(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`4 March 2010 (04.03.2010) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2010/025303 A1
`
`
`(51)
`
`(21)
`
`International Patent Classification:
`
`G01N 33/50 (2006.01)
`
`International Application N umber:
`PCT/US2009/05 525 6
`
`(74)
`
`(22)
`
`International Filing Date:
`
`27 August 2009 (27.08.2009)
`
`(81)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`29 August 2008 (29.08.2008)
`61/093,234
`7 January 2009 (07.01.2009)
`12/350,111
`PCT/USO9/30362 7 January 2009 (07.01.2009)
`
`English
`
`English
`
`US
`US
`US
`
`Applicant 0’or all designated States except US): HYPE-
`RION THERAPEUTICS [US/US]; 601 Gateway Boule-
`vard, Suite 200, South San Francisco, CA 94080 (US).
`
`(84)
`
`(72)
`(75)
`
`Inventor; and
`Inventor/Applicant (for US only): SCHARSCHMIDT,
`Bruce [US/US]; Hyperion Therapeutics, 601 Gateway
`
`Boulevard, Suite 200, South San Francisco, CA 94080
`(US).
`
`Agents: SMITH, Michael, G. et a1.; Morrison & Foerster
`LLP, 12531 High Bluff Drive, Suite 100, San Diego, CA
`92130-2040 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnationalprotection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT,
`TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, fiar every
`kind afregional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`
`[Continued on nextpage/
`
`(54) Title: DOSING AND MONITORING PATIENTS ON NITROGEN—SCAVENGING DRUGS
`
`(57) Abstract: The invention provides a method for determining a dose and
`dosing schedule, and making dose adjustments of patients taking PBA pro-
`drugs as nitrogen scavengers to treat nitrogen retention states, including am-
`monia acctunulation disorders as well as chronic renal failure, by measuring
`urinary excretion of phenylacetylglutamine and/or total urinary nitrogen. The
`invention provides 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 methods are applicable to selecting or modi-
`fying a dosing regimen for a subject receiving an orally administered waste
`nitrogen scavenging drug, and to monitoring patients receiving such drugs.
`
`Figure 1 a
`Nitrogen Retention States
`Human Nitrogen Retention States: Hereditary (UCDs) And
`Acquired (Cirrhosis) Liver Disease And Chronic Renal Failure (CFtF)
`
`HereditaryUJCDs) and
`Acquired (Cirrhosis)
`leer Disorders
`
`chronic Renal
`l-allule (cur)
`
`
`dielary
`
`pruiern '
`
`
`
`Figure lb
`The Urea Cy cle
`
`Sorlilim Fhenlyhutyvate
`
`
`
`
`
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`
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`Horizon Exhibit 2042
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`Par v. Horizon
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`IPR2017-01768
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`we2010/025303A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`IPR2017-01768
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`WO 2010/025303 A1 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, R0, SE, SI, SK, SM,
`TR), OAP1(BF, BJ, CF, CG, C1, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`Published:
`
`— with international search report (Art. 21(3))
`
`— before the expiration of the time limit for amending the
`Claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
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`WO 2010/025303
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`PCT/US2009/055256
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`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
`
`Serial No. 12/350,111, filed January 7, 2009 which is pending, and a continuation in part of
`
`International Application No. PCT/USO 8/30362, filed January 9, 2009, each of which claims
`
`benefit of priority to US. Provisional Application Serial Number 61/093,234, filed August 29,
`
`2008, each of which is incorporated herein by reference in its entirety. This application is also
`
`related to the US. 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 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-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 of a 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.
`
`CRF, while associated in some instances with mildly elevated levels of ammonia, (Deferrari, Kid
`
`@1980; 20505), 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 rctcntion states, to avoid accumulation of ammonia or
`
`metabolic products containing ammonia, e.g., urea. References herein to ammonia and ammonia
`
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`scavenging refer primarily to treating UCDs and HE and conditions that emulate UCDs, although
`
`the tenns 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 prodrugs 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 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 ammonia 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 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 FAA, 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 of liver 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 Figure
`
`1b, 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 of several ammonia—processing enzymes. Individuals born with no meaningful residual
`
`urea synthetic capacity typically present in the first few days of life (neonatal presentation).
`
`Individuals with residual function typically present later in childhood or even in adulthood, and
`
`2
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`symptoms may be precipitated by increased dietary protein or physiological stress (e. g. intercurrent
`
`illness.) Some enzymes whose deficient functioning causes UCDs include the following:
`
`0 Carbamyl phosphate synthetase (CPS),
`
`0
`
`0
`
`0
`
`0
`
`ornithine transcarbamylase (OTC),
`
`argininosuccinate synthetase (ASS),
`
`argininosuccinate lyase (ASL),
`
`arginase (ARG; EC Number 3.5.3.1; autosomal recessive), (ARG) and
`
`0 N-acetyl glutamine synthetase (NAGS)
`
`[0007] 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:
`
`0 Ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria
`
`or HHH Syndrome)
`
`0 Citrin (aspartate glutamate transporter) deficiency
`
`[0008] The common feature of UCDs and similar conditions 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
`
`nitrogen in the blood in the form urea, and the ammonia scavenging 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 ammonia does not build up to harmful
`
`levels. For patients with nitrogen rctcntion 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, 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.
`
`[0009] To avoid build-u p of ammonia to toxic levels in patients with nitrogen retention states,
`
`dietary intake of protein (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 sufficient protein to support normal growth (i.e. in growing children) and repair; thus in
`
`3
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`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 considered 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
`
`phcnylacctyl glutaminc (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.
`
`[0010] 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 PAA 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 et al., L
`
`Pediatrics, vol. 138, 856—861 (2001)) or do not comment on the implications of incomplete
`
`conversion for dosing (e. g. Singh, Urea Cycle Disorders Conference Group ‘Consensus Statement
`
`from a Conference for the Management of Patients with Urea Cycle Disorders’, Sup pl to J
`
`Pediatrics, vol. 138(1), 81-85 (2001)). Based on what is known, one expects essentially complete
`
`conversion of these drugs into urinary PAGN.
`
`[0011] PBA is currently the preferred nitrogen scavenging drug for UCD patients in need of
`
`substantial nitrogen elimination 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 ‘Consensus 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 ammonia, which can be very harmful, and it minimizes buildup of high
`
`concentrations of PAA as well.
`
`[0012] 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 contribution of increased blood levels of urea, per se, to the clinical manifestations
`
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`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 dialysis. As a corollary of the findings noted above in UCD patients
`
`(e. g. Brusilow, Pediatric Research, vol. 29, 147—50 (1991); Brusilow and Finkelstien, L
`
`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 alternative to urca cxcrction. Consistent with this, Brusilow (US Patent # 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 (Figure 14).
`
`Accordingly, PAA prodrugs, 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 PAA prodrugs and
`
`monitoring treatment 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 manifested, for
`
`example, as ascites and or peripheral edema. HPN-100 is one such sodium-free PAA prodrug.
`
`Disclosure of Embodiments of the Invention
`
`[0013] The invention provides a novel approach for determining and adjusting the schedule
`
`and dose of orally administered nitrogen scavenging drugs, including sodium phenylbutyrate and
`
`glyceryl tri-[4-phenylbutyrate] (HPN- 100), based upon the urinary excretion of the drug metabolite
`
`phenylacetylglutamine (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 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. Conversion of orally administered sodium phenylbutyrate (NaPB A, or sodium PBA) to
`
`urinary PAGN (uPAGN) is now shown to be incomplete: conversion is typically 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 experimentally 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
`
`5
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`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.
`
`[0014] Urinary PAGN can be measured in various ways; in some embodiments, as described
`
`herein, it is a 24-hour measurement, which means measurement of total urinary PAGN 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, IIE, and CRF patients receiving the nitrogen
`
`scavenging drugs described herein. Because creatinine output is relatively 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.
`
`[0015] 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 modified treatment program or adjusted drug dosage. These
`
`methods 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 embodiment, 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.
`
`[0016] Prodrugs of phenylbutyrate (PBA, the active ingredient 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.
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`“\
`
`“~/\coz’Na*
`
`phenylbutyrate
`
`I \
`/
`
`OH
`
`Phenylacetic acid
`
`0
`
`NH2
`
`HO
`
`..,,N
`H
`
`o
`
`LG
`
`Phenylacetylglutamine
`
`[0017] 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® (sodium phenylbutyrate), AMMONAPS®,
`
`butyroyloxymethyl-4-phenylbutyrate, glyceryl tri-[4-phenylbutyrate] (HPN-lOO), 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 BUPHENYL®, and
`
`BUPHENYL® was used for the Examples herein wherever test subjects were treated with sodium
`
`phenylbutyrate. 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 and/or urea levels through elimination of waste nitrogen in the form of PAGN.
`
`[0018]
`
`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 turn can be converted to PAA. Thus, HPN-l 00 is a prodrug of PBA, and
`
`also a pre—prodrug of PAA. Clinical evidence demonstrates that HPN-lOO is converted into PAA
`
`7
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`in the body as expected, and that PAA is then linked to a molecule of glutamine and converted into
`
`PAGN, which is eliminated in the urine as predicted. This process can be summarized as follows:
`
`HPN—lOO 9 3 PBA 9 3 PAA
`
`PAA + glutamine 9 PAGN.
`
`[0019] PAGN is mainly excreted in the subject’s urine, and removes two molecules of
`
`ammonia per molecule of cxcrctcd PAGN. Each HPN -100 molcculc forms thrcc PAA molcculcs,
`
`so each molecule of HPN—100 can promote excretion of six molecules of ammonia. The clinical
`
`results suggest that conversion of HPN- 100 into PBA and FAA is efficient, in that HPN-100 is
`
`generally not detectable in blood, but surprisingly suggest that some PBA derived from HPN-lOO
`
`is converted to PAGN before the HPN—lOO (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 of HPN-lOO as an ammonia scavenger.
`
`[0020]
`
`In some embodiments, the invention uses a prodrug of PBA, including IIPN-100 and
`
`other esters of phenylbutyrate. The PBA prodrug is thus a prodrug of a prodrug, since PBA acts to
`
`scavenge ammonia after it is converted to FAA and is thus considered a prodrug of PAA. In some
`
`embodiments, the PBA prodrug is an ester of phenylbutyrate, such as those described below; a
`
`preferred PBA prodrug for use in the invention is HPN-IOO. These compounds can be made and
`
`used by methods disclosed in US. Patent No. 5,968,979, which is incorporated herein by reference
`
`for its description of these compounds and methods for their administration.
`
`[002]] 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 viva. 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
`
`species is usually PAA for the prodrugs described herein, and the molar amount of a prodrug
`
`corresponds to the amount of PAA that would form in the body from that amount of the prodrug,
`
`assuming complete conversion into PAA occurs in vivo. Thus, for example, a molecule of HPN-
`
`100 can be metabolized by ester hydrolysis followed by oxidation to form three molecules of PAA,
`
`so a mole of HPN-100 would be considered equimolar to three moles of PAA. Similarly, since
`
`HPN-100 hydrolyzes to form three molecules of PBA (and one molecule of glycerol), an
`
`equimolar amount of HPN-lOO would be one-third of the molar amount of PBA.
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`[0022] The following Table sets forth amounts of HPN—lOO that correspond to equimolar
`
`amounts of certain relevant doses of BUPHENYL® (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—IOO consists of glycerol in ester linkage with 3 molecules of
`
`PBA and contains no sodium; (sodium PBA [g] X 0.95 = HPN—100 [g])] as well as correction for
`
`the specific gravity of HPN—lOO, which is 1.1 g/mL.
`
`Table 1. Conversion Factors.
`
`HPN-100
`HPN-100
`BUPHENYL®
`
`(sodium PBA)
`PBA Equivalent Dose (mg)
`PBA Equivalent Dose (mL)
`
`17.4 mL
`
`450—600 mg/kg/day
`(patients 3 20 kg)
`
`9.9-13.0 g/1112/day
`(patients > 20 kg)
`Maximum Daily Dose: 20 g
`
`428 — 570 mg/kg/day
`
`9.4 — 12.4 g/m2/day
`Maximum Daily Dose: 19 g
`
`0.39—0.52 mL/kg/day
`
`8.6-1 1.2 mI./mZ/day
`
`[0023] The present invention can use prodrugs of the formula (I):
`
`H
`
`H
`
`H
`
`H
`
`H
`
`o— R1
`
`o— R2
`
`o— R3
`
`(1)
`
`wherein R1, R2, and R3 are independently, II,
`
`313
`
`(042)”
`
`-
`
`€14
`
`(CmHzm-z)
`
`and n is zero or an even number, m is an even number and at least one of R1, R2, and R3
`
`is not H. For each R1, R2, or R3, n or m is independently selected, so the R1, R2, and R3 groups
`
`in a compound of formula I do not have to be identical. The preferred compounds are those
`
`wherein none of R1, R2, and R3 is H, and frequently each n or 111 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
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`dosage is greater with such triesters, and having all three acyl groups the same reduces issues
`
`related to mixtures of isomers. Moreover, the triol backbone liberated by hydrolysis of the
`
`esters is glycerol, a normal constituent of dietary triglyceride which is non-toxic.
`
`[0024] The present invention also utilizes phenylbutyrate and phenylacetate prodrugs of the
`
`formula II:
`
`R—Oi
`
`R4
`
`(H)
`
`wherein R is a C1—Cm alkyl group,
`
`R4 lS
`
`Hui
`
`(CH2)n
`
`or
`
`\
`
`A“) H
`
`rn 2m-2
`
`)
`
`and n is zero or an even number, and m is an even number.
`
`[0025]
`
`In Formula II, R can be, for example, ethyl, propyl, isopropyl, n—butyl, and the like.
`
`[0026] The compounds of the invention are esters of the congeners of phenylalkanoic and
`
`phenylalkenoic acids having an even number of carbon atoms in the alkanoic acid portion, which
`
`include phcnylacctic acid esters and those of phcnylbutyric 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 phcnylbutyric acid.
`
`Preferably the alkylene or alkenylene carboxylate group contains 24 or fewer carbon atoms, so 11 or
`
`m is less than 24. In some embodiments, n and m are 0, 2, 4 or 6, and in some preferred
`
`embodiments n or m is 2.
`
`[0027] Certain preferred embodiments of the invention use HPN-lOO (Formula III):
`
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`O
`
`O
`
`O
`
`O
`
`O
`
`H
`
`H
`
`H
`
`H
`
`H
`
`(111)
`
`[0028] Total daily dosage of prodrugs like sodium PBA can often be selected according to the
`
`amount needed to provide an appropriate amount of the active species, if that amount is known or
`
`can be determined. PBA is a prodrug for PAA; therefore, an initial dose of PBA could be selected
`
`if an effective dosage of PAA were known, taking into account the fraction of PBA that is
`
`converted into FAA and ultimately into PAGN. If a subject has been treated with PAA or a
`
`prodrug that forms PAA in the body, the amount of the previously used drug that was effective
`
`provides a possible starting point for selecting a dosage of a new prodru g of PAA. In this same
`
`patient, after the new prodrug is administered at the expected PAA dose equivalence, the PAA
`
`levels in the subject could be monitored and the dose of the prodrug adjusted until the same plasma
`
`level of PAA that was effective with the previous treatment is achieved. However, the current
`
`invention is based in part on finding that plasma FAA and PBA levels are not well correlated with
`
`the dose of a PBA prodrug administered or with ammonia elimination; for monitoring a dosing
`
`level of a PBA prodrug, one should not rely upon these parameters to assess the effectiveness of
`
`the prodrug. While not bound by the underlying theory, explanations for this effect (i.e. the
`
`inconsistent relationship between ammonia scavenging and PBA and/or PAA blood levels) are
`
`provided herein.
`
`[0029] The following Tables provides data from three clinical test groups showing the
`
`inconsistent relationship between plasma FAA and PBA levels among healthy volunteers, patients
`
`with cirrhosis and UCD patients, despite that fact that, as described in detail below, all groups
`
`exhibited similar ammonia scavenging activity based on urinary excretion of PAGN. Note in Table
`
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`2, for example, that plasma FAA and PBA, measured as AUC24 were both about 4-fold lower
`
`following single dose administration of HPN—lOO as compared with sodium PBA to healthy
`
`volunteers (see also Figure 4), despite similar ammonia scavenging as determined by urinary
`
`output of PAGN. Similarly, healthy volunteers and cirrhotic subjects exhibited no differences in
`
`urinary PAGN output, yet PAA blood levels tended to be higher in Child—Pugh C cirrhotics.
`
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`Table 2. Plasma Pharmacokinetics of PBA, FAA, and PAGN Comparison across Studies
`
`AU C24
`Tl/Z
`Tmax
`Cmax
`(ug-h/mL)
`(h)
`(h)
`(Mg/mL)
`Treatment
`Analyte
`
`Healthy Volunteers (Single Dose — 3 g/mzlday PBA Mole Equivalent)
`0.7
`Sodium PBA
`0.9
`
`HPN-100
`37.0
`2.4
`1.9
`137.2
`
`
`HPN-100
`14.9
`4.0
`NC
`70.9
`
`HPN-100
`
`4.0
`
`NC
`
`Healthy Volunteers and Cirrhotic Patients (Multiple day dosing of HPN-100 at 100 mg/kg BID) 1
`
`
`
`Child-Pugh A
`
`Child-Pugh B
`
`Child-Pugh C
`Volunteers
`
`UCD Subjects (Multiple Dose — PBA Mole Equivalent)
`
`——m——
`
`——m——
`Cum: maximum plasma concentration; Tmax = time of maximum plasma concentration; AUC24 = AUC from time 0 to
`24 hours; NC = not calculated
`1Study did not include a sodium phenylbutyrate comparator arm, values represent IIPN—lOO dosing only. AUC values
`represent the AUC from time 0 to the last measurable plasma concentration.
`
`[0030] The plasma and urinary pharmacokinetic parameters for 10 UCD patients are
`
`summarized at the bottom of Table 2 and in more detail in the following Table 3. Note that urinary
`
`PAGN output was very similar for sodium PBA (as BUPHENYL) and HPN—lOO in UCD patients
`
`at steady state following multiple day dosing. However, in this case, plasma PBA levels measured
`
`as AUC24 following HPN—lOO were about 27% lower following HPN—lOO administration, as
`
`compared with sodium PBA administration, whereas PAA blood levels were similar for subjects
`
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`on both drugs. Notably, peak urinary output of PAGN occurred during hours 6-12 after the first
`
`dose of PBA, but during hours 12-24 following HPN-100 dosing, again demonstrating the slow—
`
`release characteristics of HPN-100. Collectively, these