Original Article
`
`Glycerol Phenylbutyrate in Patients With
`Cirrhosis and Episodic Hepatic
`Encephalopathy: A Pilot Study of Safety and
`Effect on Venous Ammonia Concentration
`
`5,3 ACCP
`
`anumCuu'Jnu: utmhtown».'uwr
`
`Clinical Pharmacology
`in Drug Development
`2(3) ZIPS—284
`© The Author(s) 20|3
`DOI: [0.[002icpddl3
`
`Marwan Ghabril', Igor A. Zu anetsz, john Vierlingz, Parvez Mantry“, Don Rockeys,
`David Wolf", Robert O’Shea , Klara Dickinson“, Heather Gillaspya, Catherine Norriss,
`Dion F. Coakleya, Masoud Mokhtaranis, and Bruce F. ScharschmidtB
`
`Abstract
`
`Glycerol tri-(4—phenylbutyrate) (glycerol phenylbutyrate. GPB. HPN-IDO) 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 closing followed by 3 weeks of 9 mL (9.9 g) BID
`dosing and underwent repeated 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 compared to baseline. with a decrease on the eighth day of 6 mL BID dosing to 45.4
`(27.9) |JsmoliL (ULN ~48 umoll’L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more
`adverse events and higher phenylacetate (PAA) plasma concentrations (FAA (Imax of I44 [I25] vs. 292 [224] ugimL on 6
`and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared
`with baseline, was better tolerated than 9 mL BID. and is appropriate for 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 and antibiotics is based on this premise.I
`4 However, the implication of ammonia in the pathogen-
`esis of HE is based largely on correlative studies.5
`Moreover, current treatment is not ammonia selective,
`and rif‘aximin, which was recently approved for the
`treatment of episodic HE, was reported to have only a
`modest effect on ammoniaf“? Glycerol phenylbutyrate
`(GPB; glyceryl tri-(4-phenylbutyrate); also referred to as
`HPN-lOO]
`is an oral agent approved for urea cycle
`disorders (UCD) and an investigational agent under
`development for HER—1° It is a pro—drug ofphenylbutyric
`acid (PBA), currently marketed as sodium phenylbutyrate
`(BUPHENYL), for the treatment of UCDs (Figure l) .
`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
`
`
`IIndiana University School of Medicine. Indianapolis. IN. USA
`2National University of Pharmacy. Kharkiv. Ukraine
`3Baylor College of Medicine. Houston, TX. USA
`4Liver Institute at MethodiSt Dallas Medical Center, Dallas. TX. USA
`5University of Texas. Southwestern. Dallas. TX. USA
`c’New York Medical College. Valhalla. NY. USA
`7C|eveland Clinic. Cleveland. OH. USA
`8Hyperion Therapeutics. Inc.. South San Francisco. CA. USA
`Submitted for publication 28 AugUSt 2D | 2; accepted 30 January 2U| 3
`
`‘Corresponding Author:
`Bruce F. Scharschmiclt. Hyperion Therapeutics. 6m Gateway Blvd.
`Suite 200 South San Francisco. CA 94080. USA
`
`(e-mail: bruce.scharschmidt©gmail.com)
`
`10f?
`
`Horizon Exhibit 201 6
`
`Lupin v. Horizon
`|PR2018-00459
`
`

`

`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 ofthis open label, phase 2a study
`(Protocol HPN-lOO-OOS, Part A) were to evaluate the
`safety,
`tolerability and activity, assessed as ammonia
`concentration lowering, of6 and 9 mL BID GPB doses in
`patients with cirrhosis and episodic HE and to determine
`whether either dose was suitable for
`further study.
`Patients received 6mL of GPB (equivalent to 6.6g of
`GPB) BID for 7 days followed by 9mL (equivalent to
`9.9g of GPB) BID for 21 days. GPB was administered
`orally with moming 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 22 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 2hours before the second
`daily dose of GPB),
`and 12hours post-first dose
`(approximately 2hours 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 hours post—first daily dose). Urine
`was collected for PK analysis on Days 7 (for 24 hours) and
`28 (for 72 hours).
`The protocol was conducted under a US IND. The
`protocol was reviewed and approved by the Institutional
`Review Board or Ethics Committee at each investigative
`site. These included New York Medical College Office of
`Research Administration, Valhalla, NY; Methodist
`
`20f?
`
`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 ofMinistry ofHealth okaraine, Kiev,
`Ukraine. A Data and Safety Monitoring Board reviewed
`all safety information, at the end ofthe open label part and
`approved the initiation of the randomized part of the
`study. The study was listed in clinicaltrialsgov with
`registration number NCT00999167.
`Continuous variables were summarized with means,
`standard deviations, medians, minimums, and maxi-
`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 PAGN in urine were measured by Quest
`Pharma Services (QPS, LLC, Newark, DE) using liquid
`chromatography-tandem mass spectrometry.3 m Plasma
`PK parameters calculated for PBA, PAA, and PAGN
`included the following: maximum observed plasma
`concentration (Cum), minimum observed plasma concen-
`tration (Cm-n), and areas under the plasma concentration-
`time curve from time 0 to 8 (AUCn 3h) calculated using
`linear trapezoidal rule. Urine was collected on Days 7 and
`28 and urine metabolite concentrations measured during
`the 0—12- and 12—24-hour collection 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 of52.2 (5.24) years
`and model for end-stage liver disease (MELD) score of
`l 1.5 (3.66) were enrolled. All
`15 patients (100%)
`completed closing 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 and prior to completing the 4-week treatment period.
`Four patients withdrew because they met the 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 1 subject, regardless of
`relationship to study drug, were diarrhea and hypokale—
`mia in 3 patients each, and upper abdominal pain, nausea,
`
`

`

`
`280
`Clinical Pharmacology in Drug Development 2(3)
`
`Table I. Demographics and Baseline Characteristics
`
`Table 2. AEs Occurring 22 Patients
`
`
`
` Baseline Characteristic Total (N 2 IS)
`
`Age (years)
`Mean (SD)
`Median
`Min. max
`
`Sex, n (36)
`Male
`Female
`Race. n (36)
`White
`Black or African American
`Body mass index (kgi’m2)
`Mean (SD)
`Median
`
`Min. max
`Months in current remission
`
`Mean (SD)
`Median
`Min. max
`
`Child-Pugh classification. n (36)
`A
`
`B
`C
`Laetulose use at enrollment (mUday)
`Mean (SD)
`Median
`Min. max
`MELD score
`
`Mean (SD)
`Median
`Min. max
`
`HE grade. n (36)
`0
`|
`Not done
`
`52.2 (5.24)
`520
`45. 62
`
`IO (67%)
`5 (3336)
`
`I4 (9336)
`|
`(7%)
`
`29.5 (5.|4)
`28.2
`
`23. 40
`
`M (0.87)
`07
`0. 3
`
`0
`
`I0 (6736)
`5 (33%)
`
`78.0 (4|.l)
`750
`I5. I20
`
`”.5 (3.66)
`|2.0
`6.
`IS
`
`I3 (9336)
`|
`(7%)
`I
`
`Asterixis grade. n (36)
`I3 (93%)
`0
`|
`(7%)
`|
`
`Not done I
`
`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 HE events), 2 ofwhich led to death; 4 patients
`experienced an HE event. Related AEs reported in more
`than 1 patient included diarrhea, nausea, and headache in
`2 patients each. There were 2 deaths; one due to
`esophageal variceal hemorrhage and another clue to 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 renal failure occurred in a patient with
`hepatoeellular carcinoma who had earlier developed
`
`30f?
`
`|
`
` System Organ Class Preferred Total (N 2 I5)
`
`
`41W“, H3633
`(73%)
`|
`Any AE
`9 (6036)
`Gastrointestinal disorders
`3 (20%)
`Diarrhea
`2 (I336)
`Abdominal pain upper
`2 (l3%)
`Nausea
`7 (4736)
`Metabolism and nutrition disorders
`3 (20%)
`Hypokalaemia
`2 (I336)
`Hypoglycaemia
`2 (l3%)
`Hyponatraemia
`4 (2736)
`Infections and infestations
`2 (I336)
`Urinary tract infection
`4 (27%)
`Nervous system disorders
`2 (I336)
`Headache
`2 (I336)
`Blood and lymphatic system disorders
`2 (I336)
`Thrombocytopenia
`2 (l336)
`Injury. poisoning and procedural complications
`2 (I336)
`Investigations
`2 (l3%)
`Musculoskeletal and connective tissue disorders
`2 (I336)
`Psychiatric disorders
`2 (I336)
`Renal and urinary disorders
`
`Skin and subCutaneous tissue discrders 2 (l336)
`
`aAt each level of summation (overall. system organ class. preferred term),
`patients reporting more than I 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 3' 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. Ofthe 7 patients who discontinued
`from the study, 6 (40%) discontinued the study drug due
`to ABS and 1 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 and liver failure. Collectively, the
`AEs reported by the patients in this study are typical of
`those expected for the study population.
`No clinically 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 UfL at baseline to 46.6 Ui’L on Day 286early
`termination. The mean value for aspartate aminotransfer—
`ase (AST) also increased, from 56.5 Ui’L at baseline to
`75.5 Ui'L on Day 28fearly termination. These increases
`were primarily driven by 1 patient who had liver failure
`
`

`

`
`
`Ghabril et al 281
`
`MeganODDcacao
`Mnan(SD)FAA[ugJ'ij 3
`
`
`
`
`
`—L OO
`0
`
`DChild Pugh B
`DChildP hC
`
`
`
`GPB —* PBA —'PAA—* PAGN
`
`a—ketogiutarate —- glutamine,\ /
`111
`
`”pages
`(intestlne)
`
`Glutamine N-
`fl-oxidatlon
`(liver 8; most acyltransferase
`other organs)
`(liver. kidney)
`
`Alternate Pathway
`
`Figure I. Mechanism of action for GPB. GPB is digested by
`pancreatic lipases
`to release PBA which is convened to
`phenylacetic
`acid
`(PM) by beta-oxidation. PM 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 due to renal failure. When this patient
`was excluded, the change in baseline for ALT was to
`36.7 UIL and for AST was to 571.6 UI’L on Day 28i’early
`termination.
`
`PK Analyses
`PBA values for mean Cum, Cum, and AUCM“, were all
`similar during 6 and 9 mL BID dosing. These findings are
`consistent with prior studies and the sh0rt plasma halflife
`of this metabolite (Table 3).8 1"
`Consistentwith prior studies in cirrhotic patients, PAA
`levels increased with repeated GPB dosing and with the
`GPB dose level and tended to be higher during 9 mL BID
`than 6mL BID dosing and were similar on Days 14, 21,
`
`Day1 (Baseline)
`
`Day ‘I' {6 mL BID)
`
`Day1419 rnL BID]
`
`Figure 2. PAA in relation to Child Pugh classification 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 was higher 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 '1' days at 9 mL BID).(J The mean Cmin during
`9mL BID was higher than during 6mL BID, and the
`mean Cmax during 9 mL BID was twice the value ofthat
`during 6mL BID. While the mean AUCU 3., 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. PAA levels also were higher in patients with Child-
`Pugh C than B with AUCI, 3; hr SZThHgImL in Child-
`Pugh B group (N = 10) compared with 1211 h (Lgi’rnL in
`Child—Pugh C (n = 5) and Cm,“ of 95 versus 183 [,Lg/mL
`after 6mL BID dosing on Day 7.
`PAGN mean Cmin, Cum, and AUCH“, were higher
`during 9 mL BID compared with 6 mL BID dosing, and
`the increase in these parameters was roughly proportional
`to the increase in dose.
`
`PAA levels were generally higher among patients who
`experienced SAEs and withdrew from the study early
`
`Table 3. Plasma PK Parameters for PBA. FAA and PAGN During GPB Administration of 6 and 9 mL
`
`PBA
`
`PAA
`
`PAGN
`
`Days 1—7
`(6 mL BID)
`
`n23
`1 1.3 (12)
`7.49
`1.1. 34.3
`
`n :3
`120(409)
`1 15
`51.6. 199
`
`n =8
`517 (254)
`463
`87.5, 373
`
`Days 8—23
`(9 mL BID)
`
`n=15
`3.34 (23.1)
`2.13
`1.0, 92.1
`
`n = 15
`141 (43)
`129
`75.3. 231
`
`11 = 7
`503 (187)
`51 1
`263. 342
`
`Days 1—7
`(6 mL BID)
`
`n :3
`
`6.33 (4.9)
`5.3
`1.2, 15
`n :3
`
`144 (125)
`124
`13.5. 353
`n=3
`
`977 (396)
`343
`43, 2561
`
`Days 3—23
`(9 mL BID)
`
`n = 15
`
`34.4 (102)
`44.6
`1.9, 325
`n = 15
`
`292 (224)
`219
`57, 655
`n23
`
`304 (339)
`530
`137, 2764
`
`Days 1—7
`(6 mL BID)
`
`n = 3
`
`14.5 (6.3)
`14.9
`7.5, 24.6
`n = 3
`
`47.6 (14.4)
`43.7
`34.9. 30.9
`n23
`
`330 (135)
`316
`192. 620
`
`Days 3—28
`(9 mL BID)
`
`n = 15
`
`27.9 (21.9)
`23.7
`1.2, 65
`n = 15
`
`30.1 (34.7)
`63.2
`4.03, 150
`n23
`
`501 (223)
`416
`230, 974
`
`Parameter
`
`Cmin (ugmL)
`Mean (SD)
`Median
`Min. max
`
`Cmax (pgme)
`Mean (SD)
`Median
`Min. max
`
`AUCo_gh (l1 ' (Lg/NIL)
`Mean (SD)
`Median
`Min. max
`
`40f?
`
`

`

`
`282
`Clinical Pharmacology in Drug Development 2(3)
`
`Fasting Ammonia
`
`I—O—I
`
`1—9—1
`
`I—O—I
`
`i—O—t
`
`
`
`
`
`Mean(SE)AmmoniaumollL i5“r"13
`
`I—O—I
`
`1—.-|
`
`compared with patients who completed the study. Six
`patients with SAEs had PAA levels 2300 tLg/mL. PAA
`levels over time for Child-Pugh B and C patients are
`shown in 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
`6.6 g BID (6 mL) to 9.9 g BID (9 mL). These patients also
`generally had more severe liver disease with higher
`MELD scores (maximum MELD scores 13—23 vs. 7—18
`among patients who completed the study), and 4 out of 5
`patients with Child-Pugh C classification at baseline were
`among this group.
`The major urinary metabolite was PAGN. Mean 24-hr
`excretion of PAGN was 1 1.7 g while PAA excretion was
`negligible with a mean of0.02 g on Day 7. The mean (SD)
`urinary PAGN output on Day 28 was 1.78 times higher
`than on Day 7 (1 l .7 [3.7] g on Day 7 vs. 20.8 [3.7]g on
`Day 28); that is roughly proportional to the 50% increase
`in dose, and, on both days, higher during the first 12 hours
`than during the second 12 hours. Urinary excretion of
`PAGN continued 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 over the first 24 hours after 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.
`
`Ammonia
`
`Mean (SD) concentration ofammonia at baseline, prior to
`the first dose of study drug and administration ofa meal,
`was 74.4 (37.5) [Lmoli’L After the first dose of GPB,
`blood
`ammonia
`concentration
`decreased
`to
`65.1
`
`(40.7)].LmolfL. 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 ovemight
`fasting and within normal
`limits (mean [SD] of 47.8
`[33.3] tholx’L; ULN =48 tholfL). 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) [.Lmoli’L on
`Day 7. Mean fasting ammonia concentrations were lower
`at all subsequent time points on GPB relative to fasting
`ammonia concentrations at baseline. The decreases from
`
`fasting ammonia concentrations at baseline were statisti-
`cally significant at 4hours post—dose on Day 7 (P = .047);
`at pre-dose fasting (P: .007) and 4hours post-dose
`(P=.002) on Day 8; and at Shours (P=.008) and
`12 hours (P2015) post-dose on Day 28. The largest
`mean (SD) decrease from baseline was at 4hours post—
`dose on Day 8 (—29.7 [36.9] umolfL). At baseline, 9
`patients (69%) had an ammonia value that was above the
`ULN at the local laboratory. At all subsequent pre-dose
`time points, 350% ofpatients had ammonia values above
`the ULN (Figure 3).
`
`50f?
`
`Figure 3 . Mean (:tSE) fasting ammonia (ttmolfL) concentration
`over time by number of patients (n). As compared with baseline,
`ammonia concentration was decreased at all subsequent time
`points.
`
`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 concentration in patients with cirrhosis
`and episodic HER“10 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 exposures"lo In
`patients with episodic HE, blood ammonia concentrations
`decreased after the first dose ofGPB despite intake offood,
`which is typically associated with an increase in ammonia
`concentrationg'm'|| At baseline, fasting ammonia con—
`centrations were higher than the average upper limit of
`normal across sites and were within normal range after
`7 days oftreatment with GPB. As compared with baseline,
`ammonia concentration was directionally lower at all time
`points after starting GPB and fasting ammonia concentra-
`tion on Day 8, 1 week after starting GPB, was significantly
`lower than at baseline and within normal limits.
`
`The present data also provide information on dosing.
`As compared with a GPB dose of6mL BID, 9mL BID
`provided little additional effect with respect to ammonia
`control and was less well tolerated, as demonstrated by
`the frequency of ABS, SAEs, and proportion of patients
`who tolerated and completed dosing. Phase 1 studies
`involving intravenous administration of PAA to patients
`with cancer have demonstrated that PAA levels in the
`
`associated with
`range of 499—1285 ttgme were
`fatigue, dizziness,
`reversible toxicity manifested as
`lightheadedness,
`dysgeusia,
`headache,
`somnolence,
`pedal edema, nausea, vomiting, and rash.'2"3 While
`
`

`

`
`
`Ghobril et of 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
`common in 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.
`6 mL BID of GPB appears 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.14
`
`Declaration of Conflicting Interest
`
`K. Dickinson, H. Gillaspy, M. Mokhtarani, C. Norris, D.
`C oakley, and B. Scharschmidt arei’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 '[UPU[, lndianapolis, [N_; 2National University of
`Pharmacy, Kharkiv, Ukraine; 3Baylor College of Medicine
`Houston, TX; 4Liver Institute at Methodist Dallas Medical
`Center, Dallas, TX; 5University of Texas, Southwestern, Dallas,
`TX; 6l\lew York Medical College, Valhalla, NY; TCleveland
`Clinic, Cleveland, OH.
`
`References
`
`1. Bass NM. Emerging treatment options for the management
`of hepatic encephalopathy. Semt‘n LiverDt's. 2007;27(Suppl
`2): 18—25.
`2. Ferenci P. Treatment options for hepatic encephalopathy: a
`review. 59min Liver Dis. 2007;27{Suppl 2):]0—l7.
`3. Mullen KD, Ferenci P, Bass NM, et al. An algorithm for the
`management of hepatic encephalopathy. Semi}: Liver Dr's.
`2007;27(Supp| 3:32—48.
`4. Rudman D, DiFulco TJ. Galambos JT. et al. Maximal rates
`of excretion and Synthesis of urea in normal and cirrhotic
`patients. J Chin invest. 1973;52:224172249.
`5. Ong JP, Aggarwal A, Krieger D, et al. Correlation between
`ammonia levels and the severity of hepatic encephalopathy.
`AmJMed. 2003;114:188—193.
`
`6. Bass NM, Mullen KD, Sanyal A, et al. Ritaximin treatment in
`hepatic encephalopathy.NEngt'JMed.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 Hepatoi. 2010;52:S84.
`8. Lee B, Rhead W, Diaz GA, et al. Phase 2 comparison ofa
`novel ammonia scavenging agent with sodium phenyl—
`butyrate in patients with urea cycle disorders: safety,
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`pharmacokinetics and ammonia control. Mo? Genet Metal).
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`9. McGuire BM, Zupanets [, Lowe ME, et al. Pharmacology
`and safety of a novel ammonia lowering agents in healthy
`adults and adults with cirrhosis. Hepat‘ot’ogv 2010;51:
`2077—2085.
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`10. Lichter—Konecki U, Diaz GA, Merritt
`Ammonia (NH3) control
`in children with urea cycle
`disorders (UCDs); comparison of sodium phenylbutyrate
`and
`glycerol
`phenylbutyrate mo]. Genet Metab.
`2011;103:323—329.
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`ll. 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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`[serial online]. September 7, 2012. doi:
`10.1002fhep.26058 [epub ahead of print].
`12. Thibault A, Samid D, Cooper MR, et al. A phase [ and
`pharmacokinetic study of intravenous phenylacetate in
`patients with cancer. Cancer Res. 1994;541:1690—1694.
`l3. Thibault A, Cooper MR, Figg WD, et al. Phase 1 study of
`phenylacetate administered twice daily to patients with
`cancer. Cancer. 1995;75:2932—2938.
`
`l4. Rockey D, Vierling J, Mantry P, et al. Randomized,
`controlled, double—blind study of glycerol phenylbutyrate in
`patients with cirrhosis and episodic hepatic encephalopathy.
`Hepatot’ogy. 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 ofthe following criteria must be
`withdrawn from the study:
`0 AE of Grade 4 or greater severity according to
`the Common Terminology Criteria for Adverse
`Events (CTCAE) or life—threatening AE if not
`covered by CTCAE;
`0 An increase in the model for end-stage liver
`disease (MELD) score of greater than 5 from
`baseline;
`0 Any of the following laboratory abnormalities:
`0 Grade 3 liver enzyme abnormalities and 10-
`fold upper limit ofnormal (ULN) for those
`with normal values at baseline OR a 5-fold
`increase or 10—fold ULN for those with
`
`abnormal values at baseline, whichever is
`lower;
`0 Hemolgobin levels of <8 gi’dL confirmed
`in a
`repeat
`test or
`requiring blood
`transfusion
`
`o Platelet count of <35,000f|.LL confirmed
`in a repeat test
`0 Creatinine level of>3.0 X ULN confirmed
`
`in a repeat test
`
`

`

`284
`Clinical Phamiacology in Drug Development 2(3)
`
`o INR level of >21) X ULN confirmed in a
`
`repeat test
`0 Bilirubin >5 X ULN confirmed in a repeat
`test
`
`a Any laboratory abnormality of Grade 3 or great
`severity not covered above and not present at base-
`line, confirmed in a repeat test, except Grade 3 eleva-
`tions in liver enzymes in clinically stable subject;
`a Any neurological adverse event of Grade 3 or
`greater severity excluding HE events;
`a Clinically significant allergy or hypersensitivity
`reactions to [JPN—100;
`
`o QTc interval of >500 msec or an increase from
`baseline of >60 msec confirmed in a repeat test
`after at
`least 20 minute requires withdrawal
`from the study regardless of relationship to
`study drug;
`0 Liver transplant
`0 Pregnancy
`Please note: Wiley-Blackwell is not responsible for the
`content or functionality of any supporting information
`supplied by the authors. Any queries (other than missing
`content) should be directed to the corresponding author
`for the article.
`
`70f?
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`