Alternative therapies to address the unmet medical needs of patients with phenylketonuria

Figures & data

Figure 1. The phenylalanine hydroxylating system in the liver and the function of tetrahydrobiopterin in the brain. BH4 is synthesized from GTP by the enzymes GTPCH, PTPS, and SR. Hydroxylation of phenylalanine to tyrosine by PAH – and of tyrosine to l-DOPA by TH, and Trp to 5-OH-Trp by TPH – results in oxidation of BH4 to a carbinolamine intermediate, which is then reduced back to BH4 by PCD and DHPR. Dopamine and serotonin are produced by decarboxylation of their respective precursors by AADC.

Table 1. Summary of clinical trials and selected other studies assessing treatment with sapropterin dihydrochloride in patients with elevated blood phenylalanine concentrations.

Design	Subjects/patients	Objectives	Dosage	Key findings	Ref.
Phase III, randomized, multicenter, double-blind, placebo-controlled study	BH4-responsive patients (n = 89) from a prior study. No Phe-restricted diet	Evaluate the efficacy of sapropterin treatment to reduce blood Phe concentration from baseline to week 6	Sapropterin 10 mg/kg/day for 6 weeks	Sapropterin significantly reduced blood Phe concentration versus placebo A ≥ 30% reduction in blood Phe was achieved by 44% of patients on sapropterin versus 9% on placebo A significant difference in blood Phe was evident at week 1 and persisted for the duration of the trial	[22]
Phase II, open-label, multicenter, uncontrolled screening study	Patients (n = 490) aged 8 – 49 years with blood Phe > 450 μmol/l. No Phe-restricted diet	Assess response to an 8-day course of sapropterin	Sapropterin 10 mg/kg/day for 8 days	A ≥ 30% reduction in blood Phe was achieved by 20% of patients	[23]
Phase II, open-label, multicenter, uncontrolled study	Patients (n = 12) with primary BH4 deficiency and a history of blood Phe concentrations > 180 μmol/l. Diet remained unchanged	Assess safety and efficacy of sapropterin in patients with primary BH4 deficiency for 10 weeks, followed by a 7-week extension period	Sapropterin 5 – 20 mg/kg/day for 10 weeks, then a 7-week extension	In most patients, mean blood Phe concentrations were maintained below 360 μmol/l Sapropterin treatment was well tolerated by patients with primary BH4 deficiencies	[24]
Phase III, open-label, multicenter, uncontrolled extension study	Patients (n = 80) aged ≥ 8 years. Diet remained unchanged	Assess the safety and efficacy of sapropterin over 22 weeks	Sapropterin 5 – 20 mg/kg/day for 22 weeks	A ≥ 30% reduction in blood Phe was achieved by 46% of patients Dose-dependent decreases in blood Phe were maintained up to 22 weeks Sapropterin was well tolerated; all AEs except one were mild to moderate and no AE led to treatment discontinuation	[25]
Phase III multicenter study. Part 1 was an open-label, uncontrolled screening study; part 2 was a randomized, double-blind, placebo-controlled study	For part 1, patients (n = 90) were aged 4 – 12 years with blood Phe < 480 μmol/l. Part 2 assessed patient who were BH4 responsive (n = 46). Throughout, patients were on a Phe-restricted diet	In children, evaluate sapropterin treatment for increasing Phe tolerance while maintaining adequate blood Phe control	Sapropterin 20 mg/kg/day for 8 days (part 1); then sapropterin 20 mg/kg/day for 10 weeks (part 2)	In part 1, BH4-responsive patients had a mean percentage reduction in blood Phe of 64% (SD, 17.5) over 8 days In part 2, patients receiving sapropterin tolerated significantly more dietary Phe supplementation than the placebo group while maintaining blood Phe < 360 μmol/l	[26]
Phase IIIb, open-label, multicenter, long-term uncontrolled extension study	BH4-responsive patients (n = 111) from two previous studies, of whom 110 had received a daily dose of sapropterin. Diet remained unchanged	Evaluate the safety of treatment with sapropterin	Sapropterin 5 – 20 mg/kg/day	Interim 18-month report: Phe concentration levels were maintained for 18 months between 485 μmol/l (SD, 309) and 530 μmol/l (SD, 332) Safety: most AEs were mild and not dose dependent; the most common AEs were cough (16.2%), pyrexia (14.4%), and nasopharyngitis (13.5%) 3-year results: Median sapropterin exposure was 595 days Mean sapropterin dose was 16 mg/kg/day Most AEs were mild or moderate severity; three patients discontinued treatment for treatment-related AEs Of seven SAEs, one was considered treatment-related (gastroesophageal reflux) Blood Phe control was well maintained for most patients	[27,28]
Retrospective, multicenter, long-term survey	Patients (n = 147) from 6 European countries treated with BH4 for at least 6 months, either with or without a Phe-restricted diet	Evaluate patient-related outcomes with long-term usage	Dosages varied	All patients had median blood Phe concentrations within the therapeutic range Compared with diet alone, treatment with sapropterin was associated with increased median dietary Phe tolerance, dietary adherence, and quality of life Sapropterin was well tolerated, with adverse events resolving on lowering of sapropterin dose	[13]
Prospective, single-center survey	Patients (n = 37) aged ≥ 10 years who planned to initiate sapropterin treatment. Current dietary practices were maintained	Assess long-term quality of life after up to 1 year of sapropterin treatment	Initial sapropterin dose 20 mg/kg/day	For the BH4-responders (n = 17): Most could maintain blood Phe control with a less restrictive diet There were significant improvements in multiple quality-of-life assessments	[29]
Phase IIIb, open-label, multicenter, uncontrolled study	BH4-responsive patients (n = 55) aged 0 – 6 years with blood Phe concentrations ≥ 360 μmol/l	Assess neurocognitive function, blood Phe concentration, and dietary Phe intake	Initial sapropterin dose 20 mg/kg/day	2-year interim analysis: Mean blood Phe was reduced Mean dietary Phe intake increased Assessments of IQ and infant development were preserved within the normal range Sapropterin was well tolerated	[15]
Phase IV multicenter registry	Female patients treated with sapropterin before (n = 5) or during (n = 16) pregnancy	Assess the safety and efficacy of sapropterin in pregnant women	Sapropterin 5 – 20 mg/kg/day	Interim 2-year analysis: Women on sapropterin during pregnancy had lower mean blood Phe and fewer blood Phe values above the recommended threshold than women not using sapropterin during pregnancy Maintenance of blood Phe below the recommended threshold was associated with a higher percentage of normal births Sapropterin was generally well tolerated	[30]
Prospective, multicenter, long-term follow-up study	BH4-responsive pediatric patients (n = 43) from Japan	Assess the safety and efficacy of sapropterin in children of different ages	Doses varied	Mean blood Phe was reduced to the recommended range. Individuals who initiated treatment prior to 4 years of age had superior blood Phe control and have developed normally	[14]

All studies in patients with phenylketonuria unless otherwise noted.

BH-4: Tetrahydrobiopterin; Phe: Phenylalanine.

Figure 2. Degradation of phenylalanine to trans-cinnamic acid and ammonia by the enzyme PAL. Trans-cinnamic acid is converted to benzoic acid by a mechanism that is not yet well described; benzoic acid is conjugated with glycine to form hippuric acid and excreted in urine.

Table 2. Summary of clinical trials for rAvPAL–PEG (from Clinicaltrials.gov).

Phase	Identifier	Duration, weeks	Design	Dates	Objective	Results
I	NCT00634660 (PAL-001)	6	Single dose, 0.001 – 0.1 mg/kg	5/2008 – 4/2009	Safety, reduction of Phe levels [16]	Treatment was fairly safe, with development of antibodies against PEG and PAL. Reduction of Phe levels observed with 0.1 mg/kg dose [19]
II	NCT00925054 (PAL-002)	22	Multiple doses, 0.001 – 1 mg/kg/week	9/2009 – 12/2012	Reduction of Phe levels, safety, antibody response, pharmacokinetics [31]	Combined data from all phase 2 studies: from a baseline blood Phe of 1360 μmol/l, treatment reduced blood Phe 68%. Treatment was generally well tolerated; hypersensitivity-type reactions were the most frequent drug-related adverse events. Two patients discontinued due to adverse reactions [32]
II	NCT01212744 (PAL-004)	16	Multiple doses, 0.06 – 0.8 mg/kg/day	3/2011 – 1/2013	Reduction of Phe levels, safety, antibody response, pharmacokinetics [31]
II	NCT01560286 (165 – 205)	24	Multiple doses, 2.5 – 375 mg/week, divided 1 – 5 times per week	5/2012 – 1/2014	Reduction of Phe levels, safety, antibody response, pharmacokinetics [31]
II	NCT00924703 (PAL-003)	260	Stable dosing up to 5 mg/kg/week	1/2010 – present	Reduction of Phe levels, safety, antibody response, pharmacokinetics [31]	Ongoing [33]
III	NCT01819727 (165 – 301)	15 – 44	Multiple doses, 20 or 40 mg/day	5/2013 – present	Safety, reduction of Phe levels, dietary protein intake [31]	Ongoing [33]
III	NCT01889862 (165 – 302)	172	Multiple doses, 20 or 40 mg/day or placebo, randomized discontinuation	7/2013 – present	Safety, cognitive and mood symptoms, reduction of Phe levels, dietary protein intake [31]	Ongoing [33]

PAL: Phenylalanine ammonia lyase; rAvPAL–PEG: Recombinant Anabaena variabilis PAL conjugated with PEG.

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Available from: www.Clinicaltrials.gov [Accessed 6 December 2014]

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BioMarin. Press Release 26 Sep 2012 Available from: http://investors.bmrn.com/releasedetail.cfm?ReleaseID=716661

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BioMarin. Press Release 5 June 2013 Available from: http://investors.bmrn.com/releasedetail.cfm?ReleaseID=769256

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