Goodman & Gilman's: Annual FDA Approvals

Palynziq^12,44,45

Substitute phenylalanine-metabolizing enzyme

Phenylketonuria^†

Pegvaliase is pegylated recombinant phenylalanine ammonia lyase (PAL) approved to reduce blood phenylalanine (Phe) concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood Phe concentrations >600 µmol/L. PAL is a Phe-metabolizing enzyme first discovered in plants.¹¹⁷ It catalyzes the conversion of Phe to ammonia and trans-cinnamic acid (an inactive metabolite) and is intended as a substitute for deficient or absent phenylalanine hydroxylase activity, which normally catalyzes excess dietary Phe to tyrosine.

PKU is a rare genetic disorder caused by mutations in the PAH gene that codes for phenylalanine hydroxylase.¹¹⁸ In the absence of adequate phenylalanine hydroxylase activity, there is a toxic buildup of Phe. Chronic exposure to high Phe blood levels is associated with the development of intellectual disabilities, cardiovascular disorders, light hair and skin, seizures, developmental delay, behavioral problems, psychiatric disorders, and a distinctive unpleasant (“mouse-like”) odor.¹¹⁸ In the U.S., PKU testing is part of routine newborn screening panels. Dietary restriction of Phe has been the main treatment for PKU along with sapropterin (a synthetic form of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), approved by the FDA in 2007). The American College of Medical Genetics and Genomics guidelines recommend maintaining plasma Phe concentrations in the range of 120–360 μmol/L.¹¹⁹ European guidelines are more specific, recommending maintenance of normal neurocognitive and psychosocial functioning with plasma Phe concentrations of 120–360 μmol/L up to the age of 12 years and up to 600 μmol/L thereafter.¹²⁰ In premarket trials, pegvaliase was associated with a reduction in Phe concentrations to ≤360 μmol/L in 60.7% of patients treated for 24 months.⁴⁵

Pegvaliase is manufactured in E. coli bacteria that are transformed with a plasmid containing the PAL gene derived from a cyanobacterium (Anabaena variabilis).¹² Most patients develop anti-PEG IgG and IgM antibodies against pegvaliase.¹² Due to serious risks associated with anaphylaxis, pegvaliase is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.¹²¹ The REMS program requires precertification of prescribers and dispensing pharmacies, the co-prescribing of epinephrine autoinjectors, patient registration, and immediate patient access to epinephrine at all times throughout each day.¹²¹ Published guidelines for the use of pegvaliase recommend observed administration to assist the patient in detecting and managing anaphylactic episodes.¹²⁰ Premedication with acetaminophen and H1 and H2 antihistamines is strongly advised.¹²⁰

The pharmacokinetics of pegvaliase are highly variable, with a half-life ranging from 14 to 132 hours.¹² Therapy is initiated with 4 weekly doses of 2.5 mg, with slow upward titration to 20 mg/day, or up to 40 mg/day in patients who don’t achieve a sufficient response after receiving 20 mg daily for 24 weeks.¹² Therapy must be stopped in patients who do not respond to 16 weeks of maximal dosing (40 mg/day).¹² In responders, the dose must be carefully titrated to avoid hypophenylalaninemia. The labeled adverse effects of therapy include anaphylaxis (9%), non-anaphylactic hypersensitivity reactions (69%), arthralgia (83%), injection site reactions (21.9 episodes/patient-years; duration 1–970 days), non–injection site–related skin reactions (44%; duration 14–638 days), angioedema (8%), serum sickness (2%), abdominal pain, cough, diarrhea, fatigue, headache, nausea, oropharyngeal pain, pruritus, and vomiting.¹² The annual cost of therapy with pegvaliase has been estimated at ~$192,000.¹²²

• Chapter 13. 5-Hydroxytryptamine (Serotonin) and Dopamine > Synthesis and Metabolism

• eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals