T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`original article
`
`Survival after Treatment with Phenylacetate
`and Benzoate for Urea-Cycle Disorders
`Gregory M. Enns, M.B., Ch.B., Susan A. Berry, M.D., Gerard T. Berry, M.D.,
`William J. Rhead, M.D., Ph.D., Saul W. Brusilow, M.D.,
`and Ada Hamosh, M.D., M.P.H.
`
`A BS TR AC T
`
`Background
`The combination of intravenous sodium phenylacetate and sodium benzoate has been
`shown to lower plasma ammonium levels and improve survival in small cohorts of
`patients with historically lethal urea-cycle enzyme defects.
`
`Methods
`We report the results of a 25-year, open-label, uncontrolled study of sodium phenylac-
`etate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with
`urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.
`
`Results
`Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients
`survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days
`of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001).
`Patients 12 or more years of age (93 patients), who had 437 episodes, were more
`likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of
`patients who were comatose at admission survived. Patients less than 30 days of age
`with a peak ammonium level above 1000 μmol per liter (1804 μg per deciliter) were
`least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also
`used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or
`older during 7% of episodes.
`
`Conclusions
`Prompt recognition of a urea-cycle disorder and treatment with both sodium phen-
`ylacetate and sodium benzoate, in conjunction with other therapies, such as intrave-
`nous arginine hydrochloride and the provision of adequate calories to prevent catabo-
`lism, effectively lower plasma ammonium levels and result in survival in the majority
`of patients. Hemodialysis may also be needed to control hyperammonemia, especially
`in neonates and older patients who do not have a response to intravenous sodium
`phenylacetate and sodium benzoate.
`
`From the Department of Pediatrics, Stan-
`ford University, Stanford, CA (G.M.E.); the
`Department of Pediatrics, University of
`Minnesota, Minneapolis (S.A.B.); the De-
`partment of Pediatrics, Thomas Jefferson
`University, Philadelphia (G.T.B.); the De-
`partment of Pediatrics, Medical College of
`Wisconsin, Milwaukee (W.J.R.); and the
`Department of Pediatrics and Institute of
`Genetic Medicine, Johns Hopkins Univer-
`sity School of Medicine, Baltimore (S.W.B.,
`A.H.). Address reprint requests to Dr. Enns
`at the Department of Pediatrics, Division
`of Medical Genetics, Stanford University
`School of Medicine, Lucile Packard Chil-
`dren’s Hospital, 300 Pasteur Dr., H-315,
`Stanford, CA 94305-5208, or at greg.enns@
`stanford.edu.
`
`N Engl J Med 2007;356:2282-92.
`Copyright © 2007 Massachusetts Medical Society.
`
`2282
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`Survival after Phenylacetate and Benzoate for Urea-Cycle Disorders
`
`Urea-cycle disorders are inborn er-
`
`rors of metabolism that are characterized
`by episodic, life-threatening hyperammo-
`nemia resulting from partial or complete inactiv-
`ity of enzymes responsible for eliminating nitrog-
`enous waste. Historically, mortality and morbidity
`have been very high, and survivors commonly have
`had devastating neurologic sequelae.1 Initial efforts
`to remove accumulated ammonium in patients
`with hyperammonemic encephalopathy included
`lactulose therapy,2 exchange transfusion,3,4 peri-
`toneal dialysis,4 hemodialysis,5 and supplementa-
`tion with nitrogen-free analogues of essential ami-
`no acids.6 These treatments prolonged survival
`in some patients, but the overall efficacy was dis-
`appointing — and mortality and morbidity re-
`mained high.
`Current therapeutic strategies include reducing
`the production of nitrogenous waste with the use
`of a low-protein diet and preventing endogenous
`catabolism through the provision of adequate nu-
`trition. In addition, exploitation of alternative path-
`ways for excretion of waste nitrogen has played a
`critical role in the management of urea-cycle dis-
`orders since Brusilow and colleagues first sug-
`gested using endogenous biosynthetic pathways to
`eliminate non–urea-waste nitrogen as a substitute
`for defective urea synthesis.7 In theory, the total
`body load of nitrogen can be decreased, despite
`abnormal urea-cycle functioning, by promoting
`the synthesis of non-urea nitrogen-containing me-
`tabolites that have high excretion rates or rates
`that may be augmented.7-11 The first successful
`demonstration of this concept was the use of argi-
`nine supplementation for the treatment of argini-
`nosuccinate lyase deficiency.9
`An open-label, uncontrolled, multicenter study
`of intravenous sodium phenylacetate and sodium
`benzoate combined (Ammonul, Ucyclyd Pharma)
`as an emergency treatment for hyperammonemia
`in patients with urea-cycle disorders was conduct-
`ed in the United States and Canada from 1980 to
`2005. The primary purpose of the study was to
`determine whether treatment with sodium phen-
`ylacetate and sodium benzoate reduced mortality
`due to acute hyperammonemia, as compared with
`historical data.
`
`Me thods
`
`Study Design
`We conducted an open-label, uncontrolled, nonran-
`domized study at 118 hospitals in the United States
`
`and Canada between August 1980 and March 2005.
`The patients included in the study were hospital-
`ized because of hyperammonemia resulting from
`a urea-cycle defect. A total of 299 patients with
`urea-cycle disorders and 1181 episodes of hyper-
`ammonemia were included. Four patients for whom
`demographic data were incomplete were excluded.
`To enroll a patient, the investigator contacted one
`of the authors (S.W.B.) at Johns Hopkins School of
`Medicine (from 1982 through 1996), or Ucyclyd
`Pharma (from 1997 through 2005), which supplied
`the study drug and case-report forms. The insti-
`tutional review board at each participating institu-
`tion approved the study. Written informed consent
`was obtained from the parents or legal guardians
`of children enrolled and from adult patients.
`
`Treatment
`Infants and children (weighing up to 20 kg [44 lb])
`who had carbamyl phosphate synthetase deficiency,
`ornithine transcarbamylase deficiency, or argini-
`nosuccinate synthetase deficiency were treated with
`an initial (loading) dose of sodium phenylacetate
`(250 mg per kilogram of body weight) and sodium
`benzoate (250 mg per kilogram) administered in-
`travenously over a period of 90 to 120 minutes.
`Older children (weighing more than 20 kg) and
`adults were treated with sodium phenylacetate and
`sodium benzoate, 5.5 g per square meter of body-
`surface area, as an intravenous loading dose over
`a period of 90 to 120 minutes. After the loading
`dose, maintenance infusions of the same dose
`were continued over 24 hours until the patient no
`longer had hyperammonemia and oral therapy
`could be tolerated. Among the factors limiting
`tolerance were vomiting, decreased intestinal mo-
`tility, and the presence of umbilical catheters. In-
`travenous ondansetron (Zofran, GlaxoSmithKline)
`(0.15 mg per kilogram) was used in some patients
`to prevent or treat hyperemesis. Guidelines for
`administering sodium phenylacetate and sodium
`benzoate were not available for the treatment of
`argininosuccinate lyase deficiency or arginase de-
`ficiency. Loading and maintenance infusions
`also contained arginine hydrochloride (210 mg
`per kilogram for patients with ornithine trans-
`carbamylase deficiency or carbamyl phosphate syn-
`thetase deficiency, and 630 mg per kilogram for
`patients with argininosuccinate synthetase defi-
`ciency or argininosuccinate lyase deficiency). Al-
`though a dialysis protocol was not used, dialysis,
`as noted below, was recommended for any neonate
`with hyperammonemic encephalopathy or any oth-
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2283
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`er patient in whom the ammonium level did not
`decrease substantially within 8 hours after admin-
`istration of the loading infusion. Not all investiga-
`tors followed these treatment guidelines precisely.
`
`Assessment
`The primary end point was survival of the episode
`of hyperammonemia. When a patient died, the in-
`vestigator was asked to identify the primary and
`secondary causes of the death and to assess the
`relationship of the death to the primary disease and
`to the study drug. Plasma ammonium data were
`collected and analyzed according to a schedule de-
`termined by each investigator.
`
`Statistical Analysis
`Data were summarized with the use of descrip-
`tive statistics. An episode was defined as a single
`hospitalization for hyperammonemia. For com-
`parisons according to age and diagnosis, P values
`for survival were calculated with the use of Fish-
`er’s exact test for each category, as compared with
`all other categories. For the comparison accord-
`ing to peak ammonium level, P values for sur-
`vival were calculated with the use of Fisher’s ex-
`act test for each category of ammonium level, as
`compared with all categories of lower ammonium
`levels.
`Outcome at discharge (survival vs. death) was
`also compared according to coma status at admis-
`sion. Separate analyses according to coma status
`at admission were performed for all episodes and
`for different age groups and enzyme deficiency.
`P values were calculated with the use of the McNe-
`mar test for the comparison between outcome at
`discharge (alert vs. comatose vs. deceased) and
`coma status at admission (coma vs. no coma).
`
`R esults
`
`Survival
`Over the 25 years of the study, 299 patients with
`urea-cycle disorders were treated with sodium
`phenylacetate and sodium benzoate for a total of
`1181 episodes of hyperammonemia. The patients
`included 93 neonates (94 episodes) and 237 patients
`older than 30 days of age (1087 episodes) (Table 1
`and Fig. 1). Thirty-one patients were treated both
`as neonates and as older patients and thus were
`included in the totals for both groups. The mean
`(±SD) number of episodes per patient was 3.3±6.3
`(range, 1 to 79). Dialysis (including standard hemo-
`
`dialysis, various combinations of arteriovenous and
`venovenous hemofiltration, and peritoneal dialysis)
`was used during 136 of the 1181 episodes (12%)
`and in 105 of 299 patients (35%). Dialysis was used
`more commonly in neonates (56 neonates, 60% of
`episodes) than in older patients (80 patients, 7% of
`episodes). Peritoneal dialysis with no other form
`of dialysis was used in six neonates and was used
`in combination with hemodialysis, a form of he-
`mofiltration, or both in four neonates and two
`older patients. Overall the rate of survival (defined
`as survival of all known episodes for each patient)
`was 84% (250 of 299 patients) (Table 1). The sur-
`vival rate for hyperammonemic episodes was 96%
`(1132 of 1181 episodes). Patients more than 30 days
`of age were more likely to survive an episode of
`hyperammonemia than were neonates (survival
`rates, 98% and 73%, respectively; P<0.001). Patients
`more than 12 years of age (93 patients, 437 epi-
`sodes) were most likely to survive an episode of
`hyperammonemia (survival rate, 99%; P<0.001, as
`compared with all other age groups) (Table 2).
`The survival rate for episodes of hyperammo-
`nemia was significantly lower among male pa-
`tients with ornithine transcarbamylase deficiency
`(91%) than among female patients with the same
`deficiency (98%) and among patients with a defi-
`ciency of carbamyl phosphate synthetase, argini-
`nosuccinate synthetase, or argininosuccinate lyase
`(P<0.001) (Table 2). The survival rate appeared to
`be lower among patients with arginase deficiency
`(80%) than among those with a deficiency of orni-
`thine transcarbamylase, carbamyl phosphate syn-
`thetase, argininosuccinate synthetase, or argini-
`nosuccinate lyase but the difference did not reach
`statistical significance (Table 2); there were only
`five episodes reported in patients with arginase
`deficiency. Indeed, the single patient with arginase
`deficiency who died had neonatal sepsis and rela-
`tively mild hyperammonemia (<200 μmol per liter
`[361 μg per deciliter]).
`Thirteen of the 49 patients who died received
`sodium phenylacetate and sodium benzoate in
`amounts that were greater than the recommend-
`ed doses. Of these 13 patients, 7 received a bolus
`dose of sodium phenylacetate and sodium benzo-
`ate ranging from 370 to 620 mg per kilogram.
`One patient was given a bolus dose of sodium
`phenylacetate and sodium benzoate approximately
`9 times higher than that recommended (2310 mg
`of each medication per kilogram). In addition,
`seven patients were given multiple (range, one to
`
`2284
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`Survival after Phenylacetate and Benzoate for Urea-Cycle Disorders
`
`Table 1. Survival According to Diagnosis and Age at Presentation.
`
`Variable
`
`Carbamyl
`Phosphate
`Synthetase
`Deficiency
`
`All Patients
`(N = 41)
`
`Survived first known episode
`
`37/41 (90)
`
`Age ≤30 days
`
`Age >30 days
`
`9/12 (75)
`
`28/29 (97)
`
`Survived all known episodes
`
`34/41 (83)
`
`Neonatal onset (age ≤30
`days)
`
`8/12 (67)
`
`Ornithine Transcarbamylase
`Deficiency
`
`Argininosuccinate
`Synthetase
`Deficiency
`
`Argininosuccinate
`Lyase Deficiency
`
`Overall
`Survival*
`
`Male Patients
`(N = 86)
`
`Female Patients
`(N = 78)
`
`All Patients
`(N = 80)
`
`All Patients
`(N = 11)
`
`All Patients
`(N = 299)
`
`number/total number (percent)
`
`66/86 (77)
`
`24/40 (60)
`
`42/46 (91)
`
`61/86 (71)
`
`21/40 (53)
`
`70/78 (90)
`
`2/3 (67)
`
`69/75 (92)
`
`69/78 (88)
`
`2/3 (67)
`
`75/80 (94)
`
`28/32 (88)
`
`47/48 (98)
`
`73/80 (91)
`
`27/32 (84)
`
`10/11 (91)
`
`260/299 (87)
`
`5/5 (100)
`
`5/6 (83)
`
`10/11 (91)
`
`5/5 (100)
`
`68/93 (73)
`
`193/206 (94)
`
`250/299 (84)
`
`63/93 (68)
`
`Presumed late onset
`(age >30 days)
`
`27/29 (93)
`
`40/46 (87)
`
`68/75 (91)
`
`46/48 (96)
`
`5/6 (83)
`
`188/206 (91)
`
`* Three patients with arginase deficiency were treated with sodium phenylacetate and sodium benzoate; one had neonatal onset of the dis-
`ease and died during the first episode, and two had a total of four episodes and survived. Because ornithine transcarbamylase deficiency is
`an X-linked disorder, male patients typically have a more severe clinical phenotype than do female patients, so for this disorder a distinction
`on the basis of sex was made.
`
`seven) additional bolus infusions of sodium phen-
`ylacetate and sodium benzoate after administra-
`tion of the initial bolus. Two other male patients
`with ornithine transcarbamylase deficiency were
`given high maintenance doses of each medica-
`tion (an 18-year-old was given 6.25 g per square
`meter of body-surface area over a 23-hour period
`and a neonate 4380 mg per kilogram over a 25-
`hour period).
`The majority of patients had adverse events dur-
`ing treatment for hyperammonemia; disorders of
`the metabolic system, the nervous system, and the
`respiratory system were most commonly reported
`(Table 3). In the 49 patients who died, coexisting
`conditions were common and included seizures
`(19 patients), infection (18), cerebral edema or in-
`creased intracranial pressure (16), disseminated
`intravascular coagulation (9), kidney failure (6),
`multiorgan system failure (5), and cerebral hemor-
`rhage (5).
`
`Survival and Coma at Admission
`Among 209 patients, there were 1020 episodes of
`hyperammonemia without coma at the time of ad-
`mission. When coma was not present on admis-
`sion, in the overwhelming majority (992) of these
`episodes (97%), coma was also absent at the time
`of discharge. However, 22 episodes in which coma
`was absent on admission resulted in death (2%),
`and in 6 episodes (<1%) coma persisted at the time
`
`of discharge (five patients with coma at discharge
`were transferred to other hospitals for treatment
`with dialysis, and one was transferred to another
`center for liver transplantation). Among 82 pa-
`tients, there were 120 episodes in which the pa-
`tients were comatose on admission. Overall, when
`patients were comatose on admission, no coma
`was present at the time of discharge (97 episodes,
`81%); 23 episodes in which the patients were
`comatose at admission resulted in death (19%)
`(Table 2).
`The survival rate for hyperammonemic episodes
`was significantly lower among patients who were
`comatose at admission, both among neonates (P =
`0.002) and among older patients (P<0.001). Chil-
`dren 2 to 12 years of age who were comatose at
`admission had a relatively lower rate of survival
`of a hyperammonemic episode (79%) than those
`in other groups over 30 days of age. The survival
`rate was lowest among male patients with orni-
`thine transcarbamylase deficiency who were co-
`matose at admission (68%) (Table 2).
`
`Survival and Peak Ammonium Level
`Survival was significantly improved for patients
`who had hyperammonemic episodes with a peak
`plasma ammonium level of 500 μmol per liter (902
`μg per deciliter) or less than among those with
`higher peak ammonium levels (P<0.001). Patients
`less than 30 days of age with a peak ammonium
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2285
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`99
`
`96
`
`87
`
`100
`
`98
`
`93
`
`99
`
`97
`
`99
`
`97
`
`98
`
`100
`
`90
`
`91
`
`90
`
`98
`
`99
`
`94
`
`100
`
`93 91
`
`73 73
`
`77
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Survival(%)
`
`0
`
`
`
`
`
`
`
`
`First episode (N =93)
`
`
`
`
`First episode (N =41)CPS deficiency (N =203)
`
`
`
`First episode (N =206)In older patients (N =1087)In neonates (N =94)All episodes (N =1181)First episode (N =299)Recurrent episode (N =882)Recurrent episode as neonate (N =1)
`
`
`O TC deficiency in fem ale patients (N =376)
`
`AL deficiency (N =14)First episode (N =80)AS deficiency (N =305)Recurrent episode (N =225)First episode (N =78)Recurrent episode (N =298)First episode (N =86)Recurrent episode (N =192)Recurrent episode (N =881)Recurrent episode (N =162)O TC deficiency in m ale patients (N =278)
`
`First episode (N =11)
`Recurrent episode (N =3)
`
`
`
`
`
`Figure 1. Survival of Episodes of Hyperammonemia, According to Age, Diagnosis, and First Episode versus Recurrent Episodes.
`Because ornithine transcarbamylase (OTC) deficiency is an X-linked disorder, male patients typically have a more severe clinical pheno-
`type than do female patients, and for that reason a distinction on the basis of sex was made. CPS denotes carbamyl phosphate synthe-
`tase, and AS argininosuccinate synthetase.
`
`Episodes
`
`level greater than 1000 μmol per liter (1804 μg per
`deciliter) were least likely to survive a hyperammo-
`Enns
`AUTHOR:
`ICM
`nemic episode (survival, 38%; P<0.001) (Table 4
`1 of 2
`FIGURE:
`REG F
`and Fig. 2).
`CASE
`
`ts
`
`(334 and 364 μmol per liter [603 and 657 μg per
`deciliter] among neonates and 168 and 116 μmol
`1st
`RETAKE
`per liter [303 and 209 μg per deciliter] among
`2nd
`3rd
`older patients, respectively). Median ammonium
`Revised
`Line
`4-C
`levels decreased substantially in patients who
`SIZE
`EMail
`ARTIST:
`H/T
`H/T
`39p6
`survived (from 374 to 24 μmol per liter [675 to 43
`Changes in Ammonium Levels
`Enon
`Combo
`Plasma ammonium levels decreased substantially
`μg per deciliter] among neonates and 179 to 36
`AUTHOR,PLEASENOTE:
`Figurehasbeenredrawnandtypehasbeenreset.
`in most patients after therapy with the use of the
`μmol per liter [323 to 65 μg per deciliter] among
`Pleasecheckcarefully.
`intravenous treatment protocol (alternative-path-
`older patients).
`way therapy for nitrogen excretion). For all epi-
`35622
`05-31-07
`JOB:
`ISSUE:
`sodes in which both a baseline ammonium level
`(the last value recorded before treatment with so-
`dium phenylacetate and sodium benzoate plus ar-
`ginine hydrochloride was begun) and the level
`measured after treatment was initiated were known
`(582 patients), the median ammonium level fell
`from 185 μmol per liter (334 μg per deciliter) to
`36 μmol per liter (65 μg per deciliter) at the final
`assessment (−79% change from baseline). Plasma
`ammonium levels decreased substantially in both
`neonates and older patients, although the median
`ammonium levels were markedly higher in neo-
`nates than in older patients at baseline. Among
`patients who died, median ammonium levels were
`similar at baseline and at the final assessment
`
`Discussion
`
`Historically, survival among patients with urea-
`cycle disorders was poor after episodes of hyper-
`ammonemia; most children with a severe enzyme
`deficiency died as neonates — and few survived
`infancy.1,12,13 In 1979, Brusilow et al. hypothe-
`sized that hyperammonemic coma caused by
`urea-cycle disorders might be treated with a
`combination of sodium phenylacetate and sodi-
`um benzoate.7 The potential of the use of alter-
`native pathways of nitrogen excretion to treat
`hyperammonemic coma was demonstrated soon
`thereafter; the administration of sodium benzo-
`ate either orally or intravenously in four patients
`
`2286
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`Survival after Phenylacetate and Benzoate for Urea-Cycle Disorders
`
`Table 2. Outcomes of 1181 Episodes of Hyperammonemia, According to Age, Diagnosis, and Coma Status at Admission.*
`
`Variable
`
`All episodes
`Coma at admission
`No coma at admission
`Age group
`≤30 days (94 episodes)
`Coma at admission
`No coma at admission
`>30 days (1087 episodes)
`Coma at admission
`No coma at admission
`>30 days to 2 yr (171 episodes)
`Coma at admission
`No coma at admission
`>2 to 12 yr (479 episodes)
`Coma at admission
`No coma at admission
`>12 yr (437 episodes)
`Coma at admission
`No coma at admission
`Diagnosis
`Carbamyl phosphate synthetase de-
`ficiency (203 episodes)
`Coma at admission
`No coma at admission
`Ornithine transcarbamylase defi-
`ciency
`Male patients (278 episodes)
`Coma at admission
`No coma at admission
`Female patients (376 episodes)
`Coma at admission
`No coma at admission
`Argininosuccinate synthetase defi-
`ciency (305 episodes)
`Coma at admission
`No coma at admission
`Argininosuccinate lyase deficiency
`(14 episodes)
`Coma at admission
`No coma at admission
`
`Status at Discharge
`Comatose
`
`Alert
`
`Dead
`
`no. of patients/total no. (%)
`
`P Value†
`
`Survival
`
`P Value‡
`
`no. of patients/
`total no. (%)
`1132/1181 (96)
`
`<0.001
`
`97/120 (81)
`992/1020 (97)
`
`0
`6/1020 (<1)
`
`23/120 (19)
`22/1020 (2)
`
`28/43 (65)
`37/46 (80)
`
`0
`0
`
`15/43 (35)
`9/46 (20)
`
`69/77 (90)
`955/974 (98)
`
`0
`6/974 (<1)
`
`8/77 (10)
`13/974 (1)
`
`8/8 (100)
`155/159 (97)
`
`0
`1/159 (<1)
`
`0
`3/159 (2)
`
`22/28 (79)
`430/439 (98)
`
`0
`2/439 (<1)
`
`6/28 (21)
`7/439 (2)
`
`39/41 (95)
`370/376 (98)
`
`0
`3/376 (<1)
`
`2/41 (5)
`3/376 (< 1)
`
`10/12 (83)
`177/184 (96)
`
`0
`3/184 (2)
`
`2/12 (17)
`4/184 (2)
`
`23/34 (68)
`218/228 (96)
`
`0
`0
`
`11/34 (32)
`10/228 (4)
`
`18/24 (75)
`340/344 (99)
`
`0
`1/344 (<1)
`
`6/24 (25)
`3/344 (< 1)
`
`37/40 (93)
`250/256 (98)
`
`0
`2/256 (<1)
`
`3/40 (7)
`4/256 (2)
`
`7/7 (100)
`5/6 (83)
`
`0
`0
`
`0
`1/6 (17)
`
`0.002
`
`69/94 (73)
`
`<0.001
`
`<0.001
`
`1063/1087 (98)
`
`0.13
`
`168/171 (98)
`
`0.10
`
`0.005
`
`464/479 (97)
`
`0.18
`
`<0.001
`
`431/437 (99)
`
`<0.001
`
`0.11
`
`197/203 (97)
`
`0.44
`
`0.02
`
`253/278 (91)
`
`<0.001
`
`0.001
`
`367/376 (98)
`
`0.04
`
`<0.001
`
`298/305 (98)
`
`0.07
`
`0.03
`
`13/14 (93)
`
`0.45
`
`* Three patients with arginase deficiency were treated with sodium phenylacetate and sodium benzoate; one had neonatal onset of the dis-
`ease and died during the first episode, and two had a total of four episodes and survived. Because ornithine transcarbamylase deficiency is
`an X-linked disorder, male patients typically have a more severe clinical phenotype than do female patients, so for this disorder a distinction
`on the basis of sex was made. Patient status at discharge was based on the number of episodes of hyperammonemia for which coma status
`at both admission and discharge were known (291 patients and 1140 episodes).
`† P values were calculated with the use of the McNemar test for the comparison between survival status at discharge (alert plus comatose vs.
`deceased) and coma status at admission (coma vs. no coma).
`‡ P values were calculated with the use of Fisher’s exact test for the comparison between survival status in each age subgroup and all other
`age subgroups and between each subgroup according to diagnosis and all other subgroups according to diagnosis.
`
`n engl j med 356;22 www.nejm.org may 31, 2007
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`2287
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 3. Reported Adverse Events in Patients with Urea-Cycle Disorders Treated with Sodium Phenylacetate
`and Sodium Benzoate.*
`
`Variable
`
`Neonates
`
`Older Patients
`
`Patients
`(N = 93)
`
`Episodes of
`Hyperammonemia
`(N = 94)
`
`Patients
`(N = 239)
`
`Episodes of
`Hyperammonemia
`(N = 1087)
`
`Total no.†
`Blood and lymphatic system disorders
`Anemia
`Disseminated intravascular coagulation
`Thrombocytopenia
`Cardiac disorders
`Cardiac arrest
`Tachycardia
`Supraventricular tachycardia
`Gastrointestinal disorders
`Vomiting
`Diarrhea
`General disorders and administration-site con-
`ditions
`Injection-site reactions
`Fever
`Hepatobiliary disorders
`Infections and infestations
`Urinary tract infection
`Otitis media
`Metabolism and nutrition disorders
`Hypokalemia
`Hyperammonemia
`Hyperglycemia
`Acidosis
`Nervous system disorders
`Seizures
`Cerebral edema
`Mental impairment
`Psychiatric disorders
`Agitation
`Renal and urinary disorders
`Respiratory, thoracic, and mediastinal disorders
`Respiratory distress or failure
`Hyperventilation
`Skin and subcutaneous-tissue disorders
`Vascular disorders
`Hypotension
`
`50 (54)
`11 (12)
`5 (5)
`3 (3)
`3 (3)
`9 (10)
`3 (3)
`2 (2)
`2 (2)
`5 (5)
`3 (3)
`1 (1)
`7 (8)
`
`1 (1)
`0
`3 (3)
`7 (8)
`0
`0
`20 (22)
`5 (5)
`5 (5)
`5 (5)
`4 (4)
`17 (18)
`8 (9)
`3 (3)
`1 (1)
`1 (1)
`0
`4 (4)
`13 (14)
`7 (8)
`1 (1)
`3 (3)
`12 (13)
`12 (13)
`
`number (percent)
`125 (52)
`20 (8)
`7 (3)
`6 (3)
`1 (<1)
`17 (7)
`2 (<1)
`8 (3)
`0
`42 (18)
`29 (12)
`10 (4)
`34 (14)
`
`30 (13)
`16 (7)
`5 (2)
`33 (14)
`11 (5)
`5 (2)
`56 (23)
`27 (11)
`13 (5)
`12 (5)
`18 (8)
`63 (26)
`25 (10)
`12 (5)
`22 (9)
`20 (8)
`10 (4)
`6 (3)
`35 (15)
`13 (5)
`5 (2)
`17 (7)
`12 (5)
`4 (2)
`
`50 (53)
`11 (12)
`5 (5)
`3 (3)
`3 (3)
`9 (10)
`3 (3)
`2 (2)
`2 (2)
`5 (5)
`3 (3)
`1 (1)
`7 (7)
`
`1 (1)
`0
`3 (3)
`7 (7)
`0
`0
`20 (21)
`5 (5)
`5 (5)
`5 (5)
`4 (4)
`17 (18)
`8 (9)
`3 (3)
`1 (1)
`1 (1)
`0
`4 (4)
`13 (14)
`7 (7)
`1 (1)
`3 (3)
`12 (13)
`12 (13)
`
`299 (28)
`21 (2)
`8 (<1)
`6 (<1)
`1 (<1)
`23 (2)
`2 (<1)
`13 (1)
`0
`94 (9)
`70 (6)
`10 (<1)
`72 (7)
`
`43 (4)
`25 (2)
`5 (<1)
`44 (4)
`11 (1)
`6 (<1)
`85 (8)
`35 (3)
`22 (2)
`14 (1)
`20 (2)
`90 (8)
`29 (3)
`13 (1)
`27 (2)
`31 (3)
`10 (<1)
`6 (<1)
`56 (5)
`15 (1)
`8 (<1)
`29 (3)
`12 (1)
`4 (<1)
`
`* Reported adverse events are shown according to patient’s age, frequency of occurrence event, and frequency of occur-
`rence during episodes of hyperammonemia.
`† Some patients had more than one adverse event.
`
`2288
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`Survival after Phenylacetate and Benzoate for Urea-Cycle Disorders
`
`Table 4. Outcomes of 823 Episodes of Hyperammonemia, According to Age and Peak Ammonium Level.*
`
`Episode
`
`Peak ammonium level
`
`≤200 μmol/liter
`
`>200–500 μmol/liter
`
`>500–1000 μmol/liter
`
`>1000 μmol/liter
`
`Peak ammonium level at age ≤30 days (74 episodes)
`
`≤200 μmol/liter
`
`>200–500 μmol/liter
`
`>500–1000 μmol/liter
`
`>1000 μmol/liter
`
`Peak ammonium level at age >30 days to 2 yr (119 episodes)
`
`≤200 μmol/liter
`
`>200–500 μmol/liter
`
`>500–1000 μmol/liter
`
`>1000 μmol/liter
`
`Peak ammonium level at age >2 yr to 12 yr (305 episodes)
`
`≤200 μmol/liter
`
`>200–500 μmol/liter
`
`>500–1000 μmol/liter
`
`>1000 μmol/liter
`
`Peak ammonium level at age >12 yr (325 episodes)
`
`≤200 μmol/liter
`
`>200–500 μmol/liter
`
`>500–1000 μmol/liter
`
`>1000 μmol/liter
`
`Survival
`
`P Value†
`
`no. of episodes/total no. (%)
`
`341/347 (98)
`
`361/366 (99)
`
`56/67 (84)
`
`20/43 (47)
`
`9/10 (90)
`
`17/18 (94)
`
`13/17 (76)
`
`11/29 (38)
`
`49/50 (98)
`
`55/55 (100)
`
`5/6 (83)
`
`7/8 (88)
`
`140/143 (98)
`
`129/132 (98)
`
`23/28 (82)
`
`0/2
`
`143/144 (99)
`
`160/161 (99)
`
`15/16 (94)
`
`2/4 (50)
`
`0.77
`
`<0.001
`
`<0.001
`
`1.00
`
`0.18
`
`<0.001
`
`0.48
`
`0.11
`
`0.19
`
`1.00
`
`0.001
`
`0.002
`
`1.00
`
`0.14
`
`0.001
`
`* Survival according to peak ammonium level was based on the number of episodes for which ammonium data were
`available. To convert values for ammonium to micrograms per deciliter, divide by 0.5543.
`† P values were calculated by Fisher’s exact test for the comparison between survival status for subgroups according to peak
`ammonium level and subgroups according to all lower peak ammonium levels (≤200 μmol/liter for the comparison with
`>200 to 500 μmol/liter; ≤200 μmol/liter and >200 to 500 μmol/liter for the comparison with >500 to 1000 μmol/liter).
`
`with urea-cycle disorders who were in hyperam-
`monemic coma resulted in a prompt decrease in
`the plasma ammonium level and clinical improve-
`ment.14 In an additional study involving 26 patients
`with urea-cycle disorders who had hyperammo-
`nemia, prolonged survival and improved clinical
`outcome were observed after treatment with in-
`travenous sodium benzoate and arginine hydro-
`chloride, dietary restriction of protein, provision of
`adequate calories, and peritoneal dialysis.15 Subse-
`quently, a study involving seven children with urea-
`cycle disorders showed that a combination of in-
`travenous sodium phenylacetate, sodium benzoate,
`
`and arginine hydrochloride, with non-nitrogenous
`intravenous hyperalimentation, could lower plasma
`ammonium to normal or near-normal levels.16
`The 299 patients with urea-cycle disorders in
`the present observational study sustained 1181
`episodes of hyperammonemia over a 25-year pe-
`riod, with a survival rate of 96% (neonates, 73%;
`patients more than 30 days old, 98%) and a rate
`of overall survival of 84%. The use of alternative-
`pathway therapy in addition to provision of appro-
`priate nutrition and, in some cases, the use of di-
`alysis, clearly improved survival, as compared with
`historical data. Because the patients were treated
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2289
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`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`LUPIN EX. 1006
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`the ammonium level did not exceed 500 μmol per
`liter (902 μg per deciliter) resulted in survival, with
`survival decreasing with rising ammonium levels.
`A substantial decrease in plasma ammonium lev-
`els was noted in survivors, but not in those who
`died after a hyperammonemic crisis. This finding
`may reflect the presence of a severe accumulation
`of waste nitrogen that was refractory to treatment.
`It is also possible that treatment was withdrawn
`in some cases because of poor clinical status and
`prognosis, leading to persistently high ammonium
`levels.
`Adverse events were reported in just over 50%
`of treated patients (Table 3). However, most ad-
`verse events were likely to be related to the under-
`lying primary disease or the patient’s clinical sta-
`tus. Among those who died, seizures, infection,
`and cerebral edema were the most common coex-
`isting conditions. Cerebral edema or increased in-
`tracranial pressure was documented by investiga-
`tors in 16 of 49 deaths but, given t