Longo N, Zori R, Wasserstein MP, Vockley J, Burton BK, Decker C, Li M, Lau K,  Jiang J, Larimore K, Thomas JA.
Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study.
Orphanet J Rare Dis. 2018 Jul 4;13(1):108.

Pegvaliase (PEGylated recombinant phenylalanine ammonia lyase); marketed in the United States as PALYNZIQ) is an enzyme substitution therapy administered via subcutaneous injection that lowers blood Phe.

This study was an ongoing, long-term project extended from earlier pegvaliase dose-finding phase 2 studies. This meant that participants continued their dose of pegvaliase from an earlier study, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 μmol/L. 68 patients participated.

The mean decrease in plasma Phe levels to less than 600 μmol/L was sustained for 5All participants experienced adverse events, which were limited to mild or moderate severity in most (89%); the most common adverse events were injection-site reactions (73%), injection-site erythema (red skin) (68%), headache (68%), and arthralgia (pain in the joint) (65%). The adverse event rate decreased from 58.3 events per person-year in the earlier studies to 18.6 events per person-year in this extension study.

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Harding CO, Amato RS, Stuy M, Longo N, Burton BK, Posner J, Weng HH, Merilainen M, Gu Z, Jiang J, Vockley J; PRISM-2 Investigators.
Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.
Mol Genet Metab. 2018 May;124(1):20-26.

Eighty-six patients who received pegvaliase in a previous study were enrolled in this complex, double-blinded, 8 week trial.  Patients were randomized to receive either their current pegvaliase dose (either 20 or 40 mg/d) or they stopped pegvaliase and were given a placebo drug (Dextran, a glucose polymer).  The study drugs were self-administered daily for 8 weeks, rotating subcutaneous injection sites. This study evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes.

In the pegvaliase group, phenylalanine concentrations remained stable from their baseline (when they were already taking pegvaliase) to week 8 (Phe 504-559 µmol/L), while blood levels in the placebo groups increased to pre- pegvaliase trial levels.

No significant changes in mood or inattention were observed between the groups receiving pegvaliase or the placebo drug. This was perhaps due to the short duration of the trial or to the tools used to measure these symptoms in the trial.

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Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, Harding CO, Bilder DA, Weng HH, Olbertz J, Merilainen M, Jiang J, Larimore K, Gupta S, Gu Z, Northrup H; PRISM investigators.
Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).
Mol Genet Metab. 2018 May;124(1):27-38.

This Phase 3 clinical trial studied 261 patients who all had a blood Phe above 600 μmol/L before starting treatment with pegvaliase. They had been on previous shorter term pegvaliase trials (PRSIM-1 AND prism 2) prior to entering the current trial. The mean blood Phe was 1233 μmol/L at baseline (pre-pegvaliase), 565 μmol/L at 12 months treatment with pegvaliase, and 311 μmol/L at 24 months treatment with pegvaliase. Within 24 months, just over half the participants achieved a blood Phe of 120 μmol/L or less – that is, below the upper limit of normal in the non PKU population. Overall, 65% of the patients in this study remained on pegvaliase treatment.  Adverse events were described mostly as mild or moderate and resolved without needing to interrupt or reduce treatment with pegvaliase. Acute systemic hypersensitivity was observed in 12 participants, of which 6 remained on therapy. These cases occurred most frequently during upward titration of the pegvaliase dose within the first year of treatment

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Hausmann O, Daha M, Longo N, Knol E, Müller I, Northrup H, Brockow K.
Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy.
Mol Genet Metab. 2019 Sep - Oct;128(1-2):84-91.

Eight European academic immunology experts discussed recommendations for the clinical management of hypersensitivity adverse events associated with pegvaliase treatment.

Pegvaliase induces Type III hypersensitivity reactions, causing hypersensitivity adverse reactions with peak event rates during the induction/titration period and with a decline over time during maintenance therapy.

They recommended:

  • physicians and patients need to be aware of the risk of hypersensitivity adverse reactions associated with pegvaliase
  • the presence of a trained observer during early treatment may be beneficial in certain circumstances a requirement to carry auto-injectable adrenaline.

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Sri Bhashyam S, Marsh K, Quartel A, Weng HH, Gershman A, Longo N, Thomas J, Zori R.
A benefit-risk analysis of pegvaliase for the treatment of phenylketonuria: A study of patients' preferences.
Mol Genet Metab Rep. 2019 Aug 30;21:100507

The efficacy and safety of pegvaliase have been established in clinical studies. Blood Phe levels were estimated to reduce to 360 μmol/L or lower in 44.0% of patients by 12 months, and in 61% of patients by 24 months. However, any benefits must be balanced against the adverse effects of pegvaliase treatment. 94% of patients reported hypersensitivity related adverse events, with the majority (99%) being mild to moderate, including arthralgia (pain in a joint) (71%), rash (35%), and pruritus (itchy skin) (28%). 5% of these were acute systemic hypersensitivity reactions.

In this study (an online survey on 45 adults with PKU), the objective was to identify the minimum acceptable benefit of pegvaliase. This was defined as the minimum probability of achieving a reduction in blood Phe level to less than 360 μmol/L, which patients require to accept the potential risks of hypersensitivity/anaphylaxis associated with pegvaliase. Participants were asked to make choices between varying clinical benefit of lowering blood phe levels and severity levels for hypersensitivity.

Many participants felt the burden of PKU on their daily lives, were dissatisfied with current treatments, and were willing to accept the risks of hypersensitivity reactions to achieve lower blood Phe levels with pegvaliase treatment.

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Longo N, Dimmock D, Levy H, Viau K, Bausell H, Bilder DA, Burton B, Gross C, Northrup H, Rohr F, Sacharow S, Sanchez-Valle A, Stuy M, Thomas J, Vockley J, Zori R, Harding CO.
Evidence- and consensus-based recommendations for the use of  pegvaliase in adults with phenylketonuria.
Genet Med. 2019 Aug;21(8):1851-1867.

A Steering Committee comprising of 17 USA health-care professionals with experience in using pegvaliase drafted guidance statements on the use of pegvaliase. Statements included: goals of pegvaliase treatment, patient/system-related considerations prior to initiating therapy, patient education required prior to initiation, definition of treatment efficacy.  Introduction and titration of pegvaliase, adjusting diet/dose, resuming pegvaliase treatment following dose interruption, monitoring and prevention of adverse events, management of anaphylaxis, management of arthralgia and injection site reactions.

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Long-term safety and efficacy of sapropterin: the PKUDOS registry experience. Longo N, Arnold GL, Pridjian G, Enns GM, Ficicioglu C, Parker S, Cohen-Pfeffer JL;
Phenylketonuria Demographics, Outcomes and Safety Registry.
Mol Genet Metab. 2015 Apr;114(4):557-63.

This study provides safety and efficacy data from sapropterin (Kuvan) use that was collected by a USA registry. Of 1189 subjects who started sapropterin, 42% (504/1189) were maintained on continuous sapropterin and 18% (211/1189) discontinued the drug within 3-months. Overall, long term exposure to sapropterin ranged from 0.9 to 7.2 years.

Continuous, long term use of sapropterin was associated with a significant and persistent decrease in blood Phe. The mean of the median blood Phe decrease was 43% and was sustained for over 5 years. In addition, subjects with continuous use of sapropterin had a simultaneous and significant increase (mean of median: 48%) in dietary Phe tolerance.  The number of adverse effects were low.

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Muntau AC, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V, Rutsch F, Sivri HS, Vijay S, Bal MO, Gramer G, Pazdírková R, Cleary M, Lotz-Havla AS, Munafo A, Mould DR, Moreau-Stucker F, Rogoff D.
Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK  open-label, multicentre, randomized phase IIIb trial.
Orphanet J Rare Dis. 2017 Mar 9;12(1):47

The SPARK trial was a 26-week European multicentre, randomized study to assess the efficacy, and safety of sapropterin (Kuvan) in patients aged under 4 years with BH4-responsive PKU or mild HPA. Children with PKU from two paediatric centres took part from the UK: Birmingham Children’s Hospital and Great Ormond Street Children’s Hospital.

In total, 56 patients were randomly assigned to either 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to a phenylalanine-restricted diet only for 26 weeks.  The sapropterin was increased to 20 mg/kg/day after 4 weeks if phenylalanine tolerance was not increased by more than 20% compared with baseline. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 31 mg/kg/day (equivalent to around 0.5g kg/day protein) higher than in the diet-only group.

The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Patients in both groups had normal neuromotor development and stable growth. The pharmacokinetic model favoured once per day dosing with sapropterin.

Based on the SPARK trial results, sapropterin received EU approval to treat patients under 4 years with BH4-responsive phenylketonuria.

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