Pegvaliase

There are no or limited amount of data from the use of pegvaliase in pregnant women. Animal studies have shown maternal reproductive toxicity that was associated with decreased blood phenylalanine concentrations below normal levels.

Uncontrolled blood phenylalanine levels (hyperphenylalaninaemia) before and during pregnancy are associated with increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine foetal growth retardation and future intellectual disability with low IQ. In case of hypophenylalaninaemia during pregnancy, there is a risk of intrauterine foetal growth retardation. Additional risk to the unborn child due to hypophenylalaninaemia is not established.

Maternal blood phenylalanine levels must be strictly controlled between 120 and 360 micromol/l both before and during pregnancy. Pegvaliase is not recommended during pregnancy, unless the clinical condition of the woman requires treatment with pegvaliase and alternative strategies to control phenylalanine levels have been exhausted.

It is unknown whether pegvaliase is excreted in human milk. Available toxicological data in animals have shown excretion of pegvaliase in milk. In the pups of these animals, systemic exposure of pegvaliase was not detected. A risk to infants cannot be excluded. Due to lack of human data, pegvaliase should only be administered to breast-feeding women if the potential benefit is considered to outweigh the potential risk to the infant.

Fertility

No human data are available. Reduced implantations were observed in normal female rats after administration of pegvaliase.

Pegvaliase has a minor influence on the ability to drive and use machines. Hypersensitivity reactions that include symptoms such as dizziness or syncope may affect the ability to drive and use machines.

Summary of the safety profile

In clinical trials, the majority of patients experienced injection site reactions (93%), arthralgia (86%), and hypersensitivity reactions (75%). The most clinically significant hypersensitivity reactions include acute systemic hypersensitivity reaction (6%), angioedema (7%), and serum sickness (2%).

In clinical trials, adverse reaction rates were highest in induction and titration phases (time prior to reaching blood phenylalanine levels less than 600 micromol/l while on a stable dose) coinciding with the period when titres of IgM and anti-PEG antibodies were highest. Rates decreased over time as the immune response matured (see Description of selected adverse reactions section).

Tabulated list of adverse reactions

The table below provides adverse reactions from clinical trials in patients treated with pegvaliase.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions in patients treated with pegvaliase:

¹ Induction and titration phase reflects the time prior to reaching blood phenylalanine levels less than 600 micromol/l while on a stable dose. Once blood phenylalanine levels less than 600 micromol/l on stable dose was reached, patients were considered to be in the maintenance phase thereafter.
² Hypersensitivity reactions cover a group of terms, including acute systemic hypersensitivity reactions, and can manifest as a range of symptoms including angioedema, dizziness, dyspnoea, rash, serum sickness, and urticaria.
³ The frequency of anaphylaxis in the post-marketing setting cannot be determined.
⁴ Abdominal pain reflects the following terms: abdominal pain, abdominal pain upper and abdominal discomfort.
⁵ Complement factor C3/C4 decrease is defined by changing from normal or high baseline complement value to low post-baseline complement value.
⁶ Reflects high sensitivity CRP (hsCRP) levels above upper limit of normal (greater than 0.287 mg/dl) over a 6 month period.

Description of selected adverse reactions

Arthralgia and other joint related signs and symptoms

In clinical trials, 86% of patients experienced episodes consistent with arthralgia (including back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia occurred as early as the first dose and can occur at any time during treatment. The risk of arthralgia occurring is 3.1-fold higher in induction/titration phase compared to maintenance phase.

Severe arthralgia (severe pain limiting self-care activities of daily living) was experienced in 5% of patients. Arthralgia episodes were managed with concomitant medicinal products (e.g. nonsteroidal anti-inflammatory drugs, glucocorticoids, and/or antipyretic), dose reduction, treatment interruption, or treatment withdrawal, and 97% of arthralgia episodes resolved by the time of study completion.

Persistent arthralgia (lasting at least 6 months) occurred in 7% of patients. Dose was not changed for 96% of episodes and all persistent arthralgia episodes resolved without sequelae.

Injection site reactions

Injection site reactions were reported in 93% of patients. The most common injection site reactions (occurring in at least 10% of patients) were reaction, erythema, bruising, pruritus, pain, swelling, rash, induration, and urticaria. The risk of injection site reactions occurring is 5.2-fold higher in induction/titration phase compared to maintenance phase.

Injection site reactions occurred as early as the first dose and can occur at any time during treatment. The mean duration of injection site reaction was 10 days, and 99% of injection site reactions resolved by the time of study completion.

Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred 15 months after pegvaliase treatment and lasted 16 days), xanthogranuloma (occurred 12 months after pegvaliase treatment and lasted 21 months), and necrobiosis lipoidica diabeticorum (occurred 9 months after pegvaliase treatment and lasted 9 months). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All of these injection site reactions resolved. One patient reported soft tissue infection associated with mesenteric panniculitis, which resulted in treatment discontinuation.

Cutaneous reactions (not limited to the injection site) lasting ≥ 14 days

In clinical trials, 47% of patients treated with pegvaliase experienced cutaneous reactions (not limited to the injection site) lasting at least 14 days. The risk of cutaneous reactions lasting at least 14 days occurring is 1.5-fold higher in induction/titration phase compared to maintenance phase.

The most common cutaneous reactions (at least 5% of patients) reported were pruritus, rash, erythema, and urticaria. Other reactions reported included skin exfoliation, generalised rash, erythematous rash, maculo-papular rash, and pruritic rash. The mean (SD) duration of these reactions was 63 (76) days, and 86% of these reactions resolved by the time of study completion.

Immunogenicity

All patients treated with pegvaliase developed a sustained total anti-pegvaliase antibody (TAb) response with nearly all patients becoming positive by Week 4. Mean TAb titres were sustained through long-term treatment (greater than 3 years after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM was detected in nearly all treated patients by 2 months after treatment initiation, with incidence and mean titres gradually declining over time. Anti-PAL IgG was detected in nearly all patients by 4 months and mean titres were relatively stable through long-term treatment. Pegvaliase induced anti-PEG IgM and IgG responses were detected in nearly all patients, with mean titres peaking at 1 to 3 months after treatment initiation and returning to baseline levels in most patients by 6 to 9 months after treatment initiation. Neutralising antibodies (NAb) capable of inhibiting PAL enzyme activity were detected in a majority of patients by 1 year after treatment initiation and mean titres were relatively stable through long-term treatment.

All 16 patients who experienced acute systemic hypersensitivity reactions tested negative for pegvaliase-specific IgE at or near the time of the acute systemic hypersensitivity reactions episode. These reactions were consistent with a Type III immune-complex mediated hypersensitivity mechanism and were most frequent in the early phases of treatment (during the induction and titration periods) when the early immune response was dominated by PEG IgM, PEG IgG and PAL IgM responses and C3/C4 levels were at their lowest. Hypersensitivity reactions decreased over time in maintenance as the incidence of these antibodies decreased, and C3/C4 levels returned towards baseline. Presence of antibody titres was not predictive of hypersensitivity reactions.

In clinical trials, a direct correlation between pegvaliase plasma exposure and blood phenylalanine reduction was observed. Pegvaliase plasma exposure was primarily driven by immune response to pegvaliase. Patients with lower antibody titres for all antibody analytes including NAb had higher pegvaliase concentrations due to less immune-mediated pegvaliase clearance. As a consequence, these patients were more likely to develop hypophenylalaninaemia. Patients with higher antibody titres required higher doses to overcome clearance and achieve blood phenylalanine reduction. However, due to the substantial variability in antibody titres between patients, no specific antibody titre was predictive of pegvaliase dose required to reach substantial blood phenylalanine reduction, or the development of hypophenylalaninaemia. During early treatment (less than 6 months after pegvaliase administration) when immune-mediated clearance was high and doses were low, patients with higher antibody titres achieved less blood phenylalanine reduction. Following maturation of the early immune response (more than 6 months after pegvaliase administration) and dose adjustment for managing blood phenylalanine control in long-term treatment, mean blood phenylalanine levels continued to decrease in patients who continued treatment. Antibody titres were stable with long-term treatment and dose increases were not associated with increased antibody titres. Thus, mean dose levels also stabilized with long-term treatment with sustained therapeutic effect.

Paediatric population

No data are available in paediatric patients less than 16 years of age.

Twelve patients (11 patients from Study 301) aged 16 up to 18 years received pegvaliase treatment. Adverse reactions were similar in type and frequency to that of adult patients.