376
`
` LUPIN
`EX. 1021
`(Part 4 of 6)
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`per day, if that dosage is within a range considered safe to administer to the patient. Either
`
`the dosage of HPN-100 or dietary protein intake could be adjusted to optimize the treatment
`
`plan for this subject.
`
`[00] 4]]Optionally, the urinary PAGN output may be determined as a ratio of urinary
`
`PAGN concentration to urinary creatinine concentration; creatinine levels are typically
`
`stable enough for a given individual to provide a normalization factor for urine volume so
`
`that rather than determining total daily urinary PAGN, the physician can estimate total daily
`
`urinary PAGN from testing a single urine sample.
`
`[00142] The physician may also monitor the plasma ammonia levels and dietary protein
`
`intake in the patient to ascertain whether the patient’s dietary protein intake and drug
`
`treatment combined are producing the appropriate therapeutic effect. Dietary protein intake
`
`or drug dosage or both could be adjusted to attain a notrnal or desired plasma ammonia
`
`level, e.g., a level below about 40 umol;’L. However, as demonstrated by the observations
`
`described herein, the physician would not use plasma levels of PAA or PBA to adjust the
`
`dosage of HPN-I00 or otherwise guide treatment, as those levels do not correlate well with
`
`the ammonia scavenging effect of the administered I-lPN—lO0.
`
`[00143] If the 19g dose of HPN-100 is determined to be inadequate (e.g. patient requires
`
`an increase in dietary protein which would result in excretion of waste nitrogen exceeding
`
`his or her urea synthesis capacity and PAGN excretion), HPN—lOO dose would be increased
`
`sufficiently to cover the necessary dietary protein and the same methodology of dose
`
`adjustment based on urinary PAGN excretion would be applied to determine that dosage of
`
`I-lPN—l00.
`
`[00144] In a subject having little or no urea synthesis capacity where essentially all
`
`urinary nitrogen would be accounted for by PAGN, the ammonia scavenging effect may be
`
`monitored by determination of total urinary nitrogen (TUN), rather than directly measuring
`
`PAGN levels in the urine.
`
`[00145] Optionally, the TUN can be used as a measure of urea synthesis capacity, by
`
`subtracting the amount of nitrogen present as PAGN.
`
`Determination of a Dosage of HPN—lOO for a Patient already on sodium PBA
`
`Example 10
`
`[00146] A patient with a UCD already on sodium PBA who is to be transitioned to HPN—
`
`100 would undergo assessment of dietary protein and measurement of urinary PAGN
`
`excretion.
`
`54
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`[00147] If the patient is judged to be adequately controlled on sodium PBA , then the
`
`starting dose of HPN-I00 would be the amount necessary to deliver the same amount of
`
`PAA (eg. 19 grams of HPN—l00 would correspond to 20 grams of sodium PBA).
`
`Subsequent dose adjustment would be based on repeated measurement of urinary PAGN as
`
`well as assessment of dietary protein and ammonia. , However, as demonstrated by the
`
`observations described herein, the physician would not use plasma levels of PAA or PBA
`
`either to determine the initial dosage of HPN-100 or adjust the dosage of HPN-100 or
`
`otherwise guide treatment, as those levels do not correlate well with the ammonia
`
`scavenging effect of the administered I-IPN~lO0.
`
`[00148] If the patient is determined to be inadequately controlled on sodium PBA , then
`
`the starting dose of HPN-I00 would be selected to deliver an amount of PAA higher than
`
`the dose of sodium PBA provided such HPN—lO0 dosage is otherwise appropriate.
`
`Subsequent dose adjustment would be based on repeated measurement of urinary PAGN as
`
`well as assessment of dietary protein and plasma ammonia. However, as demonstrated by
`
`the observations described herein, the physician would not use plasma levels of PAA or
`
`PBA either to determine the initial dosage of I-lPN—l0O or adjust the dosage of HPN—lOO or
`
`otherwise guide treatment, as those levels do not correlate well with the ammonia
`
`scavenging effect of the administered HPN—l0O.
`
`[00149] Optionally, for example in a ‘fragile’ UCD patient with a history of repeated
`
`episodes of hyperammonemia, the conversion from sodium PBA to HPN-I00 might occur in
`
`more than one step, whereby, at each step, the dose of sodium PBA would be reduced in an
`
`amount corresponding to the amount of PAA delivered by the incremental dose of HPN-
`
`100.
`
`[00150] If the dose of HPN-100 is determined to be inadequate {_e.g. patient requires an
`
`increase in dietary protein which would result in production of waste nitrogen exceeding his
`
`or her urea synthesis capacity and PAGN excretion), HPN-100 dose would be increased
`
`sufficiently to cover the necessary dietary protein and the same methodology of dose
`
`adjustment based on urinary PAGN excretion would be applied.
`
`[00151] The examples set forth herein are illustrative only, and should not be viewed as
`
`limiting the invention.
`
`55
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`Claims
`
`1.
`
`A method to determine an effective dosage of I-lPN— [O0 for a patient in need of
`
`treatment for a nitrogen retention disorder, which comprises monitoring the effect of an
`
`initial dosage of HPN—lOO,
`
`wherein monitoring the effect consists essentially of determining the patient’s
`
`urinary phenylacetyl glutamine (PAGN) output;
`
`and determining from the urinary PAGN output whether andfor how to adjust
`
`the initial dosage of HPN~l0O to produce a desired ammonia scavenging
`
`effect.
`
`2.
`
`The method of claim 1, wherein urinary PAGN output is determined as a ratio of the
`
`concentration of urinary PAGN to urinary creatinine.
`
`3.
`
`The method of claim I, wherein the nitrogen retention disorder is chronic hepatic
`
`encephalopathy or a urea cycle disorder.
`
`4.
`
`The method of claim 1, wherein administering the effective dosage of HPN—lOO to
`
`the patient produces a normal plasma ammonia level in the patient.
`
`5.
`
`A method to determine an effective dosage of HPN-100 for a patient in need of
`
`treatment for a nitrogen retention disorder, which comprises monitoring the effect of an
`
`initial dosage of HPN-100,
`
`wherein monitoring the effect consists of determining the patient’s urinary
`
`phenylacetyl glutamine (PAGN) output andfor total urinary nitrogen.
`
`6.
`
`A method to determine a dosage of HPN—lOO for a patient having a nitrogen
`
`retention disorder, which comprises calculating the dosage of HPN—lOO based on a
`
`utilization efficiency for HPN-I00 conversion into PAGN of about 60% to about 75%.
`
`7.
`
`The method of claim 6, wherein the dosage of HPN—lOO is calculated from the
`
`patient’s dietary protein intake.
`
`8.
`
`The method of claim 7, wherein the dosage of HPN—lOO is reduced to account for the
`
`patient’s residual urea synthesis capacity.
`
`56
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`9.
`
`A method to determine a dosage of a PAA prodmg for a patient having an ammonia
`
`retention disorder, comprising:
`
`a)
`
`b)
`
`c)
`
`d)
`
`determining the patient’s residual urea synthesis capacity;
`
`determining the patient’s dietary protein intake;
`
`estimating from a) and b) the patient’s target urinary PAGN output;
`
`determining an amount of the PAA prodrug needed to produce the
`
`target amount of urinary PAGN,
`
`wherein about 60% to about 75% of the PAA prodrug is converted
`
`into urinary PAGN.
`
`10.
`
`The method of claim 9, wherein the PAA prodrug is phenylbutyric acid (PBA) or a
`
`pharmaceutically acceptable salt thereof.
`
`1 1.
`
`The method of claim 9, wherein the PAA prodrug is HPN-100.
`
`12.
`
`A method to treat a patient having an ammonia retention disorder with a suitable
`
`dosage of a PAA prodrug, comprising:
`
`at)
`
`b)
`
`c)
`
`d)
`
`determining the patient’s residual urea synthesis capacity;
`
`determining the patient’s dietary protein intake;
`
`estimating from a) and b) the patient’s target urinary PAGN output;
`
`determining an amount of the PAA prodrug needed to mobilize the
`
`target amount of urinary PAGN based on about 60% to about 75%
`
`conversion of the PAA prodmg into urinary PAGN; and
`
`e)
`
`administering to the patient the suitable dosage of the PAA prodrug.
`
`13.
`
`The method of claim 12, wherein the PAA prodrug is phenyibutyrate or a
`
`pharmaceutically acceptable salt thereof, or HPN-100.
`
`14.
`
`The method of claim 12, wherein the PAA prodrug is HPN-100, the patient is a
`
`patient with clinically significant residual urea synthetic capacity, and the HPN-100 is
`
`administered in two or three doses per day.
`
`57
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`15.
`
`A method to transition a patient receiving treatment with an initial amount of
`
`phenylacetate or phenylbutyrate to a final amount of HPN-I00, comprising:
`
`determining a replacement amount of HPN—lO0 to replace at least a portion
`
`of the phenylacetate or phenylbutyrate;
`
`substituting the replacement amount of the HPN—IOO for the phenylacetate or
`
`phenylbutyrate; and
`
`monitoring the amount of urinary PAGN excreted by the patient to assess the
`
`effectiveness of the replacement amount of the HPN-100.
`
`16.
`
`The method of claim 15, wherein an increase in the amount of urinary PAGN caused
`
`by the transition indicates that the amount of HPN-100 can be reduced.
`
`I7.
`
`A method to transition a patient taking an initial daily dosage of phenylbutyrate from
`
`phenylbutyrate to HPN-I00, comprising
`
`a")
`
`determining a suitable amount of HPN—lO0 to replace at least a
`
`portion of the initial daily dosage of phenylbutyrate;
`
`b)
`
`administering the suitable amount of HPN-I00 to the subject along
`
`with an amount of phenylbutyrate corresponding to the initial daily dosage of
`
`phenylbutyrate minus an amount corresponding to the portion replaced by
`
`HPN-100;
`
`determining the level of excreted urinary PAGN for the subject; and
`
`repeating steps a—c until all of the phenylbutyrate is replaced by I-IPN-
`
`c)
`
`d)
`
`100.
`
`18.
`
`A method to initiate treatment with phenylacetate, phenylbutyrate or a I-IPN—l0O in a
`
`step-wise fashion, comprising:
`
`a)
`
`b)
`
`estimating or measuring dietary nitrogen intake for the patient; andfor
`
`estimating the patient’s need for urinary waste nitrogen excretion
`
`based upon diet and urea synthetic capacity; then
`
`c")
`
`administering a starting dose of the drug estimated to provide a
`
`fraction of the necessary waste nitrogen clearance as urinary PAGN taking
`
`into account an estimated 60% to 75% conversion of the administered drug
`
`into PAGN; and
`
`58
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`d) increasing the dose of drug as appropriate, and repeating the steps above,
`
`to reach a maintenance dose of the drug.
`
`19.
`
`A method to treat a UCD patient with a PBA prodrug, wherein the prodrug produces
`
`equivalent or better ammonia level control compared to PBA without increasing the
`
`patient’s exposure to PBA as judged by the AUC and Cmax for PBA when the patient
`
`receives the PBA prodrug, when compared to the AUC and Cmax observed when the patient
`
`receives an equimolar amount of PBA.
`
`20.
`
`The method of claim 19, wherein the PBA prodrug is HPN-100.
`
`21.
`
`The method of claim 20, wherein the AUC for PBA exposure is lower with the
`
`prodrug than with PBA by at least about 20%.
`
`22.
`
`The method of claim 20, wherein the exposure to PBA upon treatment with the
`
`prodrug is lower by at least about 30% compared to treatment with PBA.
`
`23.
`
`A method to determine a suitable dietary protein level for a patient having a nitrogen
`
`retention disorder, comprising:
`
`determining the patient’s endogenous nitrogen elimination capacity;
`
`calculating from the endogenous nitrogen elimination capacity an amount of
`
`dietary protein the patient can process without the aid of a nitrogen
`
`scavenging drug;
`
`then adding an amount of protein that the patient should be able to process
`
`with the assistance of selected dosage of a nitrogen scavenging drug to arrive
`
`at an amount of dietary protein the patient can have while being treated with
`
`the selected dosage of the nitrogen scavenging drug, taking into account the
`
`of protein required for health and body growth.
`
`24.
`
`The method of claim 23, wherein the nitrogen scavenging drug is HPN-I00.
`
`25.
`
`The method of claim 24, wherein the selected dosage of HPN—I0O is up to about 19
`
`grams per day, and wherein the amount of dietary protein the patient should be able to
`
`59
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`

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`process with the assistance of this amount of HPN~lO0 is about I g of protein per gram of
`
`HPN—lO0.
`
`26.
`
`A method to treat a patient with a PBA prodrug, comprising administering HPN—lOO
`
`at a daily dose in excess of 19 g per day to a subject having HE or UCD.
`
`27.
`
`The method of claim 26, wherein the daily dose of HPN-I00 is between about 19g
`
`and about 57 g.
`
`28.
`
`A method to treat a patient having a nitrogen retention disorder with the PBA
`
`prodrug HPN—l0O, wherein the AUC for PBA is less than about 600 and the Cmax for PBA
`
`is less than about I00 when the PBA prodrug is administered.
`
`29.
`
`The method of claim 28, wherein the subject's plasma ammonia levels are on
`
`average normal when treated with I-IPN—l0O.
`
`60
`
`383
`
`383
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`

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`PCT/US09/30362 19-O3-2009
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`W0 2009:"134-460
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`PC T2’ US2 0095030362
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`5:
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`Exam
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`
`]_n[g1-national appjjcation N°_
`PCTHJS 09130362
`
`A.
`
`CLASSIFICATION OF SUBJECT MATTER
`
`lPC(8) - A01N 37:10: A61K 31:19 (2009.01)
`.
`USPC - 514i'5T0
`According to International Patent Classification {‘[PC) or to both national classification and IPC
`B.
`FIELDS SEARCHED
`.
`
`Minimum documentation searched (classification system followed by classification symbols)
`IPCIB}: A01 N 3?.-'10: A61K 31.-'19 (2009.01)
`USPC: 514.-'5?'0
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`|PC(8}: A01N 3?.i'10; A61 K 31.-‘19 (2009.01)
`USPC: 5143570
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`US WEST(PGPEl.USPT.EF'A.B.JPAB). Googlo Scholar. Dialog PRO (Engineering)
`ammonia scavenging. accumulation. retention. hepatic encephalopathy. urea cycle disorder. phenylacatyl glutamine. PAGN. HPN-100.
`pl-tenyl butyrate. glyceryl ti-I-{4-phanyl butyrate}
`
`C. DOCUNIENTS CONSIDERED TO BE RELEVANT
`Category‘
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`US 2D|J4t‘|J22994B A1 (SUMMAR. 81 al.) 13 November 2004 (13.11.2004). para [0D22}. [D029].
`[0035]
`
`1-11. 19-22. 28. 29
`
`US 4,284.6-4?A (BRUSILOW. at al.) 18 August 1981 (13.03.1981) col 2, In 26-32: Fig. 3: col 4.
`In 35-45.
`
`1-5. 9-18. 23-2?. 29
`
`US 5.95B.9T9 A(BRUS|LOW)19 October 1999 (19.10.1999). col 1. In 2?-34; col 1. In 41-45: col 6-29
`2. In 25-34: col 3. In 34': co! 3, In 42-59: col 4, In 1-26: col 4. In 54-53: col 5. In 3-15: In 29-35
`
`El Further docu.menLs are listed in the continuation ofl-lox C.
`
`El
`
`Special caresories of cited documents
`document defining the general state ofthe art which is not considered
`to be of particular relevance
`'
`earlier application or pale nt but published on or after IJ1e intemational
`filing date _
`document which may throiy doubts on priority clairri(s)_ or which is
`cited to establish the publication date of another citation or other
`special reason (as specified)
`docuriierit referring to an oral disclosure. use. exhibition or other
`|'l'|¢fll'1S
`
`--1“
`
`..x..
`
`document published prior to the international filing date but later than n --
`the priority date claimed
`I
`
`riority
`later document published after the inlerrtatiorial filing date or
`— date and not in conflict with the apdoltication but cited to un erstand
`the principle or theory underlying
`e invention
`document of
`'t:ular relevance; the cIairnod_invention cannot _be
`considered novel or cannot be considered to involve an inventive
`step when the document is taken alone
`document of particular relevance; the claimed imiiention cannot be
`considered to involve an inventive step when the doci.i.rnent_ is
`coi_1'ibIriod with one or more other such docmnents. such combination
`being obvious to_a person skilled in the art
`document member of the same patent fnrnily
`
`Date of the actual completion ofthe international search
`24 February 2009 (24.02.2009)
`
`Name and mailing address ofthc ISAIUS
`Mail Stop PCT. Ann: ISNUS. Commissioner for Patents
`P.O. Box 1450. Alexandria. Virgiriia 22313-‘I450
`Facsimite No.
`5?1-273-3201
`'
`
`Form PCUISAFZIO (second sheet) (April 2007)
`
`Date of mailing of die international Search report
`0 2 MAR 2009
`Authorized officer:
`
`Lee W. Young
`
`PCT Holpdoslt: 571-272-4300
`PCT OSP: 5?'1—2?2-T774
`
`399
`
`399
`
`

`
`(12) INTERNATIONAI. API’I..ICA'T'lON PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`
`4 March 2010 (04.03.2010) I|||||||||l|||||||||ll||||l|l|||||||l|||l|||||||||||||||||||||||||||||||l||J|||||||J||||||||l||
`
`(10) international Publication Number
`
`WO 2010/025303 Al
`
`International Patent Classification:
`GOJN 33/50 (2006.01)
`
`(21)
`
`International Application Number:
`PCT/US2009.r'055.".56
`
`(74)
`
`(22)
`
`International Filing Date:
`
`(25)
`
`Filing Language:
`
`(36)
`
`Publication Language:
`
`27 August 2009 (27.08.2009)
`
`(81)
`
`English
`
`I"-Znglish
`
`US
`US
`US
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Priority Data:
`29 Atlgt1st2008(29.08.2008)
`610393.234
`3" January 2009 ((}7.til .2009)
`l2r‘35(),l ll
`PC'ITUS09t30362 7 Jaituaty 2009 (07.01 .2009)
`
`Applicant i_’fiJt' rttt desigtmted Sttttes except US): HYPE-
`RION 'l‘HERAPEU'I‘lCS IUS/US |; 601 Gateway Boule-
`vard. Suite 200, South San 1'-‘rxmcisco. CA 94080 (US).
`Inventor: and
`lnventormpplleant (fir US ozrty): SCHARSCHMIITI‘.
`Bruce |USfUS]‘, Hyperion Tltcrapelilics, 601 Gateway
`
`Boulevard, Suite 200, South .3311 Francisco. CA 94080
`(US).
`
`Agents: SMITH. Michael. G. e1al.; Morrison & Foerster
`LLP, 13531 High Bluli' Drive. Suite 100. Salt Diego. CA
`92 I30-2040 (US).
`
`Designated States |!'tttti'(f.'u'§' otttcrwise indicrtted. fin‘ evetjv
`kind oftmtiotmf protection awtilobicr): AE, AG, AL, AM,
`A0, AT. AU, AZ, BA, BB. BG, BII, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO.
`DZ, BC,
`I_''];_,
`I.-‘Li, E8, E1, (ill, (ii), (iii, till, GM, GT,
`HN, HR, HU, Li), IL, IN, is, JP, Ki:-I, KG. KM, KN, K1’,
`KR, KZ. LA. LC. LK, LR. LS, LT, LU, LY, MA, MI"),
`ME, MG, MK. MN, MW, MX, MY, MZ, NA, NG, NI.
`NO, NZ, OM, l‘l."., PG, PH, PL, PT, RO, RS, RU, SC. SI),
`SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN. TR, TT,
`TZ. UA, UG. US. UZ, VC.
`ZA. ZM. ZW.
`
`(84)
`
`Designated States tniiiess otitrmwise i??diC'(i!(.’d, fiir L"-’c’tj.'
`kind ofrcgiunm’ protection mrrtitttbtc): ARIPO {'BW, GI-I,
`GM, Kli, LS, MW, MZ, NA, SI), SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), lhlropeztlt (AT, B13, HG, CI I, CY, CZ-, Dli, DK, EE,
`
`fContimtcd on m3xtpa_ge;’
`
`
`
`wo2010/025303A1||||||||||||l|||||||||||||l||||||||||||l|||l|||l|I||ll|l||||l|||l|||||I||||||||||||||||||||||||
`
`(54) Title: IJOSING AND MONITORING PATIENTS ON NITRO(jIiN—SCAVIiNGIN(i DRUGS
`
`(57) Abstract: The invention provides at utethod for determining 2: dose and
`dosing schedule, and making dose adjustments of patients taking l‘B.='-‘t pro-
`drugs as nitrogen scavengers to treat nitrogen retention states, iitcluding eun-
`nionia ncctuuulution disorders as well as chronic renal failure, by 1I1Cil5l.l.l‘l1'lg
`llrinary excretion ofpltettylaeetylgititarttinc antlfor total urinary nitrogen. The
`irivcliliou provides methods to select on appropriate dosage oi‘ It PBA prodrug
`based on the patient's dietary protein intake, or based on previous trca1mc111's
`administered to the patient. The ittctltods are applicable to selecting or modi-
`Fying u tlosirtg regimen For a subject receiving an orally mlntinislered waste
`nitrogen scavenging drug, and to monitoring patients receiving such drugs.
`
`Figure la
`Nitrogen Retention Slates
`Human Nitrogen Retention States: Hereditary Lucas: and
`Acquired {Cirrhosis} Liver Disease And chronic Renal Failure (CHI-1
`
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`
`WO 2010/025303 A1 1|||||||||||||||||||l||||||||[|||||||||l|||||||||||l||||||l|||||||||||||||J|||||||||||||||||||1
`
`1-‘[, FR, GB, GR, HR, HU, IE, IS, 11‘, LT, LU, LV,
`MC, MK, MT, NL, N0, PL, PT, RO,
`SI, SK, SM,
`TR). OAPI (BF, BJ, CF, CG, CI, CM, GA, (JN, GQ, GW,
`ML, MR, N13, srx‘, Tl), TU).
`Published:
`
`— Lvirh z'nrcJ':mr:'omn’ sea.-‘c-Ir report (Arr. 2H3);
`
`— bcjfbre fire e.\'p1'r'aricm qfrhe time ."imir‘f)r amending the
`dafms and m be republfflred in the (.‘\'{.’J?:' Q.-’ rac'e:‘;)r of
`amendments {Rule 4‘8. 30':,1)
`
`401
`
`401
`
`

`
`W0 201011125303
`
`PCTIU S2009;‘055256
`
`DOSING AND MONITORING PATIENTS ON NITROGEN-SCAVENGING DRUGS
`
`Cross—Rel'erence to Related Applications
`
`[0001] This application is a continuat.ion in part ofU.S. Nonprovisional Patent Application
`
`Serial No. l2r‘350,l l 1, filed January 7, 2009 which is pending, and a continuation in part of
`
`International Application No. l’(ITfIJS(}8f30362, filed January 9, 2009, each of which claims
`
`benefit of priority to U.S. Provisional Application Serial Number 6lz"093,234, filed August ‘.29,
`
`2008, each of which is incorporated herein by reference in its entirety. This application is also
`
`relat.ed to the U8. provisional patent. application entitled “Treating special populations having liver
`
`disease with nitrogen-scavenging compounds," naming Sharron Gargosky as inventor, serial
`
`number 61/048,830. filed on April 29, 2008.
`
`Technical Field
`
`[0002] This invention relates to treatment of patients with nitrogen retention st.at.es, including
`
`urea cycle disorders (UCDs), cirrhosis complicated by hepatic encephalopathy (HIE) and chronic
`
`renal failure (CRF). using administered compounds that. assist in eliminat.ion of waste nitrogen
`
`from the body. The compounds can be orally administered small-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 effectiveness ofa treatment. As depicted in
`
`Figure la, 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 clearance of ammonia from the portal circulation and conversion to urea via the urea
`
`cycle, depicted in Figure 1b, result. in elevated levels in the blood of ammonia. a potent. neurotoxin.
`
`CR1‘, while associated in some instances with mildly elevated levels of ammonia, (Deferrari, @
`
`@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 ofdietary protein (i.e. intake of dietary nitrogen) is comlnonly used in die
`
`management of each of these nitrogen ret.ention states. to avoid accumulation of ammonia or
`
`metabolic products containing ammonia, e. g., urea. References herein t.o ammonia and ammonia
`
`402
`
`402
`
`

`
`W0 201011125303
`
`PCTIU S2009;‘055256
`
`scavenging refer primarily to treating UCD5: and I-113 and conditions that emulate UCDs, although
`
`the terms ammonia scavenging and waste nitrogen scavenging are used interchangeably.
`
`Back round Art
`
`[0004] Drug dosing is usually based upon measurement of blood levels of the active drug
`
`species in conjunction with clinical assesslnent of treatment response. However, the present
`
`invention is based on evidence that for certain pnodrugs of phenylacetic acid (PAA), measuring the
`
`blood level of the prodrug (e.g. PBA) or of PAA formed from it is unreliable in assessing drug
`
`effect: drug levels in the blood do not correlate with efficacy in this case. In addition, assessment
`
`of treat.ment effect. by measuring levels of ammonia in the blood in IJCD 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 clinic ally impractical as a way to monitor a treated patient. The
`
`variability in blood ammonia levels reflects the fact that ammonia levels in UCD patients are
`
`affected by various factors including dietary protein and t.iming 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
`
`(PB/\'} behave similarly to sodium PB./X, in that measuring PBA levels is unreliable for assessing
`
`their effectiveness. This invention provides a novel method for closing in patients with nitrogen
`
`retention states, in particular patients with liver disease and clinical manifestations of hepatic
`
`encephalopathy and patients with UCl)s.
`
`It is particularly applicable to prodru gs that liberate or
`
`are metabolized to form phenylacetic acid, i.e., prodrugs of PAA, and those prodrugs that are
`
`metabolixed to form PB/\.
`
`[0005] Hepatic encephalopathy (I-IE) refers to a reversible spectrum of neurologic signs and
`
`symptoms which ‘frequently occur in patients with cirrhosis or certain other types of liver disease.
`
`[0006] Urea cycle disorders (UCDs) comprise several inherited deficiencies of enzymes or
`
`transporters necessary for the synthesis of urea frotn ammonia. The urea cycle is depicted in Figure
`
`lb, which also illustrates how certain ammonia—scavenging drugs act to assist in elimination of
`
`excessive ammonia. UCDs include inherited conditions associated with insufficient function of
`
`any one