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`
`US008642012B2
`
`(12) United States Patent
`Scharschmidt
`
`(10) Patent No.:
`
`(45; Date of Patent:
`
`US 8,642,012 B2
`Feb. 4, 2014
`
`(54) METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`(75)
`
`Inventor:
`
`Bruce Seharschmtdt. South San
`l" rzmcisco. C.’A (US)
`
`(73) Assignee: Hyperion Therapeutics, Inc.. South San
`Francisco, CA (US)
`
`[ “ ) Notice:
`
`Subject to any disclaimer. the term of this
`patent is extended or adjusted under 35
`U.S.C. 154-(b) by 623 days.
`
`(21) App1.No.: 121350411
`
`(22)
`
`Filed:
`
`Jan. 7, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2()10i"0008859Al
`
`Jan. 14, 2010
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 617093.234, filed on Aug.
`29, 2008.
`
`(51)
`
`Int. Cl.
`/161K 49/00
`
`(2006.01)
`
`(52) U.S. ('21.
`42419.2: 5147568: 5140432: 5147433
`USPC‘
`(58) Field of Classification Search
`
`See application file for complete search history.
`
`5147533
`
`(56)
`
`References Cited
`
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`
`4.284.647 A
`5.968.979 A
`6.060.510 A
`6.083.934 A "‘
`6.219.567 Bl
`2004.-'0229948 Al
`2006.-"Ul356i2 Al
`200850119554 Al
`2010.-"000S859 Al
`
`83198] Brusilowetal.
`10.-‘I999 Brusilow
`52000 Brusilow
`7.-“Z000 Brusilow
`4.-‘"2001 Eggers et al.
`1132004 Summaretal.
`6-‘"3006
`lierrante
`5-“"2008
`.la|a.n etal.
`I-"2010 Scharschmidl
`
`FOREIGN PATENT DOC UMENTS
`
`W0
`WU
`WO
`WO
`WC!
`
`Wt.)-200 53053607
`W0-2006.-"0 56794
`W0-2009.-"0874 74
`WO-2009-"134460 A1
`WO-2010150303 Al
`
`62005
`6-‘Z006
`752009
`l [-2009
`3-"2010
`
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`“Dose-1.-‘scaiation
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`of
`Glyceryl
`Tri
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`Oct. 5. 2009]. 4 pages.
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`Batshaw. M .L. (1984). “['lypera.Inmoncmia." in C'm'rerr.' P.v'obt‘em.s' in
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`
`Brusilow. S.W. et al. (Sep. 1. 1979). "New Pathways of Nitrogen
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`nism of Nitrogen Excretion in lnbom Errors of Urea Synthesis."
`Scieriee 201659-661.
`
`Brusilow. S.W. (Jun. 21. 1984). “Treatment of Episodic Hyperam-
`monemia in Children With Inborn Errors ofllrea Synthesis." N. Errgi‘.
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`Churchill Livingstone. New York. New York. pp. 79-94.
`
`(Continued)
`
`Jon P Weber
`Prinmr_i= Iixoiiiiner
`'l'ilTa11y Ciough
`A.vsi'srrmr Iixarirfner
`(74) Attomey. Agent, or Firm — Perkins Coie LLP: Patrick
`Morris
`
`(57)
`
`ABS'l'RAC'I'
`
`The invention provides a method for determining a dose and
`schedule and making dose adjustments of PBA prodrngs used
`to treat nitrogen retention states. or ammonia accumulation
`disorders. by measuring urinary cxcrctitm of p11enylace1yl-
`glulamine andfor total urinary nitrogen. The invention pro-
`vides methods to select an appropriate dosage of at 1313A
`prodrug based on the patient‘ 5 dietary protein intake. or based
`on previous treatments administered to the patient. The meth-
`ods are applicable to selecting or modifying a dosing regimen
`for a subject receiving an orally administered ammonia scav-
`enging drug.
`
`12 Claims, 15 Drawing Sheets
`
` LUPIN
`EX. 1001
`
`EX. 1001
`
`LUPIN
`
`

`
`US 8,642,012 B2
`Page 2
`
`(56)
`
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`[IIPN-100].
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`
`2
`
`

`
`US 8,642,012 B2
`Page 3
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`Summar. M. el al. (2007). “Description and Outcomes of 3 I6 Urea
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`I-Iepatology 51-.2077-2035 (2010).
`
`* cited by examiner
`
`3
`
`

`
`U.S. Patent
`
`Feb. 4, 2014
`
`Sheet 1 of 15
`
`US 8,642,012 B2
`
`Figure 1
`
`Sodium Phenlybutyrate
`
`Orlflllnl
`.___.
`L 3*
`
`I:
`I’:
`v’ "
`
`n
`
`lill
`
`-"__\y
`
`Fununh
`
`4
`
`

`
`U.S. Patent
`
`Feb. 4, 2014
`
`Sheet 2 of 15
`
`US 8,642,012 B2
`
`Figure 2
`
`A conventional clinical phannaculogy model in which only drug reaching the central (syslenfic)
`circulation is assumed to be active.
`
`PK/PD Modeling of PBA/PAA/PAGN/UPAGN
`- Conventional Approach -
`
`HPN-100 OI’
`
`"
`
`
`
`BSA.F1.‘f3 x VH1, \l'M2, VPB, VI‘-‘A, VPG
`
`5
`
`B"P"'°"3"@
`am’, one
`_................ .1
`"
`'
`
`This model only allows for conversion of PBA to
`PM to PAGN in the systemic (labeled ‘cenIral’)
`plasma compartment. Bioavailability and drug
`effect is assume to relate directly to plasma
`metabolite cuncantations
`
` Covarlate
`
`

`
`US. Patent
`
`Feb. 4, 2014
`
`Sheet 3 of 15
`
`US 8,642,012 B2
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`US. Patent
`
`Feb. 4, 2014
`
`Sheet 4 of 15
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`US 8,642,012 B2
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`Feb. 4, 2014
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`Sheet 5 of 15
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`Feb. 4, 2014
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`US 8,642,012 B2
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`US. Patent
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`Feb. 4, 2014
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`US 8,642,012 B2
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`US 3,642,012 B2
`
`2
`
`1
`METHODS OF TREATMENT USING
`AMMONIA-SCAVENGING DRUGS
`
`C ROSS-REF ERENC E TO RELATED
`Al-‘Pl ,lCATIONS
`
`This application claims benefit of priority to U .S. Provi-
`sional application Ser. No. 6l!093.234. filed Aug. 29. 2008.
`which is incorporated herein by reference in its entirety. This
`application is also related to the US. provisional patent appli-
`cation entitled “Treating special populations having liver dis-
`ease with nitrogen-scavenging compounds,” naming Sharron
`Gargosky as inventor, Ser. No. 6lr'C|48,830, filed on Apr. 29.
`2008.
`
`ll]
`
`TECHNICAL FIELD
`
`This invention relates to treatment of patients with nitrogen
`retention states. in particular urea cycle disorders (UCDS) and
`cirrhosis complicated by hepatic encephalopathy (I Ill). using
`administered compounds tl1at assist in elimination of waste
`nitrogen from the body. The compounds can be orally admin-
`istered s111all-molecule drugs. and the invention provides
`methods for delivering these compounds and selecting suit-
`able dosages for a patient.
`
`BACKGROUND ART
`
`Drug closing 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 o11 evidence that for certain prodrugs of
`phenylacetic acid (PAA), measuring the blood level of the
`prodrug (cg. PBA) or ofP.1\.?\ formed ii'om it is unreliable. In
`addition, assessment of treatment effect by measuring levels
`ofammonia in the blood is inconvenient. because it requires
`withdrawing multiple blood samples under carefully con-
`trolled 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-
`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 of PAA. and those prodrugs that are metabolized to
`form PBA.
`I-iepatic encephalopathy refers to a spectrum ofneurologie
`signs and symptoms which frequently occur in patients with
`cirrhosis or certain other types of liver disease.
`Urea cycle disorders comprise several inherited deficien-
`cies ofenzyines or transporters necessary for the synthesis of
`urea from ammonia. The urea cycle is depicted in FIG. 1.
`which also illustrates how certain aim11onia~scavenging drugs
`act
`to assist
`in elimination of excessive ammonia. The
`enzymes including their Enzyme Commission (EC) numbers
`and modes of inheritance include the following:
`Carbamyl phosphate synthetase (CPS; EC Number
`6.3.4.16; autosomal recessive}.
`ornithine transcarbamylase (OTC; EC Number 2.1.3.3:
`X-linked),
`argininosnecinate synthetase (ASS; EC Number 6.3.4.5:
`autosomal recessive).
`
`3t:
`
`35
`
`4t’:
`
`45
`
`50
`
`55
`
`6111
`
`argininosuccinate lyase (ASL: EC Number 4.3.2.1: auto-
`somal recessive).
`arginase {ARG: EC Number 3 .5 .3. l ; autosomal recessive).
`and
`
`IEC Number
`
`N-acetyl glutainine synthetase (NAGS 1;
`2.3.1.1: autostirllal recessive)
`Mitochondrial transporter deficiency states which mimic
`many features ofurea cycle enzyme deficiencies include the
`following:
`[l1yperon1itl1inemia.
`translocase deficiency
`Ornithine
`hyperammonemia. homocitrullinuria or l-lHl~l Syn-
`drorne)
`C itrin (aspartate glutamate transporter) deficiency
`The conirrion feature of UCD and hepatic encephalopathy
`that render them treatable by methods of the invention is an
`accumulation ofexcess waste nitrogen in the body. and hyper-
`annnonemia.
`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 UC D or
`l-lli. the body '5 intrinsic capacity for waste nitrogen excretion
`is less than the body’s waste nitrogen production based on a
`normal diet that contains signi ftcant 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 important part
`of an overall management strategy for such disorders.
`To avoid build-up of ammonia to toxic levels in patients
`with nitrogen retention states. dietary intake of protein (a
`primary source of exogenous waste nitrogen) ntust be bal-
`anced 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-
`dren; thus in addition to controlling dietary protein intake.
`drugs that assist with elimination of nitrogen are used to
`reduce ammonia build-up [hype-rammonemia). The capacity
`to eliminate excess anunonia in treated patients can be con-
`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 sotue embodiments, the
`invention relates to methods for detenniniug 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.
`Based on prior studies in individual UCD patients {e.g.
`Bmsilow. Pedfrifric Research. vol. 29, 147-50 {I991};
`Brusilow and Finkelstien. .1. Metabolfsrit. vol. 42. 1336-39
`(1993)) in which 80-90% of the nitrogen scavenger sodium
`phenylbntyrate was reportedly excreted in the urine as PAGN.
`current treaunent guidelines typically either assume complete
`conversion of sodium phenylbutyrate or other PA.-it prodrugs
`to PAGN {e.g. Berry et al.. J. r"edr'am‘cs. vol. 138. S56-S61
`(2001 )) or do not conmient on the implications of incomplete
`conversion for dosing (e.g. Singh. Urea Cycle Disorders Con-
`ference Group 'Ct'J.t‘t'S£.’."e'.$'H$ rS'tatentent_,-‘rota: a Conféreiire_{br
`the Managenuem‘ q;"Pa!r'err!.r it-'i'.'}2 Urea Cycle Disorders".
`Supp.-' to .1 Pediatrics. vol. 138(1). S l—S5 (2001)).
`Current treatment guidelines recommend 4 times per day
`dosing. based on the fact that l-‘BA is absorbed rapidly from
`the intestine when administered in the form of sodium Pl-3A
`
`19
`
`19
`
`

`
`3
`
`4
`
`US 3,642,012 B2
`
`and exhibits a short half life iii the bloodstream (Urea Cycle
`Disorders Conference Group ‘Consensus Statement‘ 2001)
`Current recommendations for sodium phenylbutyrate dos-
`ing indicate that dosage should not exceed 600 mgfkg (for
`patients weighing up to 20 kg) or in any case 20 grams total.
`
`DISCLOSURE OF EMBODIMENTS OF THE
`INVENTION
`
`The invention provides a novel approach for detemiining
`and adjusting the schedule and dose of orally administered
`nitrogen scavenging drugs_. including sodium phenylhutyrate
`and glyceryl tri-[4-phenylbtrtyratcj (IIPN-100). based upon
`the urinary excretion of the drug metabolite phenyiacetyl-
`glutamine {PAGNJ andfortotal urinary nitrogen. It is based in
`part on tl1e discoveries that bioavailability of these drugs as
`conventionally assessed based on systemic blood levels ofthe
`drugs themselves or of the active species produced 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 ammonia scavenging drugs as defined below and
`that conversion oforally administered sodium phenylbutyrate
`(NaPBA. or sodium PBA) to PAGN to urinary PAGN is
`incomplete. typically about 60-75%. Prodrugs of pl1enylbu-
`tyrate (PBA, the active ingredient in BUPHENYL=E3 (sodium
`phenylbutyrate), which is the sodium salt of PBA along with
`small amounts of inert ingredients). which is itself a prodrug
`of plienylaeetic acid (PAA). are especially subject to the
`eifects described herein.
`
`CO_=_‘l~ia‘
`
`phenylbuty rate
`OH
`
`O
`
`Phc nylacetic acid
`NH;
`
`0
`
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`
`3””
`
`ll
`
`0
`
`Phenylacetylgitltamine
`
`As used herein “ammonia scavenging drugs" is defined to
`include all orally administered drugs in the class which con-
`tain or are metabolized to phenylacetate. Thus. the term
`includes at
`least phenylbutyrate, BUPHENYL-‘E? (sodium
`phenylbutyrate). AMMONAPSKEI.
`buryroyloxyn1ethyl~4—
`phenylbutyrate. glyceryl tri-[4-phenylbutyrate] (I-IPN-l00).
`esters. ethers. and acceptable salts, acids and derivatives
`thereof. These drugs reduce high levels of endogenous
`anuttonia by providing phenylacetic acid in vivo. which is
`metabolized efiiciently 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 phenylbtttyr-ate are
`understood to inclttde reference to the drug product l3UPHI£-
`
`NYLFRJ. and BUPHENYL~'E=- was used forthe Examples herein
`wherever test subjects were treated with sodium phenylbu-
`tyrate. Thus the sodium PBA dosages used in the Examples
`generally refer to a dosage of BUPI-IENYLtEJ_. and the
`amounts of sodium phenylbutyrate in those lixamples should
`be interpreted accordingly. Note that the terms ‘ammonia
`scavenger‘ and ‘nitrogen scavenger‘ are used intercltangeably
`in this invention. rellecting the fact that the drugs described
`herein lower blood ammonia through elimination of waste
`nitrogen in the fomi of PAGN.
`In some embodiments. the invention uses prodrugs that can
`be converted into PAA within the body. Soditun phenylbu-
`tyratc [sodium PBA] is one such drug; it is converted by
`oxidative mechanisms into PAA in the body. HPN—l00 is
`another such drug: it can be hydrolyz