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`Kimberly Gregory
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`Source : Mol Genet Metab
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`Volume : 102
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`Issue: 3
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`Date: 2011 Mar
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`Pages: 276-277
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`Author: Diaz GA, et al
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`Title: Phase 3 Blinded, Randomized, Crossover Comparison of Sodium Phenylbutyrate (NaPBA) and Glycerol Phenylbutyrate (GPB):
`Ammonia (NH3) Control in Adults with Urea Cycle Disorders (UCDs)
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`Par Pharmaceutical, Inc. Ex. 1021
`Parv. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 3
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`

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`276
`
`Abstracts / Molecular Genetics and Metabolism 102 (2011) 237–324
`
`was referred for a metabolic evaluation. At the time she presented to care, there was no evidence of protein aversion, ophthalmologic
`findings, or neurologic involvement. The patient was pregnant with a fetus measuring at 7 weeks of gestation at the time of her initial
`metabolic evaluation.
`
`Results: At presentation, an acylcarnitine profile revealed an elevated Propionyl carnitine (C3) level of 1.84 (reference range 0–1.60), total
`Hcy level of 56.18 (reference range of 10.50–16.7 μmol/L) and 205 mg/g creatinine of MMA measured in urine organic acid analysis. Molecular
`genetic sequencing of the MMACHC gene revealed two missense mutations [c.388T N C (p.Y130H), c.643T N C (p.Y215H)] consistent with the
`biochemical diagnosis of Cbl C deficiency.
`The patient was treated with 1 mg of intramuscular hydroxocobalamin per week. After one dose of hydroxocobalamin, her total Hcy
`level decreased from a level of 56.18 μmol/L to a level of 37.71 μmol/L and her MMA level decreased from a level of 205 mg/g creatinine to a
`level of 150 mg/g creatinine. She remained on a weekly regimen of hydroxocobalamin and her metabolites quickly normalized and
`remained within normal limits throughout the pregnancy. The patient delivered a health child following a full term pregnancy without
`complications.
`
`Conclusion: The attenuated phenotype of Cbl C deficiency may not be apparent in early adulthood. The late onset form of Cbl C deficiency
`may respond well to therapeutic treatment with hydroxocobalamin and treatment is able to normalize metabolites throughout pregnancy.
`The association between elevated total Hcy levels and increased risk for spontaneous abortions is not well delineated and should be studied
`further.
`
`25) Phase 3 blinded, randomized, crossover comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB): Ammonia
`(NH3) control in adults with urea cycle disorders (UCDS)
`
`GA Diaz1, J Bartley2, N Longo3, W Berquist4, A Feigenbaum5, R Gallagher6, W Rhead7, D Bartholomew8, CO Harding9, MS Korson10,
`U Lichter-Konecki11, SA Berry12, W Smith13, SE McCandless14, J Vockley15, S Bart16, D Kronn17, R Zori18, Sandesh Sreenath-Nagamani22,
`M Summar11, C Jomphe19, M Beliveau19, J Mauney20, K Dickinson21, M Mokhtarani21, D Coakley21, BF Scharschmidt21, B Lee22
`
`1Mt. Sinai School of Medicine, NY, NY, USA
`2Long Beach, CA, USA
`3Univ of UT, Salt Lake City, UT, USA
`4Stanford, Palo Alto, CA, USA
`5Hospital for Sick Children, Toronto, Ontario, Canada
`6Denver Children's Hospital, Denver, CO, USA
`7Med College of WI, Milwaukee, WI, USA
`8Nationwide Children's Hospital, Columbus, OH, USA
`9Oregon Health & Sciences Univ., Portland, OR, USA
`10Tufts Medical Center, Boston, MA, USA
`11Children's National Medical Center, Washington, DC, USA
`12Univ of MN, Minneapolis, MN, USA
`13Maine Medical Ctr., Portland, ME, USA
`14UHCMC and CWRU, Cleveland, OH, USA
`15Univ of Pittsburgh, Pittsburgh, PA, USA
`16SNBL, Baltimore MD, USA
`17Westchester Medical Ctr., Westchester, NY, USA
`18Univ of FL, Gainesville, FL, USA
`19Pharsight Corp., Montreal, Quebec, Canada
`20Chiltern, Wilmington NC, USA
`21Hyperion Therapeutics, Inc., South San Francisco, CA, USA
`22Baylor College of Medicine, HHMI, Houston, TX, USA
`
`Glycerol phenylbutyrate (GPB, also referred to as GT4P or HPN-100) is being developed as a treatment alternative to sodium phenylbutyrate
`(NaPBA) for UCD patients. Both drugs mediate waste nitrogen scavenging through conjugation of phenylacetic acid (PAA, derived from
`phenylbutyric acid [PBA]) with glutamine to form phenylacetylglutamine (PAGN) which is excreted in the urine. GPB is a short chain triglyceride
`(liquid) and 5.8 mL TID is anticipated to be the equivalent of 40 tablets (20 g) of NaPBA.
`
`Study design: Protocol HPN-100-006 was a 4-week randomized, blinded, cross-over comparison of the NaPBA with a PBA-equimolar GPB dose to
`establish non-inferiority of GPB to NaPBA in NH3 control. Subjects underwent 24-h blood sampling for NH3 and PK after each two week treatment period.
`
`Results: 46 subjects (41 OTC, 3 ASS, and 2 CPS) were randomized; 45 received at least one dose of study drug and constituted the ITT
`population; 44 completed the study. Subjects were evenly distributed between treatment arms, had been taking NaPBA for an average of ~13 yr
`and received an average dose of 13.95 g/day (7.8 g/m2/day) of NaPBA and 13.49 g/day (7.55 g/m2/day) of GPB while on study. NH3 values on both
`drugs were lowest after overnight fasting and peaked postprandially. 95% confidence intervals for NH3 (24 h AUC) on GPB relative to NaPBA in the
`ITT population (0.799, 1.034) were below the predefined non-inferiority margin of 1.25; mean NH3 levels on GPB were ~10% lower than on
`NaPBA (34.7 vs. 38.4 μmol/L; not significant). Glutamine was lower on GPB than NaPBA (758 vs. 809 μmol/L; ULN= 746; p b 0.05) by post-hoc
`analysis. At baseline, 91% of patients reported ≥1 organ system complaint with GI (56%) most common. AEs on study were reported by 61% and
`51% of subjects during GPB and NaPBA treatment, respectively, with most being GI and generally mild. No clinically significant lab or ECG changes
`were observed. One subject experienced a hyperammonemic crisis and one withdrew early because of high NH3 and headache; both were on
`
`

`

`Abstracts / Molecular Genetics and Metabolism 102 (2011) 237–324
`
`277
`
`NaPBA. One subject had an SAE of gastroenteritis on GPB judged unrelated. As compared with NaPBA, 24-hour AUC and peak plasma PAA levels
`were significantly lower on GPB, trough values higher, and overall 24 h urinary PAGN output identical but with more even day/night distribution.
`
`Conclusions: This pivotal trial demonstrated non-inferiority of GPB to NaPBA for NH3 control. The authors theorize that the PK findings and
`trend toward lower NH3 and glutamine observed in the pivotal study may be explained by slower GI absorption of PBA when delivered as a
`triglyceride (GPB) rather than a salt (NaPBA), leading to higher trough levels of the active moiety, PAA. The data also support the utility of urinary
`PAGN as a clinically useful biomarker.
`
`26) Natural history study of very-long-chain Acyl-CoA dehydrogenase deficiency in The Netherlands
`
`E.F.Diekman 1, P. Vellekoop 1, R.J.A. Wanders 2, H.R. Waterham 2 H de Klerk 3, G.P.A. Smit 4, M de Vries 5, M.F.Mulder 6, G.Visser 1
`
`1UMCU Utrecht, The Netherlands
`2AMC Amsterdam, The Netherlands
`3Erasmus MC Rotterdam, The Netherlands
`4UMCG Groningen, The Netherlands
`5Radboud MC Nijmegen, The Netherlands
`6VUmc Amsterdam, The Netherlands
`
`Background: Since 2007 Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is included in the Dutch neonatal screening
`program (NSP). Evidence based guidelines for treatment and follow-up of patients detected by the NSP are crucial to sustain proper care after
`neonatal diagnosis. For VLCADD, however, these guidelines have remained ill-defined.
`VLCADD is a rare disorder affecting the mitochondrial beta-oxidation of long-chain fatty acids. Clinical symptoms arise, or are exacerbated
`during catabolic situations e.g. during illness or fasting. Organs most frequently involved are those using long-chain fatty acids as primary energy
`source, such as the heart and skeletal muscles. Age at onset, manifestation patterns and clinical severity differ between patients.
`Currently in the Netherlands dietary measures aimed at preventing catabolism are the only available treatment option for patients with
`VLCADD. Long term outcome of these measures is unknown. There is a serious lack of historical controls. In order to be able to evaluate the true
`yield of the NSP, those historical controls are, however, of the utmost importance.
`
`Goal: To gain insight into incidence, clinical presentation and treatment of VLCADD in the Netherlands.
`
`Methods: Retrospective study. Patients were searched for by contacting clinical metabolic centers; metabolic laboratories specialized in
`VLCADD diagnostics, patient organizations and the Dutch Diagnosis Registration Metabolic Diseases (www.ddrmd.nl). Patient data were
`collected by patient file analysis using a standardized protocol.
`
`Results: Thirty patients were identified including 21 males and 9 females, born between 1963 and 2010. Seven patients were identified by
`newborn screening; including one severely affected, two mildly affected and four are asymptomatic, at least until now. A broad spectrum of
`mutations was found of which c.848T N C (p.V283A) was found most frequently. Generally no complications were reported during pregnancy or
`birth. Symptoms most frequently reported in childhood were hypoglycemia, muscular pains and cramps accompanied by increased plasma
`creatine kinase (CK) levels, and hepatomegaly. In adulthood muscular complaints and severely impaired daily functioning were most prominent.
`All patients are treated with dietary measures varying from LCT restriction, MCT enrichment, fatty acid supplementation and tube feeding, to
`carbohydrate or MCT intake before exercise. Treatment with a LCT restricted, MCT enriched diet appears to be effective in short-term disease
`control. In some adult patients severe impairment of daily functioning despite dietary treatment was reported.
`
`Conclusions: Since the introduction of the NSP, more patients with VLCADD have been identified as previously (est. incidence before
`screening 1:300,000, after 1:80,000). It is not yet clear whether asymptomatic VLCADD is relatively common but under-diagnosed, or whether a
`significant portion of infants detected by NSP might never become symptomatic unless experiencing significant catabolic stress. Factors
`predicting disease course (genotype, enzyme activity, CK, e.o.) and the effects of screening and (early) treatment on long-term outcome have
`to be determined to gain more insight. We will perform structured follow-up of all identified patients in an expertise centre for metabolic
`diseases.
`
`27) Metabolic predictors of coagulation abnormalities in glycogen storage disease type 1
`
`Areeg H. El-Gharbawy1, Courtney D. Thornburg2, Stephanie Austin1, Priya S. Kishnani1
`
`1Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA
`2Department of Pediatrics, Division of Hematology/Oncology, Duke University Medical Center, Durham, NC, USA
`
`Background: Glycogen storage disease type 1(GSD1) is an inborn error of metabolism caused by defective glucose-6-phosphatase complex.
`Enzymatic deficiency leads to fasting hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. Acquired platelet dysfunction and
`reduced von Willebrand factor (VWF) have been described in patients with poorly controlled GSD1. The coagulation defects manifest as epistaxis,
`easy bruising and bleeding during surgical procedures. While, dietary intervention reportedly abrogates the bleeding diathesis, it is unknown if
`there is a specific metabolic factor which accounts for the laboratory abnormalities and clinical symptoms.
`
`Objectives: To evaluate the relationship between predictors of metabolic control and platelet aggregation and VWF in patients with GSD1.
`
`