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`
`US008642012B2
`
`(12) United States Patent
`Seharschmidt
`
`(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 Seharsehmtdt. South San
`l" rancisco. C.’A (US)
`
`(73) Assignee:
`
`I-Iyperion 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.: 121350.111
`
`(22)
`
`Filed:
`
`Jan. 7, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2()l0i"0D08859Al
`
`Jan. 14. 2010
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 611093.234. filed on Aug.
`29, 2008.
`
`(51)
`
`Int. Cl.
`/161K 49/00
`
`(2006.01)
`
`(52) U.S. (J1.
`424i‘9.2: 5140568: 5140432: 5140433
`USPC‘
`(58) Field of Classification Search
`
`See application file for complete search history.
`
`514.-‘S33
`
`(56)
`
`References Cited
`
`U.S. PA'l‘l:'.NT DOCUMENTS
`
`4.284.647 A
`5.968.979 A
`6.060.510 A
`6.083.934 A "‘
`6,219.56? Bl
`2004.-'0229948 Al
`2006.-"0l35fii2 Al
`200850119554 Al
`2010.-"0UOS859 Al
`
`83198] Brusilowetal.
`1031999 Brusilow
`52000 Brusilow
`7.-“Z000 Brusilow
`4.-‘"2001 Eggers et al.
`1132004 Summaretal.
`6-‘"3006 1"errante
`5-‘"2008
`Jalan etal.
`I-"2010 Scharsehmidl
`
`FOREIGN PATENT DOC UMENTS
`
`W0
`WU
`Wt.)
`W0
`WC!
`
`WO-200 5.305360?
`W0-2006.-"0 56794
`W0-2 009.-"0874 74
`WO-2009-"134460 A1
`WO-2010250303 A1
`
`6.2005
`6-"2006
`752 009
`I l-"2009
`3-"2010
`
`OTHER PUBLICATIONS
`
`Ben’)? el 11.. .T Pediatrics (2001) 1332356861.
`Brusilow. Pediatric Research [ 1991) 29: l4?-150.
`Brusilow. Progress in I.iver Diseases { 1995) 12:293-309.
`lirusilow and Finkelstcin. J Metabolism ([9931) 4211336-I339.
`(Thong et al.. l’1\'AS USA (200l) 9St [M29808-9813.
`I-"DA Label for Buphenyl. 6 pages.
`Kasurnov et al.. Ding Metabolism and Disposition (2004) 32t 1):10-
`I9.
`Rudman ct al. J Clin Invest (_l9?3) 522241-2249.
`Singh. Suppl to J Pediatrics (2001) 138(1):S1-55.
`ThilJa1Iltetal.. Cancer (1995) 'r'5(12):2932-2938.
`Thibanlt et al.. Cancer Research ( 1994) 54(7): 1690-1694.
`
`International Search Report and Written Opinion for P('T.-'L'S09»"
`30362. n1a.ilecl Mat’. 2. 2009. 8 pages.
`Clinical'I'ria1s.(}ov»'A1chivc View of.\‘C't'00S51200 on Dec. 1 1.200"?
`“Dose-1.-‘seaiation
`Safety
`Study
`of
`Giyecryl
`'['ri
`(4-Pheny1butyrate)(GT4l'-‘) to Treat Urea Cycle Disorders" [aeeessed
`Oct. 5. 2009]. 4 pages.
`Conitc et al. Journal of Mass Spectrometry t2002) 37(6):58 I -590.
`Lee el 50.. Journal ot'ln.herited Metabolic Disease t2008)31t'l):9l.
`Search and Exatnination Report for British Patent Application No.
`GB 09155458. dated Oct. 8. 2009. 5 pages.
`Mac.AJ‘LhtIr et al.
`(2004). Molecular Genetics and Metabolism
`8l( 1 ):S6T—S'i'3.
`Simmelletal.t_l986).1’ediaIric Research 20t_l 1 ):l l 1?-I121.
`'l‘a.nner el ai.
`('200'i'). Journal of inherited Metabolic Disease
`30(5);716-721.
`International Search Repon and Written Opinion for PC'1'»'US2009."
`055256. mailed Dec. 30. 2009. 13 pages.
`Ambrose. AA-‘l. et a1. (I933)."FtIrLher Studies on l.he Detoxifieat ion
`of 1-‘henylacctic Acid..“J. Biol. Client. 10l:669-6'35.
`Batshaw .\/1.1.. et .11. (Dec. 1980). “Treatment of ['1ypera.rnmoncmic
`Coma Caused by Inhorn Errors of Urea Synthesis.” J. Hed:‘ar.v.
`9'T(6):893-900.
`liatshaw. M .L. el :11. (Aug. [981 ). "New Approaches to the Diagnosis
`and Treatment of Inborn Errors of Urea Synthesis.“ Pea’r'at't'i'r's
`E-8(2):39U-297.
`Batshaw .\d.L. et at. (Jun. 10. 1982). "'I'reatment of lnborn ]_‘.rrors of
`Urea Synthesis: Activation of Alternative Pathways of Waste I‘~"itrn—
`gen Synthesis and Excretion.” N. Eng}. J’. Med. 306[23):13S?-1392.
`Batshaw. M .L. ( I984). “['lypcra.Inmonemia." in C'm'rerr.' i".v'obt‘em.\' in
`1'-‘edi‘nrr:'cs. Lockhan. J.D. od.: Year Book Medical Publishers. pp.
`2-69.
`
`Brttsilow. S.W. et :1]. (Sep. 1. 1979). "New Pathways of Nitrogen
`Excretion in inborn EIITJIS of Urea Synthesis.” Lrzircer 2(8140}:452—
`454.
`Brusilow. S. et al. (Feb. 8. I980). "Amino Acid Acylation: A Mecha-
`nism of Nitrogen Excretion in lnborn Errors of Urea Synthesis."
`Srmiee 201659-661.
`
`Brusilow. S.W. (Jun. 21. 1984). “Treatment of Episodic Hypersen-
`moneinia in Children With inborn Errors ot‘I Irea Synthesis." A". Errgt‘.
`J. Med. 310('2fi):t630«I634.
`Brusilow. S.W. et al. (1991). “Treatment oftirca Cycic Disorders."
`Chapter 5 in ]t’.i'er2tnieitI of Gcrierfc Diseases. Dcsnik. R.J. ct at. eds.
`Churchill Livingstone. New York. New York. pp. 1'9-94.
`
`(Continued)
`
`Jon P Weber
`Pr.5nmr_t= Iilxuniiner
`'lilTa11y Ciough
`A.vs:'srrmr Iixaiiifner
`(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 prodrtigs used
`to treat nitrogen retention states. or ammonia accumulation
`disorders. by measuring urinary excretion of phcny1ace1yl-
`glulamine andfor total urinary nitrogen. The invention pro-
`vides metltods to select an appropriate dosage of at 1313A
`prodrug based on the patient‘ s 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 anunonia scav-
`enging drug.
`
`1
`
`12 Claims, 15 Drawing Sheets
`
`PAR PHARMACEUTICAL, INC.
`EX. 1001
`PAR PHARMACEUTICAL, INC.
`EX. 1001
`
`

`
`US 8,642,012 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Brusilow. S.W. (A.mendment Dated Jul. 25. I994). "Protocols for
`Management oflntercurrent l-Iyperammonemia in Patients with Urea
`Cycle Disorders." FDA Application to Market :1 New Drug for
`Human Use or an Antibiotic Drug for I-Iurrtan Use. Fourteen pages.
`Brusilow, S.W. et al. (1995). “l.'-rea Cycle Enzymes." Chapter 32 in
`The Meta.-‘)0iir' and Mot'et‘ttiat' bares of!ttl'tet'ited t)t‘sea.re.\‘. Scriver.
`C.R. et al. eds.. McGraw-Hill. inc. New York. New York. pp. 1 187-
`I232.
`Brusilow. S.W.. et al. (1996). “Urea Cycle Disorders: Diagnosis.
`Paihophysiology. and TheI31Jy.”Ao’v: Pediatt: 43: I 27—l'?0.
`Calloway. D.Il. et al. (1971). “Sweat and Miscellaneous Nitrogen
`Losses in liuman Balance Studies." J. Ntttt'itt'on 101'.??5-‘P86.
`Calloway. D.H. et al. (19’t‘l). “Variation in Endogenous Nitrogen
`Excretion and Dietary Nitrogen Utilization as Determinants of
`Human Protein Requirements." .1’. Ntttt't'tiott lCII:205-216.
`Camacho. l..H. et al. (2007. e-pub. Oct. 20. 3006]. "Phase I Dose
`Escalation Clinical Trial of Phenylbutyrate Sodium Administered
`Twice Daily to Patients With Advanced Solid Tumors." invest. New
`Drttgs 25:131-138.
`Combined Search and Examination Report mailed on Sep. 9. 2010.
`for Great Britian Patent Application No. 10134682. filed on Aug. 27.
`2009. six pages.
`Combined Search and Examination Report mailed on Oct. 9. 2009.
`for Great Britain Patent Application No. GB0915 545 .8. filed on Aug.
`27. 2000, eight pages.
`Deferrari. G. et al. ([981). “Brain Metabolism ol'AInino Acids and
`Ammonia in Patients with Chronic Renal Insufliciency." Kt'dne3r
`Ittterttatiottet 20505-510.
`Fxarninarion Report mailed on Oct. 27. 2010. for United Kingdom
`Patent Appiication No. GB09I5545.3. filed on Aug. 27. 2009. two
`pages.
`Friarninat ion Report mailed Feb. 5. 2010. for United Kingdom Patent
`Application No. GB09155-15.8. filed on Aug. 2?. 2009. two page.
`Examination Report mailed May 11. 2010. for United Kingdom
`Patent Application No. GB09l5545.8. filed on Aug. 27. 2009. one
`page.
`FDA. (Aug. 2003). “Buphenyl® (Sodium Phenylbutyrate) Label"
`nine pages.
`Gargo-sky. S. (2.006). “High Ammonia Levels Are Associated With
`Increased .VIoi1ality and Coins.” Ucyclyd ‘Pharma. Inc_. one page.
`Gargoslty. S. et at. (Oct. 14, 2005). “Results of a Twenty-two Year
`Clinical Trial: Actue. Adjunctive Pharmacological Treatment of
`Hyperammoriemic Episodes
`in Patients with Deficiencies
`in
`Enzymes of the UreaCycIe.“ poster. Ucyclyd Pharma. Inc . . one page.
`Gargosky. S. (Aug. 2. 2005). "improved Survival of Neonates Fol-
`lowing Administration of Ammonul® (Sodium Phenylacetate &
`Sodium Benzoate] 10% .-' 10% Injection." SSIEM Poster . six pages.
`Gropinan. A.L. et al. (Sep.~Oct. 2008. e—puh. Jul. 26. 2008). " ' H MRS
`Identifies Symptomatic and Asymptomatic Sulnjects With Partial
`t.)rnithine'1'ranscarba.mylase Deficiency." Mot‘. Genet. Metrtb. 95(1-
`2):21-30.
`Hyperion Therapeutics. (Mar. 30. 2009]. "Hyperion Therapeutics
`Announces Results for Phase 11 Study in Urea Cycle Disorders."
`located
`at
`<htt'p:ttxwvw.hyperiontx.comt'press-'releaset'pr,
`1238518383? last visited on Apr. 2?. 2011. diree pages.
`Hyperion Therapeutics. (Jun. 2. 2009.) “Hyperion Therapeutics
`Announces Results of Phase 1 Study in Patients with Liver Cirrhosis"
`located
`at
`<http:ttwxwv.hyperionLx.cornt'press."reIeasetpr_
`1243891 I61>. last visited on Apr. 27. 2011. three pages.
`International Preliminary Report on Patentability mailed on Mar. 1.
`2011.12» PCTApp|ication No. PCTt’I_.’S2009.-’030362. filed on .Tan. T.
`2009. seven pages.
`lnlemational Preliminary Repon on Patentability mailed on Mar. 1.
`2011. for PCT Application No. l-’C'1‘.-’US2009t'055256. filed on Aug.
`27. 2009. six pages.
`Jatnes. MD. et al. (1972). “The Conjttgation of Phenylacetic Acid in
`Man. Sub-Human Primates and Some Other Non-Primates Species."
`Proe. R. Soc. London l82:25-35.
`
`John. B.A. et al. (Mar. 2009). "The Disposition ofHP1\'-100. A Novel
`Pharmaceutical Under Development
`for Potential Treatment of
`Hyperanunonemia. in C ynomologus Monkeys," a!).rtt'ac't ptiesettteti
`tttAC'MG .2009. one page.
`John. B.A. et .11. (Mar. 2009). “The Disposition of l-IPN- 1 00. A Novel
`Pharmaceutical Under Development
`for Potential Treatment of
`Hyperarrunonemia. in Cynomolgus .\t1on keys." AC MG 20 09 A DME,
`poster. two pages.
`Lee. B. et al. (Aug. 2009). "Dosing and Therapeutic Monitoring of
`Ammonia Scavenging Drugs and Urinary Phenylacetylglutamine
`(PAGN) as a Biomarker; Lessons From a Phase 2 Comparison ot'a
`Novel Ammonia Scavenging Agent With Sodium fhenylbutyrate
`(_NaPBA)." ab.vtm(:t presenter)’ at ICIEM 2009. Sari Diego. CA. one
`page.
`Lee. 13. et al. (Aug. 2009). “Dosing and Therapeutic Monitoring of
`Ammona Scavenging Drugs and Urinary Phenylacetylglutamine
`(PAGN) as a Biomarker: Lessons From a Phase 2 Comparison ot'a
`Novel Ammonia Scavenging Agent with Sodium Phenylbutyrate
`t’NAPBA).“ presented at ICIE.-\‘I 2009. San Diego. CA. poster. one
`page.
`Lee. B. et al. (Mar. 2009). “Phase 2 Study of A Novel Ammonia
`Scavenging Agent in Adults With Urea Cycle Disorders (L'CDs).”
`t:b.rtt'er't ptiesetttea‘ t:t.dCMG 20tJ9. one page.
`Lee. 13. et al. (Mar. 2009). “Phase 2 Study ot'A Novel Ammonia
`Scavenging Agent in Adults with Urea Cycle Disorders (UCDs)."
`ptiesetttod MACMG 2009. seventeen pages.
`I.ee. B. et al. (Aug. 2008). “Preliminary Data on Adult Patients with
`Urea Cycie Disorders (UCD) in an Open-Label. Switch—0ver. Dose-
`liscalation Study Comparing a New Ammonia Scavenger. Glyceryl
`Tri
`(4-Phenylbutyrate)
`IIIPN-100].
`to Buphenyl®- {Sodium
`Phenylbutyrate [PBA]).” abstract presettted at SSIEM 2008. Lisbon.
`Portugal. one page.
`Lee. B. et al. (Sop. 2008). “Preliminary Data on Adult Patients with
`Urea Cycle Disorders (UCD) in An Open-Label. Switch-Over. Dose
`Escalation Study Comparing a New Ammonia Scavenger. Glyceryl
`Tri
`(4-Phenylbutyrate)
`[IIPN-100].
`to Buphenyl® (Sodium
`Phenylbutyrate [PBA]." presented atSSEl’M 2008. Lisbon. Portugal.
`Poster. one page.
`Lewis. H.B. (19 14). "Studies in the Synthesisofl'lippuricAcid inthe
`Animal Organism. II. The Synthesis and Rate of Elimination of
`1-Iippilric Acid After Benzoate ingestion in Man.” J’. Biol. Chem.
`18225-23 I.
`Mansour. A. et al. (Oct. 1997). "Abdontinal Operations in Patients
`widi Cirrhosis: Still
`a Major Surgical Challenge." Stttget)-‘
`122(4)'.'t30-735. (Abstract Only. ).
`Masetri. N. E. et al. (Aug. 1992). "Plasma Crlutami ne Concentration:
`A Guide in the Management of ljrea Cycle Disorders.“ J’. Pediatt:
`l2l(2):259-261.
`McGuire. BM. el al. (2009). "Pharmacokinctic (PK) and Safety
`Analyses of a Novel Ammonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis." Hyperion Therapeutics. poster. one
`page.
`McGuire. 13.M. ct al. (May 2009). “Pharmacokinetic ('PK)and Safety
`Analyses of a Novel Aimnonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis." ai)St‘t'ct£‘fpt’r.’settt‘(’d at DDW. May 2009.
`two pages.
`McGuire. B. el al. (Apr. 2008}. Phannacokinetic Safety Study of
`Sodium Phenylacetate and Sodium Beazoate Administered to Sub-
`jects With Hepatic Lmpairments. Lt'vet'
`i’tttet'ttatt‘0t:nt' 28:'t43.
`(Abstract Oniy).
`McGuire. B. et al. (Apr. 200 8). "Pharmaco keinetic (PK) Safety Study
`of Sodium Phenylacetate and Sodium Benzoate Administered to
`Subjects with Hepatic Impairment." abstract of The 1'3"" Itt.rema—
`ttottttl Syttiposimti. Ahano (Padova). Italy. Apr. 28-May 1. 2008. two
`pages.
`McQu-ade PS. (I984). “Analysis and the Effects of Some Drugs on
`the Metabolism of Phenylethylamiae and Phenylacetic Acid."
`Netttop.':ydtopItar-ntaeoi. Biol. P.\‘ycl'tr'at. 8:607—6l4.
`Piscilelli. SC. et al. (1995). "Disposition ofl"l1enylbIJtyrate and its
`Metabolites. Phenylacetcte and l-"henylacetylglutamine." .1 C‘lt'tt.
`P.i:ot'tttocal. 35 :368-373.
`
`2
`
`

`
`US 8,642,012 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTI-IER PUBLICATIONS
`
`Prop-st. A. et al. (Aug. 1995). "Prognosis and Life Expectancy in
`Chronic Liver Disease." Dig Dis Sci 40(8): I305-l8l5. (Abstract
`On]
`)
`Rileby. "LR. et al. (Nov. I5. 2001). "Preventive: Strategies in Chronic
`Liver Disease: l-‘art Il. Cirrhosos.".4m. Fem. Plrfiiciarr 64(l0): I735-
`l'r'40. (Abstract Only).
`Shiple. GJ. et al. (I922). “Synthesis of Amino Acids in Animal
`Organisms. 1. Synthesis of Cilycocoll and Glutamine in the Human
`Organism." J. Am. Cilrem. Soc. 44:618-624.
`Summar. M.L. et al. (Oct. 2008. c-pub. Jul. 17. 2008). “Diagnosis.
`Symptoms. Frequency and Mortality of 260 Patients with Urea Cycle
`Disorders From a 2 l-Year. Multicentre Study of Acute Ilypera.m-
`monaemic Episodes.“ Acre Prtcditztr: 97: I420-I425.
`Summar. M. el al. (2007). “Description and Outcomes of 3 I6 Urea
`Cycle Patients From a 21-Year. Multicenter Study of Acute
`Hyperammonemic Episodes." Abstract.pr'-eserried at Arsenal’ Sympo-
`siren CCH—(.?J.rrgne'ss Cerrtre Hamburg, Sep. 4-7. 2007. GSSIEM
`2007. two pages.
`Swedish Orphan Intemalional. (Jan. 12. 2007). “Urea Cycle Disor-
`ders an International Perspective." Poster. Symposium Swedish
`Orphan lnternational, Barcelona. Spain. Jan. 12, 200?. one page.
`Tuchman. M. et al. (2008. e-pub. Jun. I7. 2008). "Cross-Sectional
`Multicenter Study of Patients With Urea Cycle Disorders in the
`United States.“ Mater. Geuetirrs Metal). 94:39?-402.
`Walerlow. J .C. (Mar. 1963). “The Partition oI'Nilrogen in the Urine of
`Malnourishcd Jamaican Infants.” Am. .1 q,i'Ca’."n. Nttrririorr 12:235-
`240.
`
`Zeitlin. P.I.. et al. (Jul. 2002 ). "Evidence ofCFTR Function in Cystic
`Fibrosis After System Administration of 4-l’henylbutyrate." Mot‘.
`7l:e:'rzpy {St I ):I I9- I 26.
`Enns. G. M .. et al.. "Survival After Treatment with Phcnylacetate and
`Benzoate for Urea-Cycle Disorders." N. Eng. J. Mod. 356:2282-2292
`(2007).
`United States Patent and Trademark Otlice. International Search
`Report and Written Opinion dated Jun. 4. 2012 for l-’C'l‘-'US20l2:’
`028620.
`Diaz. G.A.. et al.. "Phase 3 Blinded. Randomized. Crossover Com-
`parison of Sodium Phenylbutyrate
`(_NaPl3A)
`and Glycerol
`Phenylbutyrate (GPB): Ammonia (NH3) Control in Adults with Urea
`Cycle Disorders t’_UCDs).“ Mol. Genet. Metab. 1021276. Society of
`Inherited Metabolic Disease (SMID) Abstract. (201 1).
`Ghabril. ;\J.. et al.. “Glycerol Phenylhutyrate (GPB) Administration
`in Patients with Cirrhosis and Episodic Hepatic Encephalopaflty
`(I-lE}.“ accepted for presentation at Digestive Disease Week. 2012.
`Lee. B.. et al.. “Phase 2 Comparison ofa Novel Ammonia Scavenging
`Agent with Sodium Phenylbutyrate in Patients with Urea Cycle Dis-
`orders: Safety. Pharmaookinetics and Arnmonia Control." Mel.
`Genet. Metab. l00:22l-228 (2010).
`Lichter-Konocki. U.. et al.. “Am.monia Control in Children with Urea
`Cycle Disorders
`(UCDS); Phase 2 Comparison of Sodium
`Phenylbutyrate and Glycerol Phenylbulyrate." Mol. Genet. Metab.
`l03:323-329 (201 l).
`McGuire. B. M.. et al.. “Pharmacology and Safety of Glycerol
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis."
`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
`
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`
`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
`
`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
`
`I-IO
`
`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