observed with IPSl--7977/SOC in
`tireatment-naive, HCV GT-1 subjects, far superior to p:laceboJSOC
`(21% RVR),
`• The regimen of PSl -79177 + SOC was welll-tolerated wi1th no dose ..
`limiting toxic)ties identified; the incidence and seve11ity of lab
`abn.orma'lities and A!Es was similar ro SOC a!on.e
`• Following cessation of PSl-7977, the ,durability of antMral respo:nse
`was greatest in the 200 and 400 mg g1roups
`• No viral resistance to PSl--7977 has been detected to date
`• Resu lts from this study supported 1initiation of a 12 week study of
`PSl-7977 200 and 400 mg with SOC compar-ed 1,1ith SOC alone
`• PSl-7977 a111~iviral efficacy in GT-1 subjects in the current study
`coupled with b:road genotype in vitro ac:1ivity support the exp'loiration
`of P Sll--7977 in an H CV genotypes
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`IPR2018-00390
`
`Page 1 of 7
`
`I-MAK 1013
`
`
`61th Annual Meeting of the American
`Association for the Study of Liver Diseases
`Boston, MA, Hynes Convention Center
`October 30-November 3, 2010
`
`
`
`
`
`
`
`
`
`
`
`Back
`
`
`
`High Rapid Virologic Response (RVR) with PSI-7977 Daily Dosing plus PEG-IFN/RBV in a
`28-day Phase 2a Trial
`
`
`
`
`Reported by Jules Levin
`AASLD Nov 1 2010 Boston
`
`Lawitz E1, Lalezari J2, Rodriguez-Torres M3, Kowdley KV4, Nelson DR5, DeJesus E6, McHutchison JG7,
`Cornpropst MT8, Mader M8, Albanis E8, Symonds WT8, Berrey MM8 1Alamo Medical Research, San
`Antonio, TX, 2Quest Clinical Research, San Francisco, CA, 3Fundacion de Investigacion de Diego,
`Santurce, PR, 4 Virginia Mason Medical Center, Seattle, WA, 5 University of Florida, Gainesville, FL,
`6Orlando Immunology Center, Orlando, FL, 7 Duke Clinical Research Institute, Durham, NC,
`8Pharmasset, Inc., Princeton, NJ
`
`
`
`
`
`
`
`Conclusions
`
`• RVR rates of 88--94% were observed with IPSl--7977/SOC in
`tireatment-naive, HCV GT-1 subjects, far superior to p:laceboJSOC
`(21% RVR),
`• The regimen of PSl -79177 + SOC was welll-tolerated wi1th no dose ..
`limiting toxic)ties identified; the incidence and seve11ity of lab
`abn.orma'lities and A!Es was similar ro SOC a!on.e
`• Following cessation of PSl-7977, the ,durability of antMral respo:nse
`was greatest in the 200 and 400 mg g1roups
`• No viral resistance to PSl--7977 has been detected to date
`• Resu lts from this study supported 1initiation of a 12 week study of
`PSl-7977 200 and 400 mg with SOC compar-ed 1,1ith SOC alone
`• PSl-7977 a111~iviral efficacy in GT-1 subjects in the current study
`coupled with b:road genotype in vitro ac:1ivity support the exp'loiration
`of P Sll--7977 in an H CV genotypes
`
`
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`IPR2018-00390
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`Page 1 of 7
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`I-MAK 1013
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`
`
`B.ackground
`
`The nucleosidell:ide analog polymerase inh ibito:r d!ass has boon
`shown lo have sign ificarn potential for the treatment of ,chronic
`hepatitis C infection due to promising cflnical efficacy, safety and
`a high barrier to, resistance. PSl-7977 is a phosphoram idate
`prodrug of /3' -D-2'--d.eoxy-2'..:flu:oro-2'-C-melliyluridine 5'(cid:173)
`monophosphate (PSl..,6206 monophosphate). PSl-7977 has
`enhanced antiviral potency over earlier nu:cleoside· analogs,
`achiev,es high liver to plasma ratios of key metabolites in
`pred i1nical studies and has the potential to be dosed once dai'ly.
`
`To assess U1e sa.fety, tolerability, pharma,cokinetics and antiviral
`activity of PSl-7977 ,(1 00 to 400 mg daily) fo:r 28 days, in
`combiination wi~h Standard of Care (SOC; PEG-IFN and RBV) in
`treabnent-naive, IHCV genotype 1 {GT-1 ) infected patients.
`
`Methods
`
`•
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`•
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`•
`•
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`•
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`Double~bl'ind, randomized, placebo-oontrolled , dose-ranging,
`parall el-group study vdh subjects assigned to one of three
`da·ly doses of PSl-7977 { 100, 200 o:r 400 mg) or placebo for
`28 days, ,co~administ:er,ed with SOC
`Einrolled subjects had GT-1 intection with HGV RINA~ 5 log10
`II U/m L, we re HGV treatment-naive, and were no:n-cinhotic
`per recent liver biopsy
`Randomizatioo was. stra.tified by IL28B status (rs 1299860) for
`ClC vs. any T al lefe
`SOC was comprised of peginterferon alfa-2a (Pegasys®) and
`ribarvirin and dosed acoording1 to the package inserts for GT-1
`SOC was ,continued for 48 weeks
`•
`Al I subjects were assessed for RVR (HCV RNA < limit of
`detection [LOD] at. Day 28), and subjects are be ing followed
`for SVR12 and SVR24
`
`Safety Assessments
`•
`Physiical ,exams, vital signs, clinical labs, ECGs, and AIEs
`
`Virol!ogy Assessments
`Rlasma HGV RINA measured by Roche COBAS T aqMa:n
`•
`HGV test ,(LOD < 15 IU/ml; limit of quanfitation < 43 IU/mll)
`Samples were collected for li-lGV resistanoe testing
`
`•
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`IPR2018-00390
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`Page 2 of 7
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`I-MAK 1013
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`
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`Subject Disposition
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`•
`•
`•
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`7 US sites enrolled 63 subjects
`Baseline demographics were srm i lar across groups (Table 1)
`'62 subjects oompl1eted '1e study throug1h 28 days
`• One subject who received 1?S1-7977 200 mg QD/SOC
`was. lost to follow-up at Day 14, with no A Es reported at
`the time of loss to fol low-up
`
`Table 1. Subject Demographics and 'Baseline Datlll by Treatment
`
`11,,1
`
`.e,n{%,)
`Ca11.u:asian (n1)
`
`Median age (y)
`
`Meai,1 BMII ,(kgrm2')
`
`HCV ta/1 b (n)
`HCV RNA (log10 II :rm )
`
`IL28B CIC. n (%)
`
`HQMA-ilR ""'3 (%)
`range·
`
`NC1h'l mai fibrosis (ffi.1)
`POi'lal fibi'Osis {IF1 -2)
`Blid&i"niJ fibrosis (F3)
`
`11 {69)
`15
`
`10 (56)
`6
`
`45.0
`
`28.2
`
`1412
`6.64
`
`44.0
`
`21UI
`
`11612
`
`6.28
`
`11 (73)
`
`12
`
`45.0
`
`27.4
`
`1213
`
`6.49
`
`4 (25)
`
`5 (28)
`
`4(27)
`
`9 (56:)
`1 · •24.3
`
`7(4'7)
`13 (72)
`0.7 1226 0.519.7
`
`9 (56)
`6 (38)
`1 (12)
`
`10 (56)
`4 (22)
`4 {22)
`
`9 {61J)
`4,Gm
`2{13)
`
`111 (79)
`114
`
`48.5
`
`30.7
`
`10/4
`
`6A8
`
`4(29)
`
`7 (50)
`1.3-6.7
`
`10 (71)
`2 (14)
`2 (14)
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`IPR2018-00390
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`Page 3 of 7
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`I-MAK 1013
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`
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`•
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`• No SAEs o d'scontinuations due to adverse ,events.
`•
`Aa A!Es were of mild or l'llOderate intensity and 'were n21ported with similar
`freq,ue:m;;y aQross fir,valment g1roU,Plil· (T a'b e, 2)
`fl,4o, Grade 4 lab abnormalities; Grade 3 lab abnormalities were limited to
`hemoglobin (2 subjects each in 200 and 400 mg groups). neutropema (1
`S'ubjeot ead1 in pbo and 400 mg, 2 subj,ects each ·n ::mo mg and 400
`mg1), hypop'hosphatemia ( 1 subjeccl each in placebo, andl 100 mg group)
`!Jose.dependent deer-eases in1 ALT levels were observ;ed coincid!enl wilh
`iiCV RNA dedi~.es 0Figme 2)
`• No, significant changes in vital signs and IECG parameteffi
`
`•
`
`Table 2. Most Commonly Reportsd Drug ,rdatsd Adverse Ev13nts
`
`Sut'ijects Wiffi at 1:east 1 AE, m ii~ )
`usea
`Fatigue
`Dizziness
`Headache
`
`2(13)
`1(6)
`0
`0
`1 (6)
`
`5 (28)
`q 6)
`1 ~6)
`0
`H6)
`
`5 (33)
`4 1{27
`0
`1 {7)
`2 1{13)
`
`6(4.2)
`2 (14)
`1 (7)
`2 (14)
`0
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`IPR2018-00390
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`Page 4 of 7
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`I-MAK 1013
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`Figure 1. Hemoglobin and ANC: Change from Baseline
`
`i -
`
`.. ,
`o-
`I
`I,...
`I
`II
`
`-1
`
`1·U
`ill I
`
`:!
`
`..z
`
`-
`-
`
`-
`
`1001111
`?t
`:llD!-i!ltll-?t
`Dllll!llal,?t
`lilacli!GfOC
`
`-
`-
`-
`-
`
`100 1n~nmaoc
`l!JD IIQI 1"&~111:1™1<:
`Q "VI Pll-111:IIIOC
`fi!Htbt.'$0~
`
`II
`
`I
`f "
`i
`I
`J-u
`
`-1
`
`-2:
`
`i ~,
`
`-' ·
`
`t 1
`
`u,
`
`.1,
`0
`
`1,
`CV-"
`
`Figure 2. Median Dedine ]n ALT with PSl-7977/SOC or Placebo/SOC
`
`100 mg QD PSl!.7977/SOC
`-
`200 mg QD1 Sl-1917/SOC
`-
`400 n-.g QD PSl!.79771SOC
`-
`- IPl~ebo.l.SOC
`
`,o I
`t 00 I
`3l
`~ - 5n
`E' ie
`~ jj 6 30
`~ -' <ii( 20
`~ ,1 ,.
`
`u.. 40
`~
`
`,c
`
`0 -+-, - - - - -~ - - - - -~ - - - - - - - - - - - -
`21
`213
`1
`0
`14
`SiudyDay
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`IPR2018-00390
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`Page 5 of 7
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`I-MAK 1013
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`Viro ogic Response
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`Table 3. Rapid Virologic Resporuse Rates by Treatment
`
`RVR
`(HCV RNA< lOD, 15 II.JI/ml.)
`RVR
`(HCV RNA< lOQ, 43 IU/ml)
`
`14/16
`(88%)
`
`15/16
`(94%)
`
`117(18·
`(~%)
`
`117(18"
`(94%)
`
`14115
`(93~)
`
`15115
`(100%)
`
`3114
`(21%)
`
`3114
`(21%)
`
`*Si~ e sulJjed wilhout an RVR. in lhe PSl-7977 200 mg group discoo ·n111ed on Day 14
`· a 4.71og,0 ded ne in HCV RNA
`PSF79TT potenlly suppressed plasma HCV RNA, compared to SOC al'one
`•
`as early as 24 hours after lhe start ol dosing ( Figures 3 and 4)
`• Mea , dha11ge from lbaseljne in HCV RNA (log 111 IU/rnL} at Day 28 was -2.8
`for ph1cebo/SOC, -5.3 for PSl-7'9'77 100 mg Q[llSOC, -5.1 for PSl-7'977
`200 mg ,QDJSOC, and -5.J ror PS -7977 400 mg ·QD/SOC
`• No viral breaklhrough was ,observed ·n any i div,idual at any PSl-7977
`dose through 28 days of dos:ing1
`
`
`
`ngure J. Mean HCV RNA Decline over the 28 Day Dosin,g Period with
`PS 1-7977 or Placebo + SOC
`
`:r
`i
`:,
`
`.9:
`
`QD FSl-197 /SOC
`-+- 100
`---200rn.g 00 PSli-7ll77 SOC
`...... OOrn.g 00 PSli-7977 SOC
`PfAC.ebo.lSOC
`
`i a: 3
`
`·~
`:it:
`: 2
`
`:i
`
`1
`
`D
`
`Cl
`
`1
`
`14
`Stud, 0'8y
`
`21
`
`.28
`
`
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`IPR2018-00390
`
`Page 6 of 7
`
`I-MAK 1013
`
`
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`Figure 4. Rates of HCV RNA< LOD with PSl-7977/SOC or Placebo/SOC Over
`Time (ITT Population, Lost Observation Carried Forward)
`
`100
`
`1711:~
`
`• 100 mg PS1·7971(SOC
`Cl 200 mg PSl-7977fSOC
`0 400 mg PSl-7977'SOC
`CJ P,lacebo.fSOC
`
`li/11 ,tf'I!-
`
`1M:a
`
`-I
`
`~ E ...
`;illi! ;!·
`.,., U)
`•IIJ a. 'II"'
`0 V
`,,,:(
`Cll2
`c:n a:
`!9 -
`C: >
`a;O
`I:? - -
`IJ. ...
`-
`Cli .:C
`'i
`
`90,
`1m
`70
`
`60,
`
`50·
`
`40·
`
`30·
`
`20'
`
`110·
`
`0
`
`l rt4,
`
`W0e1k 12
`cEVR
`
`Day 3
`
`Day7
`
`DIiiy 114
`
`Day28
`RVR
`Viral Resistance
`
`•
`•
`•
`
`The S282T muttilion was not detected at baseline in any subject
`The S282T mutation was not detoctedl at Day 28 in the single subtect iri the
`100 Jl'lQ PSl-7977 gro ;p wilh HCV RNA> ·t0OO IU,m
`rn t111e 200 and 400 mg PSl-7977 g ro111ps, all sub~ois HCV RNA was.
`<A3 II tJ/rnL, precluding virall sequencing at the ,end of therapy with PSI-7977
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`IPR2018-00390
`
`Page 7 of 7
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`I-MAK 1013
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`
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