Diminishing the Burden of Phenylketonuria During Adulthood New Science & Encouraging Stories Highlighting the Critical Role of Adjunctive Therapy in Alleviating Neurocognitive Symptoms and Easing Dietary Constraints
This symposium is not a part of the official ACMG Annual Meeting program. ACMG does not approve or endorse any commercial products or services discussed during the Symposium or offered for sale by the corporate supporter of the Symposium. ACMG has reviewed and approved this symposium as appropriate for presentation as an independent educational activity held in conjunction with the ACMG Annual Meeting. Disclosures
Jerry Vockley, MD, PhD, has a financial Stephanie Sacharow, MD, FACMG, has a interest/relationship or affiliation in the form of: financial interest/relationship or affiliation in the Grant/Research Support from Aeglea form of: BioTherapeutics; BioMarin; Homology; Kaleido; Consultant and/or Advisor for BioMarin Moderna Therapeutics; Stealth BioTherapeutics; Pharmaceutical Inc. Synlogic; Ultragenyx Pharmaceutical Inc. Honoraria from BioMarin Pharmaceutical Inc.
Jerry Vockley, MD, PhD, does intend to discuss Stephanie Sacharow, MD, FACMG, does intend either non–FDA-approved or investigational use to discuss either non–FDA-approved or for the following products/devices: treatments for investigational use for the following phenylketonuria. products/devices: treatments for phenylketonuria.
This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from BioMarin Pharmaceutical Inc. Disclosures
CME Reviewer Medical Director Kaushal Patel, MD Kirk A. Tacka, PhD Medical Learning Institute, Inc. PVI, PeerView Institute for Medical Education
Kaushal Patel, MD, has no financial Kirk A. Tacka, PhD, has no financial interests/relationships or affiliations in relation to interests/relationships or affiliations in relation to this activity. this activity.
The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity during the past 12 months. Welcome and Introduction
Jerry Vockley, MD, PhD University of Pittsburgh Children's Hospital of Pittsburgh Photo Pending Pittsburgh, Pennsylvania
Go online to access full CME information, including faculty disclosures. Phenylketonuria (PKU)1
Autosomal Recessive Characterized by Mutations Inborn Error of Metabolism in Gene Encoding for the Hepatic Affecting Phe Catabolic Pathway Enzyme Phenylalanine Hydroxylase Chromosome 12
PAH gene (12q22-12q24.2)
• Identified by newborn screening • Incidence: 1:10,000 to 1:15,000
1. Vockley J et al. Genet Med. 2014;16:188-200. Alterations in Phenylalanine Metabolism in PKU1
PAH Defective
BH (cofactor) and O Phenylalanine 4 2 Tyrosine Phenylpyruvic acid
Phenyllactic acid Phenylacetic acid
1. Vockley J et al. Genet Med. 2014;16:188-200. PKU Pathophysiology1
Liver Blood Brain
BBB Reduces • Glutamatergic synaptic transmission • Pyruvate kinase activity • HMG-CoA activity
LAT1 Damages Phe Phe Phe • Myelin (white-matter lesions)
Inhibits • Tyr and Trp hydroxylase BH4 PAH
Tyr Decreased • Protein synthesis • Neurotransmitter synthesis LNAA LAT1 LNAA ↓ Trp → ↓ serotonin
(normal levels) ↓ Tyr → ↓ dopamine
and neuropsychological dysfunction neuropsychological and Cognitive deficits, neurophysiological, neurophysiological, deficits, Cognitive
1. van Wegberg AMJ et al. Orphanet J Rare Dis. 2017;12:162. Clinical Manifestations of Neurocognitive and Neuropsychiatric Effects in Early Treated PKU1-6 Executive Function Deficits Psychiatric Symptoms Psychological Behavioral • Depression • ADHD • Agoraphobia • Anxiety • Self-harm • Agitation • Mood swings • Schizophrenia
Neurological Abnormalities • Spasticity • Gait disturbances • Tremor • Seizures
1. Channon S et al. Neuropsychology. 2004;18:613-620. 2. Brumm VL et al. Mol Genet. 2010;99:S59-S63. 3. Sullivan JE, Chang P. J Pediatr Psychol. 1999;24:281-299. 4. Burton BK et al. Mol Genet Metabol. 2013;108:8-12. 5. Waisbren SE, Levy HL. J Inherit Metab Dis. 1991;14:755-764. 6. Pietz K. Curr Opin Neurol. 1998;11:679-688. Executive Function Deficits in PKU1
P < .001
25
21
a 20 15 10 5 Range, % Range, 5
Children in Severe in Children 0 Control PKU
a Based on Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite; severe range is >1 SD above the mean. 1. Anderson VA et al. Child Neuropsychol. 2002;8:231-240. Neuropsychiatric Comorbidities in Adults With PKU1
25 General population a PKU 19.5 20 b Rates of intellectual disability, 15.6 anxiety, and depression were 15 significantly higher for PKU 11.8 cohort vs general population 10 9.2
Adults, % Adults, a cohort across all age groups 4.8 (20-29, 30-39, 40-49, 50-59, 5 60-69, and 70+ years of age) 0.6 0 Intellectual Anxiety Depression Disability
a P < .0001. b P = .0001. 1. Bilder D et al. Mol Genet Metabol. 2017;121:1-8. Moving on to This Morning’s Agenda
First, we’ll review the current dietary management of PKU and consider its relevance to adult patients
Then, we’ll discuss available data on approved adjunctive pharmacologic approaches for the treatment of PKU
Be prepared for polling questions both before and during today’s scientific sessions Dietary Management of Adults With PKU Current Benefits and Shortcomings
Jerry Vockley, MD, PhD University of Pittsburgh Children's Hospital of Pittsburgh Photo Pending Pittsburgh, Pennsylvania
Go online to access full CME information, including faculty disclosures. Goals of Treatment in Patients With PKU1
Lifelong Goal for Ongoing Monitoring All Patients • Phe and Tyr testing Control blood Phe: • Nutritional markers and 120-360 μmol/La micronutrients • Plasma amino acids and protein status • Bone density • Neuropsychological testing
a European guidelines: Recommended blood Phe range for patients older than 12 years = 120-600 μM.2 1. Vockley J et al. Genet Med. 2014;16:188-200. 2. van Wegberg AMJ et al. Orphanet J Rare Dis. 2017;12:162. Recommended Intakes of Phe, Tyr, and Protein in Patients With PKU1
Age Phe Tyr Protein (mg/d) (mg/d) (g/kg)
0 to <3 mo 130-430 1,100-1,300 3-3.5
3 to <6 mo 135-400 1,400-2,100 3-3.5
6 to <9 mo 145-370 2,500-3,000 2.5-3
9 to <12 mo 135-330 2,500-3,000 2.5-3 1 to <4 y 200-320 2,800-3,500 ≥3.0 120%-140% 4 y to adult 200-1,100 4,000-6,000 RDA for age
1. Vockley J et al. Genet Med. 2014;16:188-200. Dietary Management of PKU1,2
• Omission of all high-protein food • Inclusion of modified low-protein food • Replacement of restricted protein and calories with metabolic formulas − Contain Phe-free proteins, fats, carbohydrates − Supplemented with tyrosine, vitamins, minerals However …
1. Vockley J et al. Genet Med. 2014;16:188-200. 2. Singh R et al. Genet Med. 2014;16:121-131. Dietary Management Contributes to Overall Burden of PKU1
Health Status Phe-Free • Cognitive PKU Supplements function Burden • Daily life • Symptoms • Social • Monitoring • Taste • Convenience
Psychological Family Social Diet Function Life Function • Daily life • Mood • Future family • Isolation • Food changes • Impact on • Relationships • Social • Emotions family • School • Psychological • Feelings members • Work • Family
Consequently…
1. Regnault A et al. Oprhanet J Rare Dis. 2015;10:59-76. Compliance With Dietary Treatment Decreases With Age1
Plasma Phe increases
with age as children have
a more varied diet and
mol/L μ
, , start having a social life Phe
1. Viau KS et al. J Inherit Metab Dis. 2001;34:963-971. Compliance With Medical Nutritional Therapy Decreases With Age1
Above target range Within target range Below target range
100% 4% 4% 1% 1% 2% 3%
31% 80% 49% 41% 60% 70% 73% 84% 40% 67%
Patients 58% 20% 50% 27% 12% 24% 0% 0-4 Years (N=625) 5-12 Years (N=900) 13-17 Years (N=608) 18-29 Years (N=658) ≥ 30 years (N=687) Pregnant/Planning on Becoming Pregnant (N=106) 0-4 y 5-12 y 13-17 y 18-29 y ≥30 y Pregnant/ (N = 625) (N = 900) (N = 608) (N = 658) (N = 687) Planning Pregnancy Many adult patients with PKU (N = 106) are not followed at metabolic clinics
1. Jurecki ER et al. Mol Genet Metab. 2017;120:190-197. Phenylketonuria in Adults1
• Mood and psychiatric disorders seem more frequent in adults with PKU than in the general population – Executive function is also compromised • In adults with PKU, trials have been done to decrease or increase Phe levels – In general, higher Phe is associated with worsening of behavior (even in individuals with intellectual disability missed by newborn screening) and lowering of Phe improved behavior and mood in addition to executive function
1. Bilder DA et al. Dev Neuropscyhol. 2016;41:245-260. Effects of Phe-Restricted Diet in Adults With PKU1-9
Multiple blinded crossover studies and single-cohort interventional studies have shown Phe-restricted diet is effective in lowering blood Phe in adults with PKU
Although measures and results varied, better neuropsychiatric outcomes were associated with on-diet and/or low Phe in numerous studies
1. Bilder DA et al. Dev Neuropscyhol. 2016;41:245-260. 2. Lee PJ et al. Neurosurg Psychiatry. 2009;80:631-635. 3. Marholin D et al. Pediatr Res. 1978;12:179-187. 4. ten Hoedt AE et al. J Inherit Metab Dis. 2011;34:165-171. 5. Bik-Multanowski M et al. J Inherit Metab Disord. 2008;31:S415-S418. 6. Brom MC, Guest JF. J Intellect Disabil Res. 1999;43:30-37. 7. Finkelson L et al. J Inherit Metab Dis. 2001:24:515-516. 8.Schuett VE et al. Am J Pub Health. 1985;75:39-42. 9. Yannicelli S, Ryan A. J Inherit Metab Dis. 1995;18:131-134. Psychiatric Symptoms in Adults With PKU1,2
Adults with PKU had an increase Adult patients with PKU with in psychiatric symptoms compared positive screening for psychiatric with normative population symptoms had higher Phe a P < .05. 1. Bilder DA et al. Mol Genet Metab. 2013;108:155-160. 2. Burton BK et al. Mol Genet Metab. 2013;108:8-12. Lower Phe Levels Associated With Better Executive Function in Adults1
• Z-scores calculated with data from matching group of healthy controls • Higher Z-scores always indicate worse performance a P < .05. b P < .01. 1. Romani C et al. Neuropsychology. 2017;31:242-254. High Phe Directly Affects Mood and Sustained Attention in Adults With PKU: Blinded Crossover Study1
• Adults with PKU were given Phe supplements (2.5 to 5 g/d based on weight and gender) or placebo for 4 weeks • This increased Phe levels from 709 ± 322 to 1,209 ± 332 μmol/L (P < .01)
1. ten Hoedt AE et al. J Inherit Metab Dis. 2011;34:165-171. Lower Blood Phe Levels Associated With Better Neuropsychiatric Outcomes1
Increase in Phe had negative effect on sustained attention, as well as on mood of patients
a P < .10. b P ≤ .05. c P ≤ .01. 1. ten Hoedt AE et al. J Inherit Metab Dis. 2011;34:165-171. Large Neutral Amino Acids (LNAAs) in the Treatment of PKU1 Compete with Phe for uptake by membrane transporters 0.1 to 1 g/kg/d suggested as an alternative treatment to improve cognitive outcome in patients with PKU
LNAA might: • ↓ Brain Phe • ↑ Brain neurotransmitter • ↓ Blood Phea • ↑ Brain essential amino
acids Use limited to older patients (adolescents and adults)
Should be avoided in pregnant women a Only lysine-containing formulations. 1. van Spronsen FJ et al. J Inherit Metab Dis. 2010;33:671-676. Effects of LNAA on the Function of Patients With PKU1
• No significant difference in brain Phe between phases − For samples in phase 4 of study where plasma Phe was ≥1,200 μmol/L, there was a positive correlation (Spearman’s rs = 0.90; P = .04) • Better performances on attention measures when subjects were on standard medical product (phases 1 and 2) compared with off standard medical product (phases 3 and 4) • Higher levels of anxiety symptoms also reported when on LNAA (phases 1 and 3) compared with off LNAA (phases 2 and 4)
1. Schindeler S et al. Mol Genet. 2007;91:48-54. Glycomacropeptide1
Comparison of Theoretical and Experimental Amino Acid Contents of GMP Amino Amino Theoretical Experimental Theoretical Experimental Glycomacropeptide (GMP) Acid Acid C-terminal part (f 106-169) of κ-casein, Trp 0.00 0.00 His 0.00 0.30 which is released in whey during cheese Phe 0.00 0.50 Lys 5.59 5.90 making by the action of chymosin Tyr 0.00 0.10 Met 1.89 1.80 Leu 1.70 2.60 Pro 11.73 12.50 Val 9.00 8.00 Ser 8.04 6.10 Ile 10.00 10.10 Threo 18.23 15.80 Ala 5.68 5.50 Asp 3.39 8.60 Arg 0.00 0.50 Asn 5.05 0.00 Cys 0.00 0.10 Glu 15.01 20.50 Gly 0.96 1.10 Gln 3.73 0.00
1. Badawy A. Psychopharmacology (Berl). 2013;228:347-358. GMP for Nutritional Management of PKU: A Randomized Controlled Crossover Trial1
Phe remains the same with GMP, but provides advantages in taste, convenience, and reduced GI AEs
1. Ney DM et al. Am Clin J Nutr. 2016;104:334-345. Summary
• Adults with PKU can have psychiatric and other symptoms that can be reduced by decreasing Phe • As such, adults with PKU should still be treated with diet, but dietary supplementation may improve adherence and/or lessen restrictions – These include the use of LNAA- and GMP-based supplements • Treatment should be individualized based on patient adherence to diet, blood Phe, and the presence and severity of neuropsychiatric symptoms Adjunctive Pharmacologic Approaches for the Management of Adults With PKU
Stephanie Sacharow, MD, FACMG Harvard Medical School Boston Children’s Hospital Photo Pending Boston, Massachusetts Approved Adjunctive Approaches for PKU Management
• Pharmacologic form of BH4 • Approved in 2007 • Indicated to reduce blood Phe in patients with
hyperphenylalaninemia due to BH4-responsive PKU; it is to be used in conjunction with a Phe-restricted diet Sapropterin1
• Enzyme substitution therapy • Approved in 2018 • Indicated to reduce blood Phe concentrations in adult patients with PKU who have uncontrolled blood Phe >600 μmol/L on existing management Pegvaliase-pqpz2
1. Kuvan (sapropterin dihydrochloride) Prescribing Information. https://www.kuvan.com/hcp/wp-content/file/KUVAN_Prescribing_Information1.pdf. Accessed March 11, 2019. 2. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Tetrahydrobioptern (BH4): An Important Cofactor in Phe Metabolism1
1. Thony B et al. Biochem J. 2000;347:1-16. The Role of Sapropterin in PKU Management1-6
• Approximately 25%-50% of patients with PAH deficiency are sapropterin responsive – Patients with mild-to-moderate PAH deficiency most likely to respond; some stable protein is required for sapropterin to function – However, responsive patients have been identified among those with complete PAH deficiency • Current guidelines recommend that every PAH-deficient patient should be offered a trial of sapropterin therapy to assess responsiveness, except those with two null mutations in trans
1. Levy HL et al. Lancet. 2007;370:504-510. 2. Ziesch B et al. J Inherit Metab Dis. 2012;35:983-992. 3. Leuret O et al. J Inherit Metab Dis. 2012;35:975-981. 4. Utz JR et al. Mol Genet Metab. 2012;105:193-197. 5. Vockley J et al. Genet Med. 2014;16:188-200. 6. Kuvan (sapropterin dihydrochloride) Prescribing Information. http://www.kuvan.com/hcp/wp-content/file/KUVAN_Prescribing_Information1.pdf. Accessed March 13, 2019. A Subset of Patients With Nonclassical PKU May Potentially Be Controlled With Sapropterin Alone1,2
• Retrospective chart review of mild variant PKU patients solely treated with sapropterin • N = 22 Peak Phe & Mean Pre- and Post-Sole Sapropterin Therapy
Prior to sapropterin Sole sapropterin therapy Lifetime peak Phe
16
14
12
10
8
6 Phe Concentrations, mg/dL Concentrations, Phe 4
2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patient Number 1. Paras A et al. 2018 ACMG Annucal Clinical Genetics Meeting (ACMG 2018). Abstract 70. 2. Paras A et al. Genetic Metabolic Dieticians International Conference 2018 (GDMI 2018). Poster presentation. PKU ASCEND Study: How Does Sapropterin Impact Executive Function?1
Double-Blind RCT of Sapropterin to Treat ADHD Symptoms and Executive Function Impairment in Children and Adults With Sapropterin-Responsive PKU
ADHD RS/ASRS Total Score ADHD RS/ASRS Inattention Subscale Score
a P <.05 1. Burton BK et al. Mol Genet Metab. 2015:114:415-424. Sapropterin: Practical Considerations1
Available Dosage Forms Safety and Tolerability • Tablets: 100 mg • Excellent safety profile with • Powder for oral solution: 100 mg, 500 mg minimal side effects in clinical practice Starting Dosea • Most common AEs • Patients 1 mo to 6 y: 10 mg/kg 1x/d (incidence ≥4%): • Patients 7 y and older: 10-20 mg/kg 1x/d − Headache − Rhinorrhea − Pharyngolaryngeal pain Dose Adjustmenta − Diarrhea • Doses may be adjusted in the range of − Vomiting 5-20 mg/kg 1x/d based on patient response − Cough • Blood Phe must be monitored regularly − Nasal congestion
a 20 mg/kg most commonly used dose used for initiation and maintenance.2,3 1. Kuvan (sapropterin dihydrochloride) Prescribing Information. http://www.kuvan.com/hcp/wp-content/file/KUVAN_Prescribing_Information1.pdf. Accessed March 11, 2019. 2. Gordon P et al. Mol Genet Metab. 2012;105:672-676. 3. Cunningham A et al. Mol Genet Metab. 2012;106:269-276. Enzyme-Substitution Therapy for PKU: Phenylalanine Ammonia Lyase (PAL)1
PAL • Phe-metabolizing enzyme found in many plants, several fungi, and bacteria • Requires no exogenous cofactor
NH Low 3 toxicity Ammonia Rapid conversion & urinary excretion Phenylalanine Cinnamic Acid
1. Hoskins JA et al. Biomed Mass Spectrom. 1984;11:296-300. Pegvaliase: PEGylated PAL1
Recombinant Anabaena variabilis PAL (rAV-PAL) rAV-PAL Pegvaliase-pqpz (rAV-PAL–PEG) PEGylation Intended to (partially) mask antibody Monomer binding sites on PAL (MW 64,000) ~150,000 atoms (MW 1,200,000)
1. Longo N et al. Lancet. 2014;384:37-44. PRISM-1: Phase 3, Open-Label, Randomized Trial of Fixed-Dose Pegvaliase in Adults With PKU1
PRISM-1: Phase 3 Clinical Trial of Pegvaliase
Adult patients 2.5 mg weekly 20 mg daily 20 mg daily with blood Phe >600 µmol/L 2.5 mg weekly 40 mg daily 40 mg daily
Screening Induction Upward Titration Maintenance of Patients randomized Set dose Until target dose Target Dose 1:1 to maintenance 4 weeks achieved from week 5 At least 3 weeks target dose of 20 mg up to week 34 or 40 mg daily
• PRISM-1 patients treated with pegvaliase to target maintenance dose in preparation to enter phase 3 PRISM-2 study
1. Thomas J et al. Mol Genet Metabol. 2018;124:27-38. PRISM-2: Pivotal Phase 3, Placebo-Controlled Randomized Discontinuation Trial in Adults With PKU1
PRISM-2: Pivotal Study of Pegvaliase With Randomized Discontinuation Trial (RDT)
20 mg daily 20 mg daily 20 mg daily Placebo 5 to 60 mg daily 40 mg daily 40 mg daily 40 mg daily Placebo Long-Term, ≥20% Blood Phe RDT PK and PD Open-Label Reduction From Randomized 2:1 6 weeks Extension Entry Into PRISM-1 8 weeks Dosing to individual 13 weeks efficacy targets 212 weeks Part 1 Part 2 Part 3 Part 4
1. Thomas J et al. Mol Genet Metabol. 2018;124:27-38. Outcome Date from Randomized Discontinuation Trial1
1. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Change in Blood Phe With Pegvaliase1
Time to Blood Phe Thresholds Mean Blood Phe Over Time
1500 Blood Phe 6 mo 12 mo 24 mo ≤600 μmol/L 39.8% 54.7% 68.4% 1200
≤360 μmol/L 27.1% 44.0% 60.7% 900 ≤120 μmol/L 19.7% 32.4% 51.2% 600
300 Mean Mean (SE) Blood Phe, µmol/L 0 0 3 6 9 12 15 18 21 24 Study Timepoint, mo
1. Thomas J et al. Mol Genet Metabol. 2018;124:27-38. PRISM-1 and PRISM-2: Blood Phe and ADHD1
Mean (SD) Blood Phe and Investigator-Rated ADHD-RS Inattention Over Time From PRISM-1 Pretreatment Baseline to PRISM-2 Long-Term Extension
1. Longo N et al. GDMI 2016. Poster 23. Pegvaliase: Adverse Events1
AE Overview by Treatment Phase Reported as Event Rate and Total Number of Events
Early Late Treatment Phase (>6 mo) Treatment Overall Phase (≤6 mo) >6 to ≤12 mo >12 to ≤24 mo >24 to ≤36 mo >36 mo Total
Participants, N 261 210 188 88 23 210 261 Total treatment exposure, 115.6 96.8 125.3 59.8 3.5 285.5 401.3 person-yearsa
Event rate, per person-year (total number of events)
AEs 58.6 (6,774) 23.7 (2,294) 19.1 (2,394) 13.4 (802) 17.6 (61) 19.4 (5,551) 30.7 (12,325) SAEs 0.2 (26) 0.2 (20) 0.1 (13) 0.03 (2) 0 0.1 (35) 0.2 (61) HAEs 15.6 (1,805) 4.3 (411) 4.9 (610) 2.0 (120) 1.2 (4) 4.0 (1,145) 7.4 (2,950) Acute systemic hypersensitivity 0.05 (6) 0.09 (9) 0.01 (1) 0.02 (1) 0 0.04 (11) 0.04 (17) events Injection-site reactions 25.5 (2,953) 6.2 (595) 3.4 (428) 2.1 (124) 4.9 (17) 4.1 (1,164) 10.3 (4,117) Injection-site skin reactions lasting 1.3 (153) 0.7 (66) 0.6 (75) 0.3 (20) 0 0.6 (161) 0.8 (314) ≥14 d Generalized skin reactions lasting 0.8 (93) 0.3 (32) 0.3 (36) 0.2 (10) 0.3 (1) 0.3 (79) 0.4 (172) ≥14 d Arthralgia 6.9 (794) 1.5 (147) 0.7 (90) 0.3 (20) 0.3 (1) 0.9 (258) 2.6 (1,052) a Total treatment exposure was the aggregated duration of treatment across all participants (for each participant, time from the first dose to 30 days after the last dose administered across all studies in which the participant was enrolled). Intervals of missing doses that were > 28 consecutive days were excluded from the calculation of treatment duration. 1. Thomas J et al. Mol Genet Metabol. 2018;124:27-38. Pegvaliase: Hypersensitivity Reactions1
1,000,000 500
100,000 of Number HAEs 400
x x x x x x 10,000 x x x x x x x x x x x 300 1,000 200
(Log Scale) (Log 100
Mean Antibody Titer Titer Antibody Mean 10 100
1 0 0 3 6 9 12 15 18 21 24
HAEs Study Timepoint, mo PAL IgG PEG IgG PAL IgM PEG IgM Nab x x Tab 1. Thomas J et al. Mol Genet Metabol. 2018;124:27-38. Pegvaliase: Recommended Dosing Regimen1
Treatment Pegvaliase Dosage Durationa Induction 2.5 mg 1x/wk 4 wk 2.5 mg 2x/wk 1 wk 10 mg 1x/wk 1 wk Titration 10 mg 2x/wk 1 wk 10 mg 4x/wk 1 wk 10 mg/d 1 wk Maintenance 20 mg/d 24 wk Maximumb 40 mg/d 16 wkc
a Additional time may be required prior to each dosage escalation based on patient tolerability. b Individualize treatment to the lowest effective and tolerated dosage. Consider increasing to a maximum of 40 mg once daily in patients who have not achieved a response with 20 mg once daily continuous treatment for at least 24 weeks. c Discontinue treatment in patients who have not achieved a response after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily. 1. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Pegvaliase: Blood Phe Monitoring and Dietary Considerations1
Blood Phe Monitoring Dietary Considerations • Counsel patients to monitor dietary Obtain baseline blood Phe before protein and phenylalanine intake, and initiating treatment adjust as directed by their healthcare provider Obtain blood Phe every 4 weeks • Reduce the dosage and/or modify dietary until a maintenance dosage is protein and phenylalanine intake, as established needed, to maintain blood phenylalanine concentrations within a clinically After a maintenance dosage is acceptable range and above 30 μmol/L established, periodically monitor blood Phe
1. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Pegvaliase: Safety Considerations—Anaphylaxis1
• Administer initial dose under supervision of healthcare provider equipped to manage anaphylaxis, and closely observe patients for ≥60 min following injection • Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and to administer auto-injectable epinephrine, if needed • Prescribe auto-injectable epinephrine – Prior to first dose, instruct the patient and observer (if applicable) on its appropriate use – Instruct the patient to seek immediate medical care upon its use – Instruct patients to carry auto-injectable epinephrine with them at all times during pegvaliase treatment
1. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Pegvaliase: Safety Considerations— Hypersensitivity Reactions Other Than Anaphylaxis1
• Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability • Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence, and clinical judgment, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids
1. Palynziq (pegvaliase-pqpz) Prescribing Information. https://www.palynziq.com/prescribinginformation.pdf. Accessed March 11, 2019. Summary
• Two adjunctive pharmacologic therapies are now approved for the treatment of PKU – Sapropterin – Pegvaliase-pqpz • Current guidelines recommend that every PAH-deficient patient should be offered a trial of sapropterin therapy to assess responsiveness, except those with two null mutations in trans • Pegvaliase is an effective approach for lowering blood Phe in adult patients with PKU; this new option may permit easing of dietary restrictions Questions & Answers, Reflections, and Conclusions
Jerry Vockley, MD, PhD Stephanie Sacharow, University of Pittsburgh MD, FACMG Children's Hospital Harvard Medical School Photo Photo of Pittsburgh Boston Pending Pending Pittsburgh, Pennsylvania Children’s Hospital Boston, Massachusetts
Go online to access full CME information, including faculty disclosures. Conclusions
• Although a low-Phe diet successfully prevents intellectual disability in early treated PKU patients, dietary compliance remains a major issue as patients approach adolescence and adulthood, resulting in poor blood Phe control and leading to suboptimal outcomes in psychosocial and cognitive outcomes • Sapropterin and pegvaliase offer the opportunity to substantially lower blood Phe and potentially ease dietary restrictions in patients with PKU • As such, any combination of therapies that facilitate improvement in blood Phe levels for a given patient with PKU is appropriate; treatment should be individualized Abbreviations
AA: amino acid Glu: glutamic acid ADHD-RS: Attention Deficit Hyperactivity Disorder Gly: glycine Rating Scale GMP: glycomacropeptide Ala: alanine GTP: guanosine triphosphate Arg: arginine GTPCH: GTP cyclohydrolase I Asn: asparagine HAE: hypersensitivity adverse event Asp: aspartic acid His: histidine ASRS: Adult ADHD Self-Report Scale HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA BBB: blood-brain barrier Ile: isoleucine BH : tetrahydrobiopterin 4 L-type amino acid carrier BRIEF: Behavior Rating Inventory of Executive Function Leu: leucine Cys: cysteine LNAA: large neutral amino acids DHPR: dihydropteridine reductase Lys: lysine EF: executive functioning Met: methionine Gln: glutamine MW: molecular weight Abbreviations
NAD: nicotinamide, adenine, dinucleotide rAV-PAL: recombinant Anabaena variabilis phenylalanine NADH: nicotinamide, adenine, dinucleotide, plus hydrogen ammonia lyase RDA: recommended daily allowance NH2: amidogen OH: hydroxide RDT: randomized discontinuation trial PAH: phenylalanine hydroxylase RVP: rapid visual information processing PAL: phenylalanine ammonia lyase SAE: serious adverse event PBO: placebo SD: standard deviation PCD: pterin-4 alpha-carbinolamine dehydratase Ser: serine PD: pharmacodynamics SR: sepiapterin reductase Phe: phenylalanine STM: short-term memory PK: pharmacokinetics Threo: threonine PKU: phenylketonuria Trp: tryptophan POMSr: Profile of Mood States, revised Tyr: tyrosine Pro: proline Val: valine PTPS: 6-pyruvoyl tetrahydropterin synthase Please remember to complete and submit your Post-Test and Evaluation for CME credit. Missed anything?
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