111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20120022157Al
`
`(19) United States
`c12) Patent Application Publication
`Scharschmidt
`
`(10) Pub. No.: US 2012/0022157 A1
`Jan. 26, 2012
`(43) Pub. Date:
`
`(54) DOSING AND MONITORING PATIENTS ON
`NITROGEN-SCAVENGING DRUGS
`
`(75)
`
`Inventor:
`
`Bruce Scharschmidt, South San
`Francisco, CA (US)
`
`(73) Assignee:
`
`UCYCLYD PHARMA, INC,
`Scottsdale, AZ (US)
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61K 311216
`A61P 3100
`G01N 33100
`A61P 13112
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(21) Appl. No.:
`
`13/061,509
`
`(22) PCTFiled:
`
`Aug.27,2009
`
`(86) PCTNo.:
`
`PCT/US09/55256
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jun.15,2011
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. PCT/US09/
`30362, filed on Jan. 7, 2009, Continuation-in-part of
`application No. 12/350,111, filed on Jan. 7, 2009.
`
`(60) Provisional application No. 61/093,234, filed on Aug.
`29, 2008, provisional application No. 61/093,234,
`filed on Aug. 29, 2008.
`
`(52) U.S. Cl . ......................... 514/533; 514/532; 73/61.41
`
`(57)
`
`ABSTRACT
`
`The invention provides a method for determining a dose and
`dosing schedule, and making dose adjustments of patients
`taking PBA prodrugs as nitrogen scavengers to treat nitrogen
`retention states, including ammonia accumulation disorders
`as well as chronic renal failure, by measuring urinary excre(cid:173)
`tion of phenylacetylglutamine and/or total urinary nitrogen.
`The invention provides methods to select an appropriate dos(cid:173)
`age of a PBA prodrug based on the patient's dietary protein
`intake, or based on previous treatments administered to the
`patient. The methods are applicable to selecting or modifying
`a dosing regimen for a subject receiving an orally adminis(cid:173)
`tered waste nitrogen scavenging drug, and to monitoring
`patients receiving such drugs.
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 48
`
`

`

`> ......
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`?
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`
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`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`l Mildly Toxic
`
`Urea
`
`('Uremia')
`
`Figure la
`
`l Body Protein j l Severely Toxic
`
`j
`
`Ammonia
`
`Protein \ (aut etc.} J
`Dietary
`
`J
`
`............. -·.._.....
`:
`~~ih lrP.tr.RF)
`Chronic Renal
`
`Acquired(Cirrhos;s)
`Hereditary(UCDs) and
`
`Livt;r Dismdci'S
`
`Acquired (Cirrltosis) liver Disease And Chronic Renal Failure (CRF)
`
`Human Nitrogen Retention States: Hereditary (UCDs} And
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 2 of 48
`
`

`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 2 of 17
`
`US 2012/0022157 A1
`
`Carbamyl Phosphate
`
`I
`
`Sodium Phenlybutyrate
`t
`NH + 4
`-Katoglu':arate
`NH+ 4 ~-~ Glutamate---"'--~ Glutamine
`"=IP"h-en-y-r-la-ce-;-t--,at-.el
`Y
`HC03~A'"P
`I Phenylacetylglutamine I
`[QE§1
`Urine E~cretion
`·~ /i
`l.Q.rn ~ /
`I
`I Citrulline ~--/ f
`j
`
`Ornithine
`
`IASSI
`
`spartate
`/
`I ,
`IArgininosuccinates} ... "
`
`Supplemented --~ Arginille
`Arginine
`...
`
`Fumarate
`
`Figure lb
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 3 of 48
`
`

`

`> ......
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`0
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`
`c
`
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`w
`.....
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`!Jl =(cid:173) !'0
`
`N
`0 ......
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`9'
`N
`?
`~
`
`.... 0 =
`"a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 = .....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`______________ J. _________ ---------------------·
`
`UPAGN
`
`K67
`
`Delay
`
`K56
`
`Figure 2
`
`BSN1.73 x VM1, VM2, VPB, VPA, VPG
`
`Covariate
`
`: ____________________________________________________ _
`
`RIB, Exponent fa•
`• r
`
`I
`
`1PAGN (PGBL)
`Background
`
` .. -i
`
`1~
`
`100%
`KM2, VM2 PAGN (VPG)
`
`100%
`
`PAA (VPA)
`
`KM 1, VM1
`
`100%
`
`-.,.-------'
`
`I
`I
`I
`--------~----·------------------------------------------------------------------------------------~
`1 KA1 K02 i
`
`Plasma (Central Compartment)
`
`metabolite concentrations
`effect ts assume to relate directly to plasma
`plasma compartment. Bioavailability and drug
`PAA to PAGN in the systemic {labeled 1Gentral')
`This model only allows for conversion of PBA to
`
`______ I
`
`: F1 I F2 :
`
`,,,u,,.4.
`
`I
`
`~-~~:,-1------:
`Oral! Dose
`
`Note:
`
`PK/PD Modeling of PBA/PAA/PAGN/UPAGN
`
`• Conventiona' Approach •
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 4 of 48
`
`

`

`> ......
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`N ......
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`
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`
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`
`~
`......
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`
`N
`0 ......
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`9'
`N
`?
`~
`
`.... 0 =
`'a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 = ......
`
`~ ......
`
`(')
`
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`"tt
`
`~ ......
`
`(')
`
`· !
`
`I
`
`to Model
`was Added
`Compartment
`Pr~-cenfral
`
`1
`
`I
`
`Figure 3
`
`UPAGN
`
`K67
`Oe,ay
`
`Plasma (Systemic)
`·------------------------•r-••---------------------, ______________ j
`
`K56
`
`F*Ka*a.*~
`
`F*Ka*a.*(1-~)
`
`F*Ka*(1-a.}
`
`~-=--:-_ ::-_-: _-_ -~ = =---:_ -::_-::_-__-_-:_-:_-:_-:: _-_ _-_: :-_ -:_: _-:: _-_ _-_: :-_ ::-_:_-: --=::. ==--~ ~
`
`~ ~-::: =--=--=---= -::-.: =-=--~-=---= --=-==--=--=--.:-.::: =--=---=---= -_: -_:-_-=-=--=--.:-_:-=~-'
`l
`: I
`. I
`I
`I
`I
`: I
`:~:
`1
`I
`: I
`I
`, .
`I
`'
`I
`
`:
`
`PAGN (VPG)
`
`I
`
`• i I PBA (VPB) I K341 PAA (VPA) I K45
`
`I
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 5 of 48
`
`

`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 5 of 17
`
`US 2012/0022157 A1
`
`-a:
`:::::1 -= .s
`"' -...... c::::
`
`.......
`
`G:2
`~ s::
`Q
`c.,:)
`C'O
`E
`t":l -CL
`""'
`
`c::::
`I:':S
`G:2
`:;::
`
`5000 -
`
`-
`500 -
`
`-
`50 -
`
`10 -
`5 -
`
`1 -
`
`5000-
`
`500-
`
`-
`50-
`
`10~
`5-
`
`-:a: =s -c::::
`0 ·--r! -= CL)
`
`(Ill
`
`~-
`e
`u
`I:':S
`E
`C'O a:
`c::::
`I:':S
`a:ll
`:;::
`
`Buphenyl®(3g/m2)
`
`f\0
`~"0 ...
`fbP~~~--,
`\\) ··'€~:.
`c;p
`~.~\.. .
`:
`·:&-
`\\\
`. -·: ..
`.
`f)
`\\\
`..
`c;t
`~
`\\
`~ .. ~ •.
`t
`1:
`•••
`\~
`¢
`. . . ~ ...
`·:~--
`Q
`~
`
`-~\.
`
`'"'\:
`
`'\:,
`
`- .. ·; .-·-:-:-:·:·:·:·:,·,·,·,-.,.,. ... 0
`
`0
`
`5
`
`I
`
`I
`
`I
`
`20
`15
`10
`Time (Hours)
`HPN-1 00(3g/m2)
`
`....... __ PBA
`-... -.. PAA
`• • . , PAGN
`
`a
`
`•
`
`25
`
`I
`
`30
`
`--- PBA
`~---- PAA
`·
`·· PAGN
`
`~:-~ ..
`.. , --, '~· .. ,~,-~ ..
`.. ,.
`ltl"""·'·,{: ....
`fl. •'. ... · .. I
`' '\-..-~--:~~- .. ·-.
`t I
`.
`.. :-_ ·. -. ·. -::: _.- ...... .
`,,
`\ '~
`'.
`.. ---- -~-._-_---·.: :.·.:. ·..: ;_:~:: ~ ~::::: ~ ~
`!!A
`'
`,• - - - · .•••. - : .•• - .. :: ••• - • - .. - . -
`\
`~
`- ..... -- - - - - - -'"":_----....... __ _
`
`'
`
`I
`
`- -
`
`- - -
`
`1-~-----T·----~----~----~----~----~
`6
`~.
`25
`1'o
`15
`20
`30
`Time (Hours)
`
`Figure 4
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 6 of 48
`
`

`

`.... 0 =
`"a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 =
`.....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`> ......
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`0
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`
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`
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`0\
`.....
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`
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`?
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`
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`
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`
`Figure 5
`
`nitrogen scavenging could occur before the
`
`drug reaches the systemic circulation
`
`Note: Unlike for most drugs, waster
`
`Hepatic vein
`
`Cavae
`Vena
`
`I
`I
`L
`'
`I
`----------------------~------------~-----------------1
`
`I
`I
`I
`~------------------~-~~-----~--~----r----------1
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 7 of 48
`
`

`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 7 of 17
`
`US 2012/0022157 A1
`
`...__ ___ _
`
`UP1204~00?: Blood Metabolite Concentrations
`Vs. Time in Healthy Adults*
`
`Ana lyle= PBA
`
`* Shows BID dosing from days 8-15.
`Plasma PBA levels returned to near predose
`level between doses on each day during
`multiple dosing for healthy individuals.
`PAA levels increase, but reach a steady(cid:173)
`state after 3 days of BID dosing
`
`100
`
`.s -N e
`
`2:
`.e 10
`== Cl:l
`~ 5
`= _,
`
`200
`
`350
`300
`250
`Time (Hours)
`
`400
`
`Analyte==PAA
`
`Ana lyle= PAGN
`
`100
`
`100
`
`R:l
`
`~ 50
`R:l s:
`.5 -CN e
`
`:E
`..:. 10
`c
`«:1
`~ 5
`..5
`
`ca
`~ 50
`
`0:: ·= c:::i' e a :::I -= ca
`
`~ 5
`c _,
`
`200
`
`350
`300
`250
`Time (Hours)
`
`400
`
`200
`
`350
`300
`250
`Time (Hours)
`
`400
`
`Figure 6
`
`Par Pharmaceutical, Inc. Ex. 1021
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`Page 8 of 48
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`

`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 8 of 17
`
`US 2012/0022157 A1
`
`UP1204-0m?: Blood Metabolite Concentrations
`Vs. Time in Palients With Cirrhosis (Childs·Pugh C)
`Analyte = PIJA
`
`* Shows BID dosing from days 8-15.
`Plasma PBA levels returned to near predose
`level between doses on each day during
`multiple dosing in cirrhotics. PAA levels
`increase and require 4 days to reach
`steady·state with BID dosing
`
`,l)
`
`('!;
`
`~ 100
`I:'Q
`0:
`c
`
`50 -N
`E :a
`:::1 - 10 = ~
`
`G.:l
`::'iii:
`c:
`....J
`
`5
`
`200
`
`350
`300
`250
`Time (Hours)
`
`400
`
`Anafyte=PAA
`-~
`
`(Q
`
`~ 100
`cog
`0::
`.5 50
`N'
`E
`:.;;!::
`
`~ - 10-= (Q
`::s
`5 =
`
`G.:l
`
`....J
`
`Analyte = PAGN
`
`Clll
`
`~ 100
`('!; a:
`
`.5 50 -N e
`:iE = - 10 = ra
`2 =
`
`G.:l
`
`....J
`
`200
`
`350
`300
`250
`Time (Hours)
`
`400
`
`200
`
`Figure 7
`
`300
`250
`350
`Time (Hours)
`
`400
`
`Par Pharmaceutical, Inc. Ex. 1021
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`Page 9 of 48
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`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 9 of 17
`
`US 2012/0022157 A1
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`Par Pharmaceutical, Inc. Ex. 1021
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`Patent Application Publication
`
`Jan. 26, 2012 Sheet 10 of 17
`
`US 2012/0022157 A1
`
`20
`
`15
`
`10
`
`5
`
`0
`
`PAA AUC and HPN Dose
`-o- HPN-100
`-o- PAA
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Figure Sb
`
`3500
`
`-3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
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`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 11 of 17
`
`US 2012/0022157 A1
`
`20-
`18
`16
`14
`12-
`
`10
`
`8
`6
`4
`2
`
`lJ-PAGN and HPN Dose
`-o- HPN-PBA
`16000000
`~,.-o-__ u_-P_A_GN_, -14000000
`
`12000000
`
`10000000
`
`8000000
`
`6000000
`
`4000000
`
`2000000
`
`o~--~----~~~~--~--~~--~--+o
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`
`Figure 8c
`
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`

`Patent Application Publication
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`Jan. 26, 2012 Sheet 12 of 17
`
`US 2012/0022157 A1
`
`80
`70 -
`
`60 ...
`~50 -
`::::L -c.,:) 40
`-
`::::a
`<C z 30
`-
`20 -
`
`I-
`
`10 -
`
`0
`
`80
`70 ...
`
`TN-AUC
`BUPHENYL ® HPN-1 00
`-Mean
`---
`Median
`
`-9-
`
`.---
`
`1--.-----
`
`'---b-
`
`I
`
`~
`
`1-------
`
`,,..
`
`I
`
`-1)
`
`Cmax
`BUPHENYL ® HPN-100
`--Mean
`--- Median
`
`-9-
`
`- 50
`-
`:2:
`::l
`.._
`-
`(Ill 40
`t'O e 30
`-
`20 -
`10 -
`
`(Ill
`>C
`
`c..,:)
`
`60 ...
`
`0
`
`.----
`
`!--,_ ______
`
`-9-
`
`-·-v-
`
`I
`
`1----
`
`-
`
`~
`
`I
`
`)
`
`HPN·100
`BUPI ·lENVL®
`38.4 t/- 19.6 26.1 +/- 1 0.3
`56.3 +/- 27.9
`79.1 +/- 40.1
`
`AUC
`Cmax
`
`Figure 9
`
`-...I
`~ = E
`:::1.. -t"')
`::c z
`
`-...I
`~ e e
`:::::l -~ :c z
`
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`Page 13 of 48
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`

`Patent Application Publication
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`Jan. 26, 2012 Sheet 13 of 17
`
`US 2012/0022157 A1
`
`:::::1 30 -t----r
`
`== ~Q 25-t---v
`
`E
`..:.. 2 0 -t------;.
`
`~ ·-2; 15-t---v
`e
`~ 10-+----r
`5+-----L
`
`0~--~~~~~------~~~~~~~
`
`0-12rtr
`
`12-24Hr
`
`Figure 10
`
`Par Pharmaceutical, Inc. Ex. 1021
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`Page 14 of 48
`
`

`

`> ......
`-...}
`Ul
`N ......
`N
`0
`0
`N ..._
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`!Jl
`
`c
`
`~ ......
`0
`.j;;>.
`......
`.....
`!'0
`!Jl =(cid:173) !'0
`
`-...}
`
`N
`0 ......
`N
`9'
`N
`?
`~
`
`.... 0 =
`"a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 = .....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`---<>--5002 [8. 76] [8.85]
`5001 [8.76} [8.85]
`--3004 [13J} [13.1]
`---;-3002 [16.5] [17.7]
`~ 2003 [11 .8} [12.2]
`~ 2001 [6.57] [6.71 1
`--*-1006 {17.5] l17.7}
`--lr-1 004 [9.20] [9.16]
`~ 1002 [15.8} [15.9]
`---<>--1001 [17.5] [13.1]
`
`-
`
`Subject IBUP]{HPN] dose*
`
`Figure 11
`
`HPN-TNAUC
`
`BUP-TNAUC
`
`I
`
`0
`10
`20
`30
`40
`50
`60
`70
`80
`
`Par Pharmaceutical, Inc. Ex. 1021
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`Page 15 of 48
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`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 15 of 17
`
`US 2012/0022157 A1
`
`Ammonia(TI(I-AUC) After 7 Days of Treatment
`with BUPHENY~ and HPN-1 00
`
`80
`
`~
`
`-60
`~
`0
`E
`:::J ._
`- _,..
`..
`C'CI 40
`BUPHENYL®[~ Upper Limit of Normal
`
`·= = e
`~ 20
`-
`
`-.-
`
`~~.::;~ ~--~ _ _ ___________ ... _-----_____ I" _H ~;~~o·-
`
`.-
`
`26.1 +/-1 0.3
`
`0
`
`I
`
`BUPHENYL®
`
`HPN-100
`
`Figure 12
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 16 of 48
`
`

`

`Patent Application Publication
`
`Jan. 26, 2012 Sheet 16 of 17
`
`US 2012/0022157 A1
`
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`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 17 of 48
`
`

`

`> ......
`-...}
`Ul
`N ......
`N
`0
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`Figure 14
`
`Time {Days)
`
`12
`
`I
`
`11
`
`10
`
`9
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`8
`
`7
`
`6
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`From US Patent #4,284~647 (Brusilow; August 1981)
`
`Nitrogen in Treating Uremia
`Administration on Serum Urea
`
`Effect of Sodi urn Benzoate
`
`110
`
`120
`
`130
`
`140
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 18 of 48
`
`

`

`US 2012/0022157 AI
`
`Jan.26,2012
`
`1
`
`DOSING AND MONITORING PATIENTS ON
`NITROGEN-SCAVENGING DRUGS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application is a continuation in part of U.S.
`Nonprovisional patent application Ser. No. 12/350, Ill, filed
`Jan. 7, 2009 which is pending, and a continuation in part of
`International Application No. PCT IUS08/303 62, filed Jan. 9,
`2009, each of which claims benefit of priority to U.S. Provi(cid:173)
`sional Application Ser. No. 61/093,234, filed Aug. 29, 2008,
`each of which is incorporated herein by reference in its
`entirety. This application is also related to the U.S. provi(cid:173)
`sional patent application entitled "Treating special popula(cid:173)
`tions having liver disease with nitrogen-scavenging com(cid:173)
`pounds," naming Sharron Gargosky as inventor, Ser. No.
`61/048,830, filed on Apr. 29, 2008.
`
`TECHNICAL FIELD
`
`[0002] This invention relates to treatment of patients with
`nitrogen retention states, including urea cycle disorders
`(UCDs), cirrhosis complicated by hepatic encephalopathy
`(HE) and chronic renal failure (CRF), using administered
`compounds that assist in elimination of waste nitrogen from
`the body. The compounds can be orally administered small(cid:173)
`molecule drugs, and the invention provides methods for
`delivering such compounds and selecting suitable dosages for
`a patient as well as adjusting dosages and monitoring effec(cid:173)
`tiveness of a treatment. As depicted in FIG. 1a, inherited
`disorders (e.g., UCDs) and acquired disorders (e.g. cirrhosis,
`typically with portal systemic shunting, complicated by HE)
`involving the liver which impair the normally efficient clear(cid:173)
`ance of ammonia from the portal circulation and conversion
`to urea via the urea cycle, depicted in FIG. 1b, result in
`elevated levels in the blood of ammonia, a potent neurotoxin.
`CRF, while associated in some instances with mildly elevated
`levels of ammonia, (Deferrari, Kid Int. 1980; 20:505), results
`in retention of other nitrogenous waste products normally
`excreted in the urine, in particular urea, the blood levels of
`which are commonly used to assess renal function.
`[0003] Restriction of dietary protein (i.e. intake of dietary
`nitrogen) is commonly used in the management of each of
`these nitrogen retention states, to avoid accumulation of
`ammonia or metabolic products containing anunonia, e.g.,
`urea. References herein to ammonia and ammonia scaveng(cid:173)
`ing refer primarily to treating UCDs and HE and conditions
`that emulate UCDs, although the terms ammonia scavenging
`and waste nitrogen scavenging are used interchangeably.
`
`BACKGROUND ART
`
`[0004] Drug dosing is usually based upon measurement of
`blood levels of the active drug species in conjunction with
`clinical assessment of treatment response. However, the
`present invention is based on evidence that for certain pro(cid:173)
`drugs of phenylacetic acid (PA..A.), measuring the blood level
`of the prodrug (e.g. PBA) or ofPAA formed from it is unre(cid:173)
`liable in assessing drug effect: drug levels in the blood do not
`correlate with efficacy in this case. In addition, assessment of
`treatment effect by measuring levels of ammonia in the blood
`in UCD patients is also potentially unreliable. Individual
`ammonia level measurements vary several-fold over the
`course of a day for a given patient, and withdrawing multiple
`blood samples under carefully controlled conditions over an
`
`extended period of time is clinically impractical as a way to
`monitor a treated patient. The variability in blood ammonia
`levels reflects the fact that anu11onia levels in UCD patients
`are affected by various factors including dietary protein and
`timing in relation to meals, such that any individual value fails
`to provide a reliable measure of how much ammonia the drug
`is mobilizing for elimination; i.e. drug effect. The invention
`demonstrates that prodrugs of phenylbutyric acid (PBA)
`behave similarly to sodium PBA, in that measuring PBA
`levels is unreliable for assessing their effectiveness. This
`invention provides a novel method for dosing in patients with
`nitrogen retention states, in particular patients with liver dis(cid:173)
`ease and clinical manifestations of hepatic encephalopathy
`and patients with UCDs. It is particularly applicable to pro(cid:173)
`drugs that liberate or are metabolized to form phenylacetic
`acid, i.e., prodrugs of PAA, and those prodrugs that are
`metabolized to form PBA.
`[0005] Hepatic encephalopathy (HE) refers to a reversible
`spectrum of neurologic signs and symptoms which frequently
`occur in patients with cirrhosis or certain other types ofliver
`disease.
`[0006] Urea cycle disorders (UCDs) comprise several
`inherited deficiencies of enzymes or transporters necessary
`for the synthesis of urea from ammonia. The urea cycle is
`depicted in FIG. 1b, which also illustrates how certain ammo(cid:173)
`nia-scavenging drugs act to assist in elimination of excessive
`ammonia. UCDs include inherited conditions associated with
`insufficient function of any one of several anunonia-process(cid:173)
`ing enzymes. Individuals born with no meaningful residual
`urea synthetic capacity typically present in the first few days
`oflife (neonatal presentation). Individuals with residual func(cid:173)
`tion typically present later in childhood or even in adulthood,
`and symptoms may be precipitated by increased dietary pro(cid:173)
`tein or physiological stress (e.g. intercurrent illness.) Some
`enzymes whose deficient functioning causes UCDs include
`the following:
`[0007] Carbamyl phosphate synthetase (CPS),
`[0008] ornithine transcarbamylase (OTC),
`[0009]
`argininosuccinate synthetase (ASS),
`[0010]
`argininosuccinate lyase (ASL),
`[0011]
`arginase (ARG; EC Number 3.5.3.1; autosomal
`recessive), (ARG) and
`[0012] N-acetyl glutamine synthetase (NAGS)
`[0013] Mitochondrial transporter deficiency states which
`mimic many features of urea cycle enzyme deficiencies, and
`thus emulate UCDs and are treatable by the methods
`described herein for treating UCDs, include the following:
`[0014] Ornithine
`translocase deficiency (hyperorni(cid:173)
`thinemia, hyperanunonemia, homocitrullinuria or HHH
`Syndrome)
`[0015] Citrin (aspartate glutamate transporter) defi-
`ciency
`[0016] The common feature of UCDs and similar condi(cid:173)
`tions and hepatic encephalopathy that render them treatable
`by methods of the invention is an accumulation of excess
`waste nitrogen in the body, and hyperammonemia. CRF is
`similarly characterized by build-up of excessive waste nitro(cid:173)
`gen in the blood in the form urea, and the anunonia scaveng(cid:173)
`ing drugs described herein are likewise effective to prevent
`accumulation of excess levels of urea. In normal individuals,
`the body's intrinsic capacity for waste nitrogen excretion is
`greater than the body's waste nitrogen production, so waste
`nitrogen does not accumulate and anunonia does not build up
`to harmful levels. For patients with nitrogen retention states
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 19 of 48
`
`

`

`US 2012/0022157 AI
`
`Jan.26,2012
`
`2
`
`such as UCD or HE, the body's intrinsic capacity for waste
`nitrogen excretion is less than the body's waste nitrogen
`production based on a nom1al diet that contains significant
`amounts of protein. As a result, waste nitrogen builds up in the
`body of a patient having a nitrogen retention disorder, which
`usually results in excess ammonia in the blood. This has
`various toxic effects; drugs that help eliminate the excess
`ammonia are an important part of an overall management
`strategy for such disorders.
`[0017] To avoid build-up of ammonia to toxic levels in
`patients with nitrogen retention states, dietary intake of pro(cid:173)
`tein (a primary source of exogenous waste nitrogen) must be
`balanced by the patient's ability to eliminate excess mania.
`Dietary protein can be limited, but a healthy diet requires
`sufficient protein to support normal growth (i.e. in growing
`children) and repair; thus in addition to controlling dietary
`protein intake, drugs that assist with elimination of nitrogen
`are used to reduce ammonia build-up (hypermonemia).
`The capacity to eliminate excess ammonia in treated patients
`can be considered the sum of the patient's endogenous capac(cid:173)
`ity for nitrogen elimination (if any) plus the amount of addi(cid:173)
`tional nitrogen-elimination capacity that is provided by a
`nitrogen scavenging drug. The methods ofthe invention use a
`variety of different drugs that reduce excess waste nitrogen
`and mania by converting it to readily-excreted forms, such
`as phenylacetyl glutamine (PAGN). In some embodiments,
`the invention relates to methods for determining or adjusting
`a dosage of an oral drug that forms PAA in vivo, which is
`converted into PAGN, which is then excreted in urine and thus
`helps eliminate excess nitrogen.
`[0018] Based on prior studies in individual UCD patients
`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
`Brusilow and Finkelstien, J. Metabolism, vol. 42, 1336-39
`(1993)) in which 80-90% of the nitrogen scavenger sodium
`phenylbutyrate (a PA.A prodrug) was reportedly excreted in
`the urine as PAGN, current treatment guidelines typically
`either assume complete conversion of sodium phenylbutyrate
`or other PAA prodrugs to PAGN (e.g. Berry eta!., J. Pediat(cid:173)
`rics, vol. 138, S56-S61 (2001)) or do not comment on the
`implications of incomplete conversion for dosing (e.g. Singh,
`Urea Cycle Disorders Conference Group 'Consensus State(cid:173)
`ment from a Conference for the Management of Patients with
`Urea Cycle Disorders', Suppl to J Pediatrics, vol. 138(1),
`S1-S5 (2001)). Based on what is known, one expects essen(cid:173)
`tially complete conversion of these drugs into urinary PAGN.
`[0019] PBA is currently the preferred nitrogen scavenging
`drug for UCD patients in need of substantial nitrogen elimi(cid:173)
`nation capacity. Current treatment guidelines recommend 4
`times per day dosing with PBA, based on the fact that PBA is
`absorbed rapidly from the intestine when administered in the
`form of sodium PBA and exhibits a short half life in the
`bloodstream (Urea Cycle Disorders Conference Group 'Con(cid:173)
`sensus Statement' 2001). Current recommendations for
`sodium phenylbutyrate dosing in UCD patients indicate that
`dosage should not exceed 600 mg/kg (for patients weighing
`up to 20 kg) or in any case 20 grams total per day. Frequent
`dosing helps minimize the peak levels of mania, which can
`be very harmful, and it minimizes buildup of high concentra(cid:173)
`tions ofPAA as well.
`[0020] CRF (chronic renal failure) resulting from a variety
`of causes (e.g. diabetes, hypertension, glomerular disease,
`etc.) is associated with diminished excretion from the body of
`water soluble waste products normally present in the urine,
`including nitrogenous waste such as urea. While the contri-
`
`bution of increased blood levels of urea, per se, to the clinical
`manifestations of CRF and end-stage renal disease (ESRD)
`known as uremia is uncertain, urea levels in the blood are
`commonly used as one measure of renal function and the need
`for and frequency of renal replacement therapy such as dialy(cid:173)
`sis. As a corollary of the findings noted above in UCD patients
`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
`Brusilow and Finkelstien, J. Metabolism, vol. 42, 1336-39
`(1993)), increased waste nitrogen excretion in the form of
`PAGN resulting from administration of PAA prodrugs
`decreases urea synthesis and therefore can serve as an alter(cid:173)
`native to urea excretion. Consistent with this, Brusilow (U.S.
`Pat. No. 4,284,647) has demonstrated that administration of
`sodium benzoate, which increases waste nitrogen excretion in
`the form of hippuric acid, lowered blood urea levels in a
`patient with renal failure (FIG. 14). Accordingly, PAA pro(cid:173)
`drugs, including PBA and HPN -100 can be used to treat CRF
`as well as UCDs and HE, and methods for determining and
`adjusting dosage of these P AA pro drugs and monitoring treat(cid:173)
`ment efficacy are among the inventions disclosed herein. In
`general, and without being limited by theory, prodrugs of
`PAA which do not contain sodium would be preferred for
`treatment of treatment of those nitrogen retention states,
`including CRF as well as cirrhosis and HE, which are also
`known to be associated with sodium and fluid retention mani(cid:173)
`fested, for example, as ascites and or peripheral edema. HPN-
`100 is one such sodium-free PAA prodrug.
`
`DISCLOSURE OF EMBODIMENTS OF THE
`INVENTION
`
`[0021] The invention provides a novel approach for deter(cid:173)
`mining and adjusting the schedule and dose of orally admin(cid:173)
`istered nitrogen scavenging drugs, including sodium phenyl(cid:173)
`butyrate and glyceryl tri-[4-phenylbutyrate] (HPN-100),
`based upon the urinary excretion of the drug metabolite phe(cid:173)
`nylacetylglutamine (PAGN) and/or total urinary nitrogen. It
`is based in part on the discovery that bioavailability of these
`drugs as conventionally assessed based on systemic blood
`levels of the drugs themselves or of the active species pro(cid:173)
`duced in vivo from these drugs does not accurately predict
`removal of waste nitrogen or reduction of plasma ammonia in
`healthy human volunteers, adults with liver disease, or
`patients with UCDs receiving mania scavenging drugs as
`defined below. Conversion of orally administered sodium
`phenylbutyrate (NaPBA, or sodium PBA) to urinary PAGN
`(uPAGN) is now shown to be incomplete: conversion is typi(cid:173)
`cally about 40-70%, or about 54% on average. (A preliminary
`analysis suggested the range would be around 60-75%, but
`final analysis shows the average is about 54%.) The average
`value of about 54% conversion was determined experimen(cid:173)
`tally for orally administered HPN -100 or PBA converting into
`urinary PAGN, and a range of about 40-70% represents the
`average plus or minus approximately one standard deviation
`for this data set. By comparison, correlating urinary PAGN
`with drug dosage using information available in the art would
`have provided substantially different results, since the prior
`art suggests a much higher conversion, e.g., 90% or more. As
`used in this context, "about 54%" refers to a value between
`50% and 60%, and the urinary PAGN output refers to a
`measure of urinary PAGN output for a subject receiving
`ongoing stable daily dosages of the nitrogen scavenging drug.
`[0022] Urinary PAGN can be measured in various ways; in
`some embodiments, as described herein, it is a 24-hour mea(cid:173)
`surement, which means measurement of total urinary PAGN
`
`Par Pharmaceutical, Inc. Ex. 1021
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 20 of 48
`
`

`

`US 2012/0022157 AI
`
`Jan.26,2012
`
`3
`
`output for a period of 24 hours following the first dose of the
`day of a nitrogen scavenging drug. In other embodiments, a
`12-24 hour urinary PAGN level is used, which is the total
`amount of urinary PAGN excreted over the time period 12-24
`hours after the first dose of the day. As an alternative, as
`described herein, spot testing of urinary PAGN levels can be
`used, by normalizing the value as a ratio to urinary creatinine
`output. Daily creatinine output is relatively stable for most
`subjects, and this has been found to be true even in the UCD,
`HE, and CRF patients receiving the nitrogen scavenging
`drugs described herein. Because creatinine output is rela(cid:173)
`tively stable, it can be used to normalize urinary PAGN output
`levels: from a 'spot test' of a partial sample, the ratio of
`uPAGN to urinary creatinine can be used to estimate a total
`daily urinary PAGN output. These values may be used in
`calculations of dosages or protein intake based on urinary
`PAGN output as well as for determining initial drug dosage
`for a patient taking a given amount of protein.
`[0023] The invention further provides methods to easily
`monitor treated patients to determine from urinary PAGN
`output whether their overall treatment program (diet and
`medication) is working, and when the patient needs a modi(cid:173)
`fied treatment program or adjusted drug dosage. These meth(cid:173)
`ods comprise monitoring urinary PAGN output, either as a 24
`hour output, or as a 12-24 hour total urinary PAGN output, or
`as an estimated value from a spot test, where the urinary
`output is normalized to urinary creatinine and converted to an
`estimated 24-hour (or 12-24 hour) output. In one embodi(cid:173)
`ment, the method comprises comparing that value for urinary
`PAGN to a cut-off value that distinguishes patients likely to
`have normal ammonia levels from patients likely to have high
`ammonia levels.
`[0024] Prodrugs of phenylbutyrate (PBA, the active ingre(cid:173)
`dient in BUPHENYL® (sodium phenylbutyrate), which is
`the sodium salt of PBA along with small amounts of inert
`ingredients), which is itself a prodrug of phenylacetic acid
`(PAA), are especially subject to the effects described herein.
`
`phenylbutyrate
`~OH
`g
`
`v
`
`Phenylacetic acid
`NH2
`
`0
`
`HO
`
`0
`
`Phenylacetylglutamine
`
`[0025] As used herein "ammonia scavenging drugs" is
`defined to include all orally administered drugs in the class
`which contain or are metabolized to phenylacetate. Thus, the
`
`term includes at least phenylbutyrate, BUPHENYL® (so(cid:173)
`dium phenylbutyrate), AMMONAPS®, butyroyloxymethyl-
`4-phenylbutyrate, glyceryl
`tri-[ 4-phenylbutyrate]
`(HPN-
`1 00), esters, ethers, and acceptable salts, acids and derivatives
`thereof. These drugs reduce high levels of endogenous
`ammonia by providing phenylacetic acid in vivo, which is
`metabolized efficiently to form phenylacetyl glutamine
`(PAGN). PAGN is efficiently excreted in urine, carrying away
`two equivalents of nitrogen per mole of PAA converted to
`PAGN. References herein to sodium phenylbutyrate are
`understood to include reference to the drug product BUPHE(cid:173)
`NYL®, and BUPHENYL® was used for the Examples herein
`wherever test subjects were treated with sodium phenylbu(cid:173)
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPHENYL®, and the
`amounts of sodium phenylbutyrate in those Examples should
`be interpreted accordingly. Note that the terms 'ammonia
`scavenger' and 'nitrogen scavenger' are used interchangeably
`in this invention, reflecting the fact that the drugs described
`herein lower blood ammonia an