Original Article
`
`Glycerol Phenylbutyrate in Patients With
`Cirrhosis and Episodic Hepatic
`Encephalopathy: A Pilot Study of Safety and
`Effect on Venous Ammonia Concentration
`
`Ba) ACCP
`
`Auenican Cowese oF Conical PHarmacooay
`
`Clinical Pharmacology
`in Drug Development
`2(3) 278-284
`© The Author(s) 2013
`DOK 10.1002/cpdd.18
`
`Marwan Ghabril', Igor A. Zu anets”, John Vierling’, Parvez Mantry’, Don Rockey’,
`David Wolf’, Robert O’Shea’, Klara Dickinson®, Heather Gillaspy’*, Catherine Norris®,
`Dion F. Coakley®, Masoud Mokhtarani®, and Bruce F. Scharschmidt®
`
`Abstract
`
`Glyceroltri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through
`conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to
`assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy
`(HE). Patients underwent one week of 6 mL (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID
`dosing and underwentrepeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were
`enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia
`concentrations were lower on GPB comparedto baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4
`(27.9) umol/L (ULN ~48 prmol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more
`adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cyax of 144 [125] vs. 292 [224] jrg/mL on 6
`and 9 mL,respectively). GPB dosed at 6mL BID loweredfasting ammonialevels in cirrhotic patients with HE as compared
`with baseline, was better tolerated than 9 mL BID,and is appropriatefor further evaluation in patients with cirrhosis and
`episodic HE.
`
`Keywords
`ammonia,cirrhosis, hepatic encephalopathy, phenylacetylglutamine, phenylbutyrate
`
`is
`The pathogenesis of hepatic encephalopathy (HE)
`widely assumed to involve the systemic accumulation of
`ammonia resulting from portal-systemic shunting and
`intrinsically impaired hepatic conversion of ammonia to
`urea, and current
`treatment with poorly absorbable
`disaccharides andantibiotics is based on this premise.
`* However, the implication of ammonia in the pathogen-
`esis of HE is based largely on correlative studies.”
`Moreover, current treatment is not ammonia selective,
`and rifaximin, which was recently approved for the
`treatment of episodic HE, was reported to have only a
`modest effect on ammonia.*’ Glycerol phenylbutyrate
`(GPB;glyceryl tri-(4-phenylbutyrate); also referred to as
`HPN-100)
`is an oral agent approved for urea cycle
`disorders (UCD) and an investigational agent under
`developmentfor HE.*!°Itisa pro-drug of phenylbutyric
`acid (PBA), currently marketed as sodium phenylbutyrate
`(BUPHENYL), for the treatment of UCDs (Figure 1) .
`GPB, which consists of 3 molecules of PBA joined to
`
`glycerol via ester linkage, is a pale-yellow, odorless and
`nearly tasteless sodium-free liquid.
`As a prelude to a randomized, blinded, placebo
`controlled trial in patients with episodic HE, the present
`open label study was performed. The major objective
`of the study was to determine whether GPB doses of
`
`
`‘Indiana University School of Medicine, Indianapolis, IN, USA
`2National University of Pharmacy, Kharkiv, Ukraine
`3Baylor College of Medicine, Houston, TX, USA
`‘Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA
`SUniversity of Texas, Southwestern, Dallas, TX, USA
`®New York Medical College, Valhalla, NY, USA
`Cleveland Clinic, Cleveland, OH, USA
`Hyperion Therapeutics, Inc., South San Francisco, CA, USA
`Submitted for publication 28 August 2012; accepted 30 January 2013
`
`“Corresponding Author:
`Bruce F. Scharschmidt, Hyperion Therapeutics, 601 Gateway Blvd,
`Suite 200 South San Francisco, CA 94080, USA
`(e-mail: bruce.scharschmidt@gmail.com)
`
`1 of 7
`
`Horizon Exhibit 2016
`Lupin v. Horizon
`IPR2018-00459
`
`

`

`279
`Ghabril et al
`
`6 or 9mL BID, which correspond to the mid and
`upper end of the range commonly used in adult UCD
`patients, exhibit satisfactory safety and sufficient evi-
`dence of activity, assessed as ammonia lowering,
`to
`warrant further study.
`
`Materials and Methods
`
`Study Design and Treatments
`This primary objectives of this open label, phase 2a study
`(Protocol HPN-100-008, Part A) were to evaluate the
`safety,
`tolerability and activity, assessed as ammonia
`concentration lowering, of 6 and 9 mL BID GPBdosesin
`patients with cirrhosis and episodic HE and to determine
`whether either dose was suitable for
`further study.
`Patients received 6mL of GPB (equivalent to 6.6 g of
`GPB) BID for 7 days followed by 9mL (equivalent to
`9.92 of GPB) BID for 21 days. GPB was administered
`orally with morning and evening meals. Patients
`continued to receive their standard of care treatment for
`HE.
`
`Patient Population
`Adult patients with Child-Pugh B or C cirrhosis who
`experienced 2 or more documented episodes of West
`Haven Grade > 2 HE in the prior 6 months,at least 1 of
`which occurred within 3 months of randomization, were
`eligible. Patients were stable and judged by the
`investigator to be in clinical remission at the time of
`enrollment.
`
`Safety, Pharmacokinetic (PK) and Ammonia
`Sampling
`Safety assessments including vital signs, electrocardio-
`grams (ECGs), hematologic and chemistry evaluations
`were collected.
`In addition to a safety assessments,
`patients underwent 12-hour blood sampling for venous
`ammonia and levels of plasma and urine metabolites
`including PBA, phenylacetate (PAA), and phenylacetyl-
`glutamine (PAGN) on Days 7 (last day of 6mL BID
`dosing) and 28 (last day of 9mL BID dosing), at the
`following time points: 0 (pre-first, fasting daily dose of
`GPB), 2, 4, 8 (approximately 2 hours before the second
`daily dose of GPB),
`and 12hours post-first dose
`(approximately 2 hours after the second daily dose of
`GPB). Additional ammonia and PK samples were
`collected on Days 1, 8, 14, 15, and 21 (at pre-first,
`fasting daily dose and 4 hourspost-first daily dose). Urine
`wascollected for PK analysis on Days7 (for 24 hours) and
`28 (for 72 hours).
`The protocol was conducted under a US IND. The
`protocol was reviewed and approved bythe Institutional
`Review Board or Ethics Committee at each investigative
`site. These included New York Medical College Office of
`Research Administration, Walhalla, NY; Methodist
`
`2 of 7
`
`Health System IRB, Dallas, TX; Baylor College of
`Medicine, Houston, TX; UT Southwestern Medical
`Center Institution, Dallas, TX; Western IRB, Olympia,
`WA;Cleveland Clinic IRB, Cleveland, OH: and Central
`Ethics Committee of Ministry of Health of Ukraine, Kiev,
`Ukraine. A Data and Safety Monitoring Board reviewed
`all safety information, at the end ofthe openlabel part and
`approved the initiation of the randomized part of the
`study. The study was listed in clinicaltrials.gov with
`registration number NCT00999167.
`Continuous variables were summarized with means,
`standard deviations, medians, minimums, and makxi-
`mums. Categorical variables were summarized by counts
`and
`by
`percentage of patients
`in
`corresponding
`categories.
`
`PK Analyses
`Concentrations of PBA, PAA and PAGN in plasma
`and PAA and PAGNin urine were measured by Quest
`Pharma Services (QPS, LLC, Newark, DE) using liquid
`chromatography-tandem mass spectrometry.*'° Plasma
`PK parameters calculated for PBA, PAA, and PAGN
`included the following: maximum observed plasma
`concentration (C,,ax), minimum observed plasma concen-
`tration (C,,;,), and areas under the plasma concentration-
`time curve from time 0 to 8 (AUC_g,) calculated using
`linear trapezoidalrule. Urine was collected on Days 7 and
`28 and urine metabolite concentrations measured during
`the 0—12- and 12—24-hourcollection intervals on Days 7
`and 28.
`
`Results
`
`Patient Demographics and Disposition
`Ten Child Pugh B and 5 Child Pugh C patients (10 males
`and 5 females) with a mean (SD) age of 52.2 (5.24) years
`and model for end-stage liver disease (MELD)score of
`11.5 (3.66) were enrolled. All
`15 patients (100%)
`completed dosing at 6mL BID and escalated to 9mL
`BID, and 8 patients (53%) completed the study. Seven
`patients withdrew after the dose escalation to 9mL BID
`GPB andprior to completing the 4-week treatmentperiod.
`Fourpatients withdrew because they metthe pre-specified
`study stopping rules, and 3 patients withdrew for other
`adverse events (AEs) that did not correspond to stopping
`rule criteria. Of the 5 patients with Child-Pugh C liver
`disease, only 1 completed the study, while 7 of 10 patients
`with Child-Pugh B completed the study (Table 1).
`
`Safety and Tolerability
`Eleven patients
`(73%) experienced a total of 66
`treatment-emergent AEs, excluding HE events. The
`only AEs reported in more than | subject, regardless of
`relationship to study drug, were diarrhea and hypokale-
`mia in 3 patients each, and upper abdominalpain, nausea,
`
`

`

`Clinical Pharmacology in Drug Development 2(3)
`280
`
`Table |. Demographics and Baseline Characteristics
`
`Table 2. AEs Occurring >2 Patients
`
`
`
` Baseline Characteristic Total (N= 15)
`
` System Organ Class Preferred Total (N = 15)
`
`Age (years)
`Mean (SD)
`Median
`Min, max
`Sex, n (%)
`Male
`Female
`Race, n (%)
`White
`Black or African American
`Body mass index (kg/m?)
`Mean (SD)
`Median
`
`Min, max
`Months in current remission
`
`B
`Cc
`Lactulose use at enrollment (mL/day)
`Mean (SD)
`Median
`Min, max
`MELDscore
`
`Mean (SD)
`Median
`Min, max
`HE grade, n (%)
`0
`|
`Not done
`
`Asterixis grade, n (%)
`13 (93%)
`0
`|
`(7%)
`I
`
`Not done |
`
`infection,
`hypoglycemia, hyponatremia, urinary tract
`headache, and thrombocytopenia in 2 patients each. All
`3 patients with diarrhea were on lactulose (Table 2).
`Five patients (33%) had 7 serious AEs
`(SAEs)
`(excluding HEevents), 2 ofwhichled to death; 4 patients
`experienced an HE event. Related AEs reported in more
`than | patient included diarrhea, nausea, and headachein
`2 patients each. There were 2 deaths; one due to
`esophagealvariceal hemorrhage and anotherdueto renal
`failure. In both cases, the immediate cause of death was
`judged by the investigator to be unrelated to study drug.
`The death due to renalfailure occurred in a patient with
`hepatocellular carcinoma who had earlier developed
`
`3 of 7
`
`
`Fern}
`(73%)
`Il
`Any AE
`9 (60%)
`Gastrointestinal disorders
`3 (20%)
`Diarrhea
`2 (13%)
`Abdominal pain upper
`2 (13%)
`Nausea
`7 (47%)
`Metabolism and nutrition disorders
`3 (20%)
`Hypokalaemia
`2 (13%)
`Hypoglycaemia
`2 (13%)
`Hyponatraemia
`4 (27%)
`Infections and infestations
`2 (13%)
`Urinary tract infection
`4 (27%)
`Nervous system disorders
`2 (13%)
`Headache
`2 (13%)
`Blood and lymphatic system disorders
`2 (13%)
`Thrombocytopenia
`2 (13%)
`Injury, poisoning and procedural complications
`1.1 (0.87)
`Mean (SD)
`0.7
`Median
`2 (13%)
`Investigations
`0, 3
`Min, max
`Musculoskeletal and connective tissue disorders=2. (13%)
`Child-Pugh classification, n (%)
`Psychiatric disorders
`2 (13%)
`A
`Renal and urinary disorders
`2 (13%)
`
`Skin and subcutaneous tissue disorders 2 (13%)
`
`52.2 (5.24)
`52.0
`45, 62
`
`10 (67%)
`5 (33%)
`
`14 (93%)
`|
`(7%)
`
`29.5 (5.14)
`28.2
`
`23, 40
`
`0
`
`10 (67%)
`5 (33%)
`
`78.0 (41.1)
`75.0
`15, 120
`
`11.5 (3.66)
`12.0
`6, 18
`
`13 (93%)
`|
`(7%)
`|
`
`“At each level of summation(overall, system organclass, preferred term),
`patients reporting more than | AE are counted only once. HE events are
`excluded.
`
`hepatic failure, for which the study drug could not be
`ruled out as a contributing factor.
`The 7 SAEs (excluding HE events) included uncon-
`trolled diabetes (manifested by hyperglycemia), psycho-
`sis,
`liver
`failure, hypoglycemia, postural orthostatic
`tachycardia syndrome,
`renal
`failure, and esophageal
`variceal hemorrhage. Of the 7 patients who discontinued
`from the study, 6 (40%) discontinued the study drug due
`to AEs and | patient discontinued after experiencing an
`HE event. Patients who discontinued study drug were
`reported to have the following AEs: psychosis, thrombo-
`cytopenia, anemia, uncontrolled diabetes, HE, esophage-
`al variceal hemorrhage, hypokalemia, peripheral edema,
`abdominal pain, nausea andliver failure. Collectively, the
`AEsreported by the patients in this study are typical of
`those expected for the study population.
`Noclinically significant changes from baseline were
`observed in vital signs, ECG parameters, hematology or
`coagulation parameters. The mean value for alanine
`aminotransferase (ALT)increased during the study from
`36.3 U/L at baseline to 46.6U/L on Day 28/early
`termination. The mean value for aspartate aminotransfer-
`ase (AST) also increased, from 56.5 U/L at baseline to
`75.5 U/L on Day 28/early termination. These increases
`were primarily driven by | patient who hadliver failure
`
`

`

`
`Ghabril et al
`28!
`
`we urea cycle —> urea
`
`2 NH,
`FeteReece cerenagiereepeeengereeeneaEee
`; a-ketoglutarate — glutamine
`:
`GPB — PBA —PAA— PAGN :
`;
`
`Urine
`
`_ 600
`—= 400
`2 300
`8 00
`3 400
`0
`
`Child Pugh B
`romeo.
`
`
`
`Day 1 (Baseline)
`
`Day7 (6 mL BID)
`
`Day 14 [9 mL BID)
`
`Lipases
`(intestine)
`
`Glutamine N-
`B-oxidation
`(liver & most acyltransferase
`otherorgans)
`(liver, kidney)
`
`Alternate Pathway
`
`Figure |. Mechanism of action for GPB. GPB is digested by
`pancreatic lipases
`to release PBA which is converted to
`phenylacetic
`acid
`(PAA) by beta-oxidation. PAA is
`then
`conjugated with glutamine to form phenylacetyl glutamine
`(PAGN) which is excreted in the urine, thereby providing an
`alternate pathway for waste nitrogen excretion.
`
`with hepatocellular carcinoma due to chronic hepatitis C
`infection and died dueto renal failure. Whenthis patient
`was excluded, the change in baseline for ALT was to
`36.7 U/L and for AST was to 57.6 U/L on Day 28/early
`termination.
`
`PK Analyses
`PBA values for mean Cyins Cmax: and AUCo_g, wereall
`similar during 6 and 9 mL BIDdosing.Thesefindingsare
`consistent with prior studies and the short plasma half life
`of this metabolite (Table 3).*"'°
`Consistent with priorstudies in cirrhotic patients, PAA
`levels increased with repeated GPB dosing and with the
`GPBdoselevel and tended to be higher during 9 mL BID
`than 6mL BID dosing and were similar on Days 14, 21,
`
`Figure 2. PAA in relation to Child Pughclassification and dose:
`the panel depicts plasma PAA levels in Child Pugh B and C
`patients at baseline, Day 7 (n= 10 and n=5, respectively) and
`Day 14 (n= 10 and n=3,respectively). Plasma PAA increased
`with increasing dose and washigher in patients with more severe
`liver dysfunction (Child Pugh C vs. Child Pugh B).
`
`and 28, confirming that steady state had been reached by
`Day 14 (after 7 days at 9 mL BID).’ The mean Cinin during
`9mL BID was higher than during 6mL BID, and the
`mean C,,x during 9 mL BID wastwice the value ofthat
`during 6mL BID. While the mean AUCp_g, values on
`Days 7 and 28 were similar,
`this comparison is
`confounded by the fact that the highest plasma PAA
`levels occurred among patients who discontinued the
`study. PAAlevels also were higher in patients with Child-
`Pugh C than B with AUCo_g 1 527h g/mL in Child-
`Pugh B group (N = 10) compared with 1211 h jzg/mLin
`Child-Pugh C (n= 5) and C,,,x of 95 versus 183 g/mL
`after 6mL BID dosing on Day7.
`PAGN mean Cyins Cmax, and AUCp_g, were higher
`during 9 mL BID compared with 6mL BID dosing, and
`the increase in these parameters was roughly proportional
`to the increase in dose.
`PAAlevels were generally higher among patients who
`experienced SAEs and withdrew from the study early
`
`Table 3. Plasma PK Parameters for PBA, PAA and PAGN During GPB Administration of 6 and 9 mL
`
`PBA
`
`PAA
`
`PAGN
`
`Days |-7
`(6mL BID)
`
`n=8
`11.3 (12)
`7.49
`1.1, 34.8
`n=8
`120 (40.9)
`115
`51.6, 199
`n=8
`517 (254)
`468
`87.5, 873
`
`Days 8-28
`(9mL BID)
`
`n=15
`8.84 (23.1)
`2.18
`1.0, 92.1
`n=15
`141 (43)
`129
`75.8, 231
`n=7
`503 (187)
`511
`263, 842
`
`Days |-7
`(6mL BID)
`
`n=8
`
`6.33 (4.9)
`5.3
`1.2, 15
`n=8
`
`144 (125)
`124
`13.5, 358
`n=8
`
`977 (896)
`843
`43, 2561
`
`Days 8-28
`(9mL BID)
`
`n=15
`
`84.4 (102)
`44.6
`1.9, 325
`n=15
`
`292 (224)
`219
`57, 655
`n=8
`
`804 (839)
`530
`187, 2764
`
`Days |-7
`(6mL BID)
`
`n=8
`
`14.5 (6.3)
`14.9
`7.5, 24.6
`n=8
`
`47.6 (14.4)
`43.7
`34.9, 80.9
`n=8
`
`330 (135)
`316
`192, 620
`
`Days 8-28
`(9mL BID)
`
`n=15
`
`27.9 (21.9)
`23.7
`1.2, 65
`n=15
`
`80.1 (34.7)
`63.2
`4.03, 150
`n=8
`
`501 (223)
`416
`280, 974
`
`Parameter
`
`Cin (Keg/mL)
`Mean (SD)
`Median
`Min, max
`Crrax (Meg/mL)
`Mean (SD)
`Median
`Min, max
`AUCo_sh (h . Jug/mL)
`Mean (SD)
`Median
`Min, max
`
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`Clinical Pharmacology in Drug Development 2(3)
`282
`
`Fasting Ammonia
`
`90 4
`
`= 80
`Oo
`
`& 604
`
`E 70 4
`5= 504
`
`Baseline
`
`compared with patients who completed the study. Six
`patients with SAEs had PAAlevels >300 g/mL. PAA
`levels over time for Child-Pugh B and C patients are
`shownin Figure 2. All but 1 patient with an SAE, who
`died due to bleeding esophageal varices, had PAA levels
`that increased substantially after dose escalation from
`&g 40 +
`6.6 g BID (6 mL) to 9.9 g BID (9 mL). Thesepatients also
`generally had more severe liver disease with higher
`a 30 +
`MELDscores (maximum MELDscores 13-23 vs. 7-18
`= 204
`= 104
`among patients who completed the study), and 4 out of 5
`0
`
`patients with Child-Pugh C classification at baseline were
`Day 1 Day 14|Day 15
`
`n=13
`among this group.
`
`The major urinary metabolite was PAGN. Mean 24-hr
`6 mL BID
`9mL BID
`
`excretion of PAGN was11.7 g while PAA excretion was
`Figure 3. Mean (SE) fasting ammonia (LLmol/L) concentration
`negligible with a mean of0.02 g on Day 7. The mean (SD)
`over time by number ofpatients (n). As comparedwith baseline,
`urinary PAGN output on Day 28 was 1.78 times higher
`ammonia concentration was decreased at all subsequent time
`than on Day 7 (11.7 [3.7] g on Day 7 vs. 20.8 [3.7] g on
`points.
`Day 28); that is roughly proportional to the 50% increase
`in dose, and, on both days, higher during thefirst 12 hours
`than during the second 12 hours. Urinary excretion of
`PAGNcontinued through at least 72 hours post-dose on
`Day 28, but approximately 80% of the PAGN excretion
`occurred during the first 24 hours. The total mean (SD)
`PAGN excretion overthe first 24 hoursafter the first dose
`on Day 28 was 20.8 (3.7) g; cumulative excretion from 0
`to 72 hours was 25.8 (7.1) g.
`
`0
`
`°
`
`°
`
`
`
`Discussion
`
`The findings in this pilot study suggest that, similar to
`findings in patients with UCD, GPB-mediated excretion of
`waste nitrogen in the form of PAGN appears capable of
`lowering ammonia concentrationin patients with cirrhosis
`and episodic HE.*!° As previously reported in clinically
`well-controlled UCD patients, ammonia concentrations
`tended to be lowest after overnight fasting and increased
`postprandially, thus underscoring the importance of data
`collection at multiple time points
`in a controlled
`environment
`for assessing ammonia exposure.*!° In
`patients with episodic HE, blood ammonia concentrations
`decreasedafterthe first dose ofGPB despite intake offood,
`whichis typically associated with an increase in ammonia
`concentration.*'°'' At baseline, fasting ammonia con-
`centrations were higher than the average upperlimit of
`normalacross sites and were within normal range after
`7 days oftreatment with GPB. As comparedwith baseline,
`ammonia concentration wasdirectionally loweratall time
`points after starting GPB and fasting ammonia concentra-
`tion on Day8, | weekafter starting GPB, wassignificantly
`lower than at baseline and within normal limits.
`The present data also provide information on dosing.
`As compared with a GPB dose of 6mL BID, 9mL BID
`providedlittle additional effect with respect to ammonia
`control and wasless well tolerated, as demonstrated by
`the frequency of AEs, SAEs, and proportion ofpatients
`who tolerated and completed dosing. Phase 1 studies
`involving intravenous administration of PAA to patients
`with cancer have demonstrated that PAA levels in the
`range of 499-1285 1g/mL were
`associated with
`reversible toxicity manifested as
`fatigue, dizziness,
`dysgeusia,
`headache,
`somnolence,
`lightheadedness,
`pedal edema, nausea, vomiting, and rash.'2!> While
`
`Ammonia
`Mean (SD) concentration of ammoniaat baseline, prior to
`the first dose of study drug and administration of a meal,
`was 74.4 (37.5) wmol/L. After the first dose of GPB,
`blood
`ammonia
`concentration
`decreased
`to
`65.1
`(40.7) wmol/L. After 7 days of treatment with 6mL
`BID (Day 7) a time point at which data from all 15
`patients remaining in the study were available, ammonia
`concentrations were lowest at pre-dose after overnight
`fasting and within normal
`limits (mean [SD] of 47.8
`[33.3] mol/L; ULN = 48 pmol/L). However, ammonia
`concentrations gradually increased post-prandially dur-
`ing the day reaching the highest concentration at 12 hours
`post-dose with a mean (SD) of 75.1 (58.5) Wmol/L on
`Day 7. Mean fasting ammonia concentrations were lower
`at all subsequent time points on GPBrelative to fasting
`ammonia concentrations at baseline. The decreases from
`fasting ammonia concentrationsat baseline werestatisti-
`cally significant at 4 hours post-dose on Day 7 (P = .047);
`at pre-dose fasting (P=.007) and 4hours post-dose
`(P=.002) on Day 8; and at 8hours (P=.008) and
`12 hours (P=.015) post-dose on Day 28. The largest
`mean (SD) decrease from baseline was at 4 hours post-
`dose on Day 8 (—29.7 [36.9] mol/L). At baseline, 9
`patients (69%) had an ammonia value that was abovethe
`ULNat the local laboratory. At all subsequent pre-dose
`time points, <50% of patients had ammonia values above
`the ULN (Figure 3).
`
`5 of 7
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`

`
`
`Ghabril et al 283
`
`the SAEs and reasons for study discontinuation were
`generally consistent with those expected for the study
`population that
`is Child-Pugh B or C patients with
`clinically decompensated cirrhosis,
`it
`is possible that
`elevated PAA levels contributed to AEs or SAEs among
`some patients, particularly those which tend to be
`commonin clinical trials and which were reported in
`phase
`1
`cancer
`studies
`(e.g., headache, nausea).
`Moreover,
`the higher PAA levels observed at
`the
`9mL BID GPB dose,
`suggest
`that
`some patients,
`particularly Child-Pugh C patients, are less able to
`effectively convert PAA to PAGN.For these reasons,
`6mL BID of GPBappears to be an appropriate dose for
`further
`study,
`and
`the preliminary results of
`a
`subsequent
`randomized, double blind and placebo
`controlled study using 6mL BID suggest clinical
`benefit. '4
`
`Declaration of Conflicting Interest
`
`K. Dickinson, H. Gillaspy, M. Mokhtarani, C. Norris, D.
`Coakley, and B. Scharschmidt are/were employees of Hyperion
`at the time of the study. None of the other authors have a
`financial interest in Hyperion, although payments were made by
`Hyperion to 'I[UPUI, Indianapolis, IN; "National University of
`Pharmacy, Kharkiv, Ukraine; *Baylor College of Medicine
`Houston, TX; *Liver Institute at Methodist Dallas Medical
`Center, Dallas, TX; *University ofTexas, Southwestern, Dallas,
`TX; °New York Medical College, Valhalla, NY; ’Cleveland
`Clinic, Cleveland, OH.
`
`References
`
`1. Bass NM. Emerging treatment options for the management
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`2. Ferenci P. Treatment options for hepatic encephalopathy: a
`review. Semin Liver Dis. 2007;27(Suppl 2):10-17.
`3. Mullen KD, Ferenci P, Bass NM, et al. An algorithm for the
`management of hepatic encephalopathy. Semin Liver Dis.
`2007;27(Suppl 2):32-48.
`4, Rudman D, DiFulco TJ, Galambos JT, et al. Maximal rates
`of excretion and synthesis of urea in normal and cirrhotic
`patients. J Clin Invest, 1973;52:2241—2249,
`5. Ong JP, Aggarwal A, Krieger D, et al. Correlation between
`ammonia levels and the severity of hepatic encephalopathy.
`Am J Med. 2003;114:188-193.
`6. Bass NM, Mullen KD, Sanyal A,etal. Rifaximin treatment in
`hepatic encephalopathy. N Engl.J Med. 2010;362:1071—1081.
`7. Sanyal A, Bass N, Poordad F, et al. Rifaximin decreases
`venous ammonia concentrations and time-weighted average
`ammonia concentrations correlate with overt hepatic
`encephalopathy (HE) as assessed by Conn score in a 6-
`month study. J Hepatol, 2010;52:584.
`8. Lee B, Rhead W, Diaz GA, et al. Phase 2 comparison of a
`novel ammonia scavenging agent with sodium phenyl-
`butyrate in patients with urea cycle disorders: safety,
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`and safety of a novel ammonia lowering agents in healthy
`adults and adults with cirrhosis. Hepatology. 2010;51:
`2077-2085.
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`et al.
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`Ammonia (NH3) control
`in children with urea cycle
`disorders (UCDs); comparison of sodium phenylbutyrate
`and
`glycerol
`phenylbutyrate mol. Genet Metab.
`2011;103:323-329.
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`11. Diaz GA, Krivitsky LS, Mokhtarani M, et al. Ammonia
`control and neurocognitive outcome among urea cycle
`disorder patients treated with glycerol phenylbutyrate.
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`10.1002/hep.26058 [epub ahead of print].
`12. Thibault A, Samid D, Cooper MR, et al. A phase I and
`pharmacokinetic study of intravenous phenylacetate in
`patients with cancer. Cancer Res. 1994;54:1690-1694.
`13. Thibault A, Cooper MR, Figg WD,et al. Phase I study of
`phenylacetate administered twice daily to patients with
`cancer. Cancer. 1995;75:2932-2938.
`14. Rockey D, Vierling J, Mantry P, et al. Randomized,
`controlled, double-blind study of glycerol phenylbutyrate in
`patients with cirrhosis and episodic hepatic encephalopathy.
`Hepatology. 2012;56:248A.
`
`Supporting Information
`Additional supporting information may be found in the
`online version ofthis article at the publisher’s web-site.
`Supplemental Table 4. Stopping Rules
`Subjects meeting any of the followingcriteria must be
`withdrawn from the study:
`e AEof Grade 4 or greater severity according to
`the Common Terminology Criteria for Adverse
`Events (CTCAE)orlife-threatening AE if not
`covered by CTCAE;
`e An increase in the model for end-stage liver
`disease (MELD) score of greater than 5 from
`baseline;
`e Anyofthe following laboratory abnormalities:
`o Grade 3 liver enzyme abnormalities and 10-
`fold upper limit of normal (ULN)for those
`with normal valuesat baseline OR a 5-fold
`increase or 10-fold ULN for those with
`abnormal values at baseline, whichever is
`lower;
`o Hemolgobin levels of <8 g/dL confirmed
`in a
`repeat
`test or
`requiring blood
`transfusion
`o Platelet count of <35,000/L confirmed
`in a repeattest
`o Creatinine level of >3.0 X ULN confirmed
`in a repeattest
`
`

`

`
`
`284 Clinical Pharmacology in Drug Development 2(3)
`
`e QTcinterval of >500 msec or an increase from
`o INR level of >2.0 X ULN confirmed in a
`baseline of >60 msec confirmedin a repeat test
`repeattest
`after at
`least 20minute requires withdrawal
`o Bilirubin >5 X ULNconfirmedin a repeat
`from the study regardless of relationship to
`test
`study drug;
`e Any laboratory abnormality of Grade 3 or great
`e Liver transplant
`severity not covered above and notpresentat base-
`
`line, confirmedinarepeattest, except Grade3 eleva- e Pregnancy
`tionsin liver enzymesin clinically stable subject;
`Please note: Wiley-Blackwell is not responsible for the
`e Any neurological adverse event of Grade 3 or
`content or functionality of any supporting information
`greater severity excluding HE events;
`supplied by the authors. Any queries (other than missing
`e Clinically significant allergy or hypersensitivity
`content) should be directed to the corresponding author
`reactions to HPN-100;
`for the article.
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