111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20100008859Al
`
`CI9) United States
`c12) Patent Application Publication
`SCHARSCHMIDT
`
`(10) Pub. No.: US 2010/0008859 A1
`Jan. 14, 2010
`(43) Pub. Date:
`
`(54) METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`(76)
`
`Inventor:
`
`Bruce SCHARSCHMIDT, South
`San Francisco, CA (US)
`
`Correspondence Address:
`MORRISON & FOERSTER LLP
`12531 HIGH BLUFF DRIVE, SUITE 100
`SAN DIEGO, CA 92130-2040 (US)
`
`(21) Appl. No.:
`
`12/350,111
`
`(22) Filed:
`
`Jan.7,2009
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/093,234, filed on Aug.
`29, 2008, provisional application No. 61/048,830,
`filed on Apr. 29, 2008.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 49100
`(2006.01)
`A61K 311192
`(2006.01)
`A61P 13100
`(52) U.S. Cl ........................................... 424/9.2; 514/568
`ABSTRACT
`(57)
`
`The invention provides a method for determining a dose and
`schedule and making dose adjustments ofPBA prodrugs used
`to treat nitrogen retention states, or ammonia accumulation
`disorders, by measuring urinary excretion of phenylacetyl(cid:173)
`glutamine and/or total urinary nitrogen. The invention pro(cid:173)
`vides methods to select an appropriate dosage of a PBA
`prodrug based on the patient's dietary protein intake, or based
`on previous treatments administered to the patient. The meth(cid:173)
`ods are applicable to selecting or modifYing a dosing regimen
`for a subject receiving an orally administered ammonia scav(cid:173)
`enging drug.
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 39
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`

`

`Patent Application Publication
`
`Jan. 14, 2010 Sheet 1 of 15
`
`US 2010/0008859 A1
`
`Figure 1
`
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`Page 2 of 39
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`

`

`Patent Application Publication
`
`Jan. 14, 2010 Sheet 2 of 15
`
`US 2010/0008859 A1
`
`Figure 2
`
`A conventional clinical pharmacology model in which only drug reaching the central (systemic)
`
`circulation is assumed to be active.
`
`PKIPD Modeling of PBAIPAA/PAGN/UPAGN
`- Conventional Approach -
`
`Note:
`This model only allows for conversion of PBA to
`PAA to PAGN in the systemic (labeled 'central')
`plasma compartment. Bioavailability and drug
`effect is assume to relate directly to plasma
`metabolite concentations
`
`Oral Dose
`r·G~i- ---------1
`i
`.
`.
`: F1
`F2
`L.~J -~Q? ____ j
`
`PAGN (VPG)
`100%
`
`Background
`
`PAGN (PGBL) . . .
`
`Covariate
`BSA/1.73 x VM1, VM2, VPB, VPA, VPG
`
`i<ss··------------------------------·
`
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`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 3 of 39
`
`

`

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`NH3 were added
`compartments &
`
`Pre-central
`
`to model
`
`UPAGN·
`
`Delay
`
`············~···
`•
`
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`prior to reaching the systemic circulation is fully active with respect to excretion of waste nitrogen. As a corollary, concentrations of metabolites
`
`A modified clinical pharmacology model as described in this application in which an ammonia scavenging agent converted into PAGN
`
`in the systemic circulation do not correlate consistently with drug effect.
`
`Figure 3
`
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`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 4 of 39
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`

`

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`PAGN levels. PAA levels were not determined after approximately12 hours, and fall generally close to the PAGN curves up to that time.
`levels. In the right panel, the three lowest curves at the 10-15 hour time span are all for PBA; and the highest three curves at 15-25 hours represent
`the upper curve represents PBA levels; the intermediate one represents PAA levels; and the lowest of the three sets of lines represents PAGN
`dosage. Three curves for each material are for three subjects who received the specified dosages of sodium PBA or HPN-100. In the left panel,
`(sodium PBA) at 3g/m2 dosage, or HPN-100 in an amount calculated to provide an equimolar amount of PBA to that provided by the sodium PBA
`In each panel, the curves represent measured levels of PBA, PAA or PAGN in subjects receiving BUPHENYL ®(sodium phenylbutyrate)
`
`30
`
`25
`
`Time (hours)
`20
`
`15
`
`10
`
`5
`
`0
`
`30
`
`25
`
`20
`
`Time (hours)
`10
`
`15
`
`5
`
`0
`
`--········
`
`....J
`
`·-
`
`----~
`...... ........................ _______ _
`'--------
`\ ,._. --
`--.::::.::::.:.-.-----
`.=::.:::.:::.::----
`'.:=-.::::-..:::::__--~------
`' ~
`\ ,~,·~ ..... ·---
`\
`\
`'\""'~;~".~ ...
`~~'::-.....
`
`\
`\
`
`HPN-1 00 (3g/m2)
`
`I~
`
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`
`1:
`
`0
`
`-~ ---~~
`
`--~ ........
`
`~. ~.
`
`., ~----,
`
`PAGN
`PAA
`PBA
`
`.
`
`BUPHENYL® (3g/m2)
`
`0
`0
`
`FIGURE4
`
`I: 1 (\~
`
`~ ~ j 1
`c 8 g ~ I
`Cl) u
`.. -c
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`II)
`
`ftl
`
`....
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`II)
`
`:E
`Cl)
`ftl
`c
`a.
`
`ftl
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 5 of 39
`
`

`

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`0+-----.----~---.-----.--~__,
`
`Urinary PAGN (grams)
`
`:£tl
`
`2U
`
`ltl
`
`lU
`
`!;)
`
`u
`
`120 -r-------------------------.
`
`collection, which ranged from 6 to 12 hours.
`10 subjects during steady state treatment with HPN-100 or sodium PBA. Partial AUCs are plotted against the corresponding time of the urine
`
`Relationship between blood ammonia levels (partial time-normalized area under the curve [partial AUC]) and urinary output of PAGN in
`
`Figure 5
`
`•
`
`y = -1.06 X+ 49.9 (CI = -2.21, 0.09)
`y = -2.35 X+ 54.5 (CI :::::·.:3.97' -0.73)
`
`• Buphenyl
`•· HPN-100
`
`20
`
`40
`
`60
`
`so
`
`1 DO
`
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`
`• • I
`••
`
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`• • •
`•
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 6 of 39
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`

`

`.... 0 =
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`
`the systemic circulation (e.g. in the liver) is still effective in clearing ammonia from the body.
`most drugs which need to pass through the liver to the systemic circulation to exert an effect, PAA converted to PAGN prior to reaching
`Schematic anatomic depiction of the systemic and presystemic (represented by the portal vein) compartments. Unlike the case for
`
`reaches the systemic circulatiQ~dential
`
`trapping could occur before the drug
`NOTE: Unlike for most drugs, NH3
`
`Rest assumed non-bioavai
`mouth to systemic circu
`only on drug that gets from
`
`Bioavailability is usually based
`
`FIGURE 6
`
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`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 7 of 39
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`

`

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`r--------------------------------------------------------------·-· .. ··-·
`
`.. ~.
`between doses on each day clu.riilg multiple dosing for healthy individuals. PAA levels
`*Shows BID dosing from days 8-15. Plasma PBA levels returned to near predose level
`
`increase, but reach a steady~state after. 3 days of BID dosing
`
`Time (hours)
`
`Time (hours)
`
`Time (hours}
`
`400.
`
`350
`
`. ·. 200 250 300
`
`200 250 300 350 400
`
`200 250 300 350 400
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`• •
`Analyte= PAGN
`
`5
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`
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`
`Figure 7
`
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`Par Pharmaceutical, Inc. Ex. 1020
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`Page 8 of 39
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`

`

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`Analyte= PBA
`
`Figure 8
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`between doses on each day during multiple dosing in cirrhotics. PAA levels increase
`* Shows BID dosing from days 8-15. Piasma PBA leve(~ returned to near predose level
`
`and require 4 days to reach steady-state with BID dosing
`
`·
`
`Time {hours}
`
`Time (hours)
`
`Time (hours)
`
`i'. ; 200 250 300 350 400
`
`200 250 300 350 400 .
`
`200 250 300 350 400
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`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 9 of 39
`
`

`

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`
`Subjects
`
`1 2 3 4 5 6 7 8 9 10
`
`HPN Dose
`
`~ · ~ • ~· ... ~· ... ~· ._"'t· ~· co· co· ro·
`'\ '\ ~ " " "'t "ro co" co" '\"
`
`-HPNDose
`
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`-+-PBA AUC0-24
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`0
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`1000
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`400
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`Ia 600
`800
`1000
`1200
`
`PBA AUC and HPN Dose
`
`PBA Cmax and AUC and HPN dose
`
`Figure 9 depicts the lack of correlation between drug dose and plasma PBA (9a) and plasma P AA (9b ), as compared with a significant
`
`correlation with urinary output of PAGN (9c).
`
`Figure 9a
`
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`

`

`Patent Application Publication
`
`Jan. 14, 2010 Sheet 10 of 15
`
`US 2010/0008859 A1
`
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`Page 11 of 39
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`

`

`Patent Application Publication
`
`Jan. 14, 2010 Sheet 11 of 15
`
`US 2010/0008859 A1
`
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`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 12 of 39
`
`

`

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`--------------Median
`-----Mean
`
`56.3 +I-27.9
`
`79.1 +1-40.1
`
`38.4 +1-19.6
`26.1 +1-1 0.3
`BUPHENYL® HPN-100
`
`Cmax
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`.... 0 = "tt c:
`~ 'e -....
`!'0 = .....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`160 .------------------------------------------------------.
`
`80 ~----------------------------------------------.
`
`BUPHENVL ® HPN-1 00
`
`BUPHENVL® HPN-100
`
`Cmax
`
`TN-AUC
`
`Figure 10
`
`•
`
`•
`
`20
`
`40
`
`60
`
`so
`
`z
`(") J:
`E:: 0
`E ~~
`0 ~ 100
`...._
`...I
`.-.
`
`120
`
`140
`
`l-1)
`
`~ .
`
`.
`
`0 ~------------~---------------r------------~
`
`10
`
`20
`
`~ 30
`~ 40
`
`~ 50
`
`60
`
`70
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 13 of 39
`
`

`

`> ....
`
`\0
`Ul
`QO
`QO
`0
`0
`0
`0 ..._
`0 ....
`c
`
`N
`!Jl
`
`0
`
`N
`
`.... 0 =
`"a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 = .....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`~ ....
`.... w
`.....
`!'0
`!Jl =(cid:173) !'0
`0 ....
`~ ...
`? ....
`~
`
`Ul
`
`0
`
`Plasma ammonia levels (time-normalized area under the curve [TN-AUC or AUC]) during the day and night in 10 UCD patients treated
`
`for seven days with either sodium PBA (BUP) or a PBA equimolar dose of HPN-10.
`
`12-24 Hr
`
`0-12 Hr
`
`~
`
`p
`
`Cumulative Ammonia Concentration TN-AUC
`
`Figure 11
`
`0
`<(
`E 5
`E 10
`0
`c
`·-
`15
`cu
`._.. 20
`j
`E 25
`0
`!.. 30
`......... .c
`
`40 -...J 35
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 14 of 39
`
`

`

`.... 0 =
`"a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 =
`
`~ ......
`
`(')
`
`......
`~ ......
`"tt
`
`> ......
`
`\0
`Ul
`QO
`QO
`0
`0
`0
`0 ..._
`0 ......
`N
`!Jl
`
`c
`
`Ul
`~ ......
`0
`...... ...
`......
`!'0
`!Jl =(cid:173) !'0
`
`0
`0 ......
`N
`~ ...
`......
`?
`~
`
`~ ......
`
`(')
`
`5002 [8. 76] (8.85]
`5001 [8. 76] [8.85]
`-3004[13.1] (13.1]
`-t-3002 [16.5] [17.7]
`~2003 [11.8] [12.2)
`__..._ 2001 [6.57] [6. 71]
`--*-·1006 [17.5] [17.7]
`1004[9.20] [9.16]
`-11-1002 [15.8] [15.9]
`-+-1001 [17.5][13.1]
`
`-
`
`HPN-lNAUC
`
`(1Jmoi/L)
`
`BUP-lNAUC
`
`(IJmoi/L)
`
`I
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`.-----~~~-------------------Subject [BUP][HPN] dose*
`
`Plasma ammonia levels (time-normalized area under the curve [TN-AU C) in 10 UCD patients treated for seven days with sodium
`
`PBA (BUP) followed by seven days with a PBA equimolar dose of HPN-1 00.
`
`FIGURE 12
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 15 of 39
`
`

`

`> ....
`
`\0
`Ul
`QO
`QO
`0
`0
`0
`0 ..._
`0 ....
`c
`
`N
`!Jl
`
`~ ....
`0
`Ul
`....
`.....
`!'0
`!Jl =(cid:173) !'0
`0 ....
`~ ....
`? ....
`~
`
`0
`
`N
`
`Ul
`
`.... 0 =
`'a' -....
`.... 0 = "tt c:
`~ 'e -....
`!'0 = .....
`~ .....
`"tt
`
`~ .....
`
`(')
`
`~ .....
`
`(')
`
`Mean plasma ammonia levels (time-normalized area under the curve [TN-AUC]) in 10 UCD patients treated for seven days with
`
`sodium PBA followed by seven days with a PBA equimolar dose of HPN-1 00.
`
`HPN-100
`
`BUPHENYL
`
`0
`
`E
`0
`::::
`:::J 60 .
`
`:I -ca 40
`
`c( 20
`E
`E
`0
`·c
`
`with BUPHENVL and HPN-100
`
`Ammonia (TN·AUC) After 7 days of Treatment
`
`80
`
`Figure 13
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 16 of 39
`
`

`

`US 2010/0008859 AI
`
`Jan. 14,2010
`
`1
`
`METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims benefit of priority to U.S.
`Provisional application Ser. No. 611093,234, filed Aug. 29,
`2008, which is incorporated herein by reference in its entirety.
`This application is also related to the U.S. provisional patent
`application entitled "Treating special populations having
`liver disease with nitrogen-scavenging compounds," 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, in particular urea cycle disorders
`(UCDs) and cirrhosis complicated by hepatic encephalopathy
`(HE), using administered compounds that assist in elimina(cid:173)
`tion of waste nitrogen from the body. The compounds can be
`orally administered small-molecule drugs, and the invention
`provides methods for delivering these compounds and select(cid:173)
`ing suitable dosages for a patient.
`
`BACKGROUND ART
`
`[0003] 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 addition, assessment of treatment effect by measur(cid:173)
`ing levels of ammonia in the blood is inconvenient, because it
`requires withdrawing multiple blood samples under carefully
`controlled conditions. Because blood ammonia levels are
`affected by various factors including dietary protein, they also
`fail to provide a direct measure of how much ammonia the
`drug is mobilizing for elimination. The invention demon(cid:173)
`strates 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 disease and
`clinical manifestations of hepatic encephalopathy and
`patients with UCDs. It is particularly applicable to prodrugs
`that liberate or are metabolized to form phenylacetic acid, i.e.,
`prodrugs ofPAA, and those prodrugs that are metabolized to
`formPBA.
`[0004] Hepatic encephalopathy refers to a spectrum of neu(cid:173)
`rologic signs and symptoms which frequently occur in
`patients with cirrhosis or certain other types of liver disease.
`[0005] Urea cycle disorders comprise several inherited
`deficiencies of enzymes or transporters necessary for the
`synthesis of urea from ammonia. The urea cycle is depicted in
`FIG. 1, which also illustrates how certain ammonia-scaveng(cid:173)
`ing drugs act to assist in elimination of excessive ammonia.
`The enzymes including their Enzyme Commission (EC)
`numbers and modes of inheritance include the following:
`[0006] Carbamyl phosphate synthetase (CPS; EC Num(cid:173)
`ber 6.3.4.16; autosomal recessive),
`[0007] ornithine transcarbamylase (OTC; EC Number
`2.1.3.3; X-linked),
`
`[0008]
`argininosuccinate synthetase (ASS; EC Number
`6.3.4.5; autosomal recessive),
`[0009]
`argininosuccinate lyase (ASL; EC Number 4.3.2.
`1; autosomal recessive),
`[0010]
`arginase (ARG; EC Number 3.5.3.1; autosomal
`recessive), and
`[0011] N-acetyl glutamine synthetase (NAGS 1; EC
`Number 2.3 .1.1; autosomal recessive)
`[0012] Mitochondrial transporter deficiency states which
`mimic many features of urea cycle e=yme deficiencies
`include the following:
`[0013] Ornithine translocase deficiency (hyperomithine(cid:173)
`mia, hyperammonemia, homocitrullinuria or HHH Syn(cid:173)
`drome)
`[0014] Citrin (aspartate glutamate transporter) defi-
`ciency
`[0015] The common feature ofUCD and hepatic encepha(cid:173)
`lopathy that render them treatable by methods of the inven(cid:173)
`tion is an accumulation of excess waste nitrogen in the body,
`and hyperammonemia. 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 ammonia does not build up to harmful
`levels. For patients with nitrogen retention states 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 normal diet that contains significant amounts of
`protein. As a result, nitrogen builds up in the body of a patient
`having a nitrogen retention disorder, and usually results in
`excess ammonia in the blood. This has various toxic effects;
`drugs that help eliminate the excess ammonia are an impor(cid:173)
`tant part of an overall management strategy for such disor(cid:173)
`ders.
`[0016] 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 ammonia.
`Dietary protein can be limited, but a healthy diet requires a
`significant amount of protein, particularly for growing chil(cid:173)
`dren; thus in addition to controlling dietary protein intake,
`drugs that assist with elimination of nitrogen are used to
`reduce ammonia build-up (hyperammonemia). The capacity
`to eliminate excess ammonia in treated patients can be con(cid:173)
`sidered the sum of the patient's endogenous capacity for
`nitrogen elimination (if any) plus the amount of additional
`nitrogen-elimination capacity that is provided by a nitrogen
`scavenging drug. The methods of the invention use a variety
`of different drugs that reduce excess waste nitrogen and
`ammonia 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.
`[0017] Based on prior stndies in individual UCD patients
`(e.g. Brusilow, Pediatric Research, vol. 29, 147-50 (1991);
`Brusilow and Finkelstien, .!. Metabolism, vol. 42, 1336-39
`(1993)) in which 80-90% of the nitrogen scavenger sodium
`phenylbutyrate was reportedly excreted in the urine as PAGN,
`current treatment guidelines typically either assume complete
`conversion of sodium phenylbutyrate or other PAA. prodrugs
`lo PAGN (e.g. Berry el a!.,.!. Pediatrics, vol. 138, S56-S61
`(2001)) or do not comment on the implications of incomplete
`conversion for dosing (e.g. Singh, Urea Cycle Disorders Con-
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 17 of 39
`
`

`

`US 2010/0008859 AI
`
`Jan. 14,2010
`
`2
`
`ference Group 'Consensus Statement from a Conference for
`the Management of Patients with Urea Cycle Disorders',
`Suppl to J Pediatrics, vol. 138(1), S1-S5 (2001)).
`[0018] Current treatment guidelines recommend 4 times
`per day dosing, 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 'Consensus Statement'
`2001)
`[0019] Current recommendations for sodium phenylbu(cid:173)
`tyrate dosing indicate that dosage should not exceed 600
`mg/kg (for patients weighing up to 20 kg) or in any case 20
`grams total.
`
`DISCLOSURE OF EMBODIMENTS OF THE
`INVENTION
`
`[0020] 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 discoveries 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 anunonia scavenging drugs as
`defined below and that conversion of orally administered
`sodium phenyl butyrate (NaPBA, or sodium PBA) to PAGN to
`urinary PAGN is incomplete, typically about 60-75%. Pro(cid:173)
`drugs of phenylbutyrate (PBA, the active ingredient in
`BUPHENYL® (sodium phenylbutyrate), which is
`the
`sodium salt of PBA along with small amounts of inert ingre(cid:173)
`dients), which is itself a pro drug of phenylacetic acid (PAA),
`are especially subject to the effects described herein.
`
`phenylbutyrate
`~OH
`g
`
`v
`
`Phenylacetic acid
`NH2
`
`0
`
`HO
`
`0
`
`Phenylacetylglutaminc
`
`[0021] 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-
`
`I 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 faet that the drugs described
`herein lower blood ammonia through elimination of waste
`nitrogen in the form ofPAGN.
`[0022]
`In some embodiments, the invention uses prodrugs
`that can be converted into PAA within the body. Sodium
`phenylbutyrate (sodium PBA) is one such drug; it is converted
`by oxidative mechanisms into PAA in the body. HPN-100 is
`another such drug: it can be hydrolyzed to release PBA, which
`in tum can be oxidized to fom1 PAA. Thus, HPN-100 is a
`prodrug of PBA, and also a prodrug of PAA. Clinical evi(cid:173)
`dence demonstrates that HPN-100 is converted into PAA in
`the body as expected, and that PAA is then linked to a mol(cid:173)
`ecule of glutamine and converted into PAGN, which is elimi(cid:173)
`nated in the urine as predicted. This process can be summa(cid:173)
`rized as follows:
`
`HPN-100~3PBA~3PAA
`
`PAA+glutamine~ PAGN.
`
`[0023] PAGN is mainly excreted in the subject's urine, and
`removes two molecules of ammonia per molecule of excreted
`PAGN. EachHPN-lOOmolecule forms three PAAmolecules,
`so each molecule of HPN -I 00 can promote excretion of six
`molecules of ammonia. The clinical results suggest that con(cid:173)
`version of HPN -I 00 into PBA and P AA is efficient and fairly
`rapid, but surprisingly suggest that some conversion ofHPN
`to PAGN may occur before the HPN-100 (or PBA, or PAA
`derived from PBA) enters systemic circulation. As a result,
`systemic levels of PAA or PBA are not reliably correlated
`with the efficacy ofiiPN-100 as an ammonia scavenger.
`[0024]
`In some embodiments, the invention uses a prodrug
`of PBA, including HPN-100 and other esters of phenylbu(cid:173)
`tyrate. The PBA prodrug is thus a prodrug of a prodrug, since
`PBA acts to scavenge ammonia after it is converted to PAA
`and is thus considered a prodrug of PAA. In some embodi(cid:173)
`ments, the PBA pro drug is an ester of phenylbutyrate, such as
`those described below; a preferred PBA pro drug for use in the
`invention is HPN-100. These compounds can be made and
`used by methods disclosed in U.S. Pat. No. 5,968,979, which
`is incorporated herein by reference for its description of these
`compounds and methods for their administration.
`[0025] Where an 'equal molar' or 'equimolar' amount of a
`second drug is to be used along with or instead of a certain
`amount of a first drug, the amount of each drug is calculated
`on a molar basis, and the equimolar amount of the second
`drug is the amount that produces an equal molar amount of
`active drug in vivo. Where one of the drugs is a prodrug, the
`amount of prodrug will typically refer to the molar amount of
`the active species formed from that prodrug. That active spe(cid:173)
`cies is usually P AA for the prodrugs described herein, and the
`molar amount of a pro drug corresponds to the amount ofPAA
`that would form in the body from that amount of the prodrug,
`assuming complete conversion into PAA occurs in vivo.
`
`Par Pharmaceutical, Inc. Ex. 1020
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 18 of 39
`
`

`

`US 2010/0008859 AI
`
`Jan. 14,2010
`
`3
`
`Thus, for example, a molecule ofHPN-100 can be metabo(cid:173)
`lized by ester hydrolysis followed by oxidation to form three
`molecules ofPAA, so a mole ofHPN-100 would be consid(cid:173)
`ered equimolar to three moles ofPAA. Similarly, since HPN-
`100 hydrolyzes to form three molecules of PBA (and one
`molecule of glycerin), an equimolar amount of HPN-100
`would be one-third of the molar amount ofPBA.
`[0026] The following Table sets forth amounts ofHPN -100
`that correspond to equimolar amounts of certain relevant
`doses ofBUPHENYL® (sodium phenylbutyrate). Note that
`the conversion of the dose of sodium PBA to the dose of
`HPN-100 involves correction for their different chemical
`forms [i.e. HPN -100 consists of glycerol in ester linkage with
`3 molecules of PBA and contains no sodium; (sodium PBA
`[g]x0.95=HPN-1 00 [g])] as well as correction for the specific
`gravity ofHPN-100, which is 1.1 g/mL.
`
`BUPHENYL®
`(sodium PBA)
`
`450-600 mgikgiday
`(patients :S: 20 kg)
`9.9-13.0 g/m2/day
`(patients > 20 kg)
`Maximum Daily
`Dose: 20 g
`
`HPN-100 PBA
`Equivalent
`Dose (mg)
`
`HPN-100 PBA
`Equivalent
`Dose (mL)
`
`428-570 mgikg/day
`
`0.39-0.52 mL/kg/day
`
`9.4-12.4 g/m2/day
`
`8.6-11.2 mL!m2/day
`
`Maximum Daily
`Dose: 19 g
`
`17.4 mL
`
`[0027] The present invention can use prodrugs of the for(cid:173)
`mula (I):
`
`(I)
`
`H$H O-R1
`O-R2
`O-R3
`
`H
`
`H
`
`H
`
`[0028] wherein R 1 , R2 , and R, are independently, H,
`
`[0029]
`and n is zero or an even number, m is an even
`number and at least one ofRu R2 , and R3 is not H. For
`each Ru R2 , or R3 , norm is independently selected, so
`the R 1 , R2 , and R3 groups in a compound offormula I do
`not have to be identical. The preferred compounds are
`those wherein none of Ru R2 , and R3 is H, and fre(cid:173)
`quently each n or m for a particular embodiment is the
`same, i.e., R1 , R2 , and R3 are all the same. The advantage
`over the prior art of decreased dosage is greater with
`such triesters, and having all three acyl groups the same
`reduces issues related to mixtures of isomers. Moreover,
`
`the trio! backbone liberated by hydrolysis of the esters is
`glycerol, a normal constituent of dietary triglyceride
`which is non-toxic.
`[0030] The present invention also utilizes phenylbutyrate
`and phenylacetate prodrugs of the formula II:
`
`(II)
`
`0
`
`R-0~
`
`~
`
`[0031]
`[0032]
`
`wherein R is a C 1 -C 10 alkyl group,
`R4 is
`
`and n is zero or an even number, and m is an even
`
`[0033]
`number.
`[0034]
`In Formula II, R can be, for example, ethyl, propyl,
`isopropyl, n-butyl, and the like.
`[0035] The compounds of the invention are esters of the
`congeners ofphenylalkanoic and phenylalkenoic acids hav(cid:173)
`ing an even number of carbon atoms in the alkanoic acid
`portion, which include phenylacetic acid esters and those of
`phenylbutyric acid, etc., which can be converted by efficient
`beta-oxidation processes to phenylacetic acid in the body.
`They are thus prodrugs for phenylacetic acid. Where n is 2 or
`4, the esters are also prodrugs for phenylbutyric acid. Prefer(cid:173)
`ably the alkylene or alkenylene carboxylate group contains 24
`or fewer carbon atoms, so n or m is less than 24. In some
`embodiments, nand mare 0, 2, 4 or 6, and in some preferred
`embodiments norm is 2.
`[0036] Certain preferred embodiments of the invention use
`HPN-100 (Formula III):
`
`(Ill)
`
`0
`
`=-
`
`II$H 0 0
`: ~~
`
`H
`
`[0037] Total daily dosage ofprodrugs like sodium PBA can
`often be selected according to