Summary Basis of Decision for Palynziq

Clinical Pharmacology

Pegvaliase is produced through the addition of polyethylene glycol (PEG) moieties to the recombinant phenylalanine ammonia lyase (rAvPAL) enzyme. The rAvPAL enzyme converts phenylalanine to ammonia and trans-cinnamic acid, thereby reducing the elevated blood phenylalanine levels characteristic of phenylketonuria (PKU).

The major pharmacokinetic aspects of the absorption, distribution, metabolism, and elimination of pegvaliase were characterized in patients with PKU. The pharmacokinetics of pegvaliase exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Immune response affects clearance and time to reach steady state, with higher antibody titers correlating with higher pegvaliase clearance.

The pharmacokinetic profile of pegvaliase was developed primarily through data from the Phase III Studies 301 and 302, with Part 3 of Study 302 focusing specifically on the pharmacokinetics and pharmacodynamics of pegvaliase. In Part 3 of Study 302, no clinically meaningful increase in pegvaliase exposure was observed between the 20 mg and 40 mg once daily doses with respect to the maximum concentration (C_max) or the area under the plasma drug concentration time curve from 0 to 24 hours post-dose (AUC_0-24). The mean (± standard deviation [SD]) C_max was 14.04 ± 16.26 mcg/mL at the 20 mg once daily dose and 16.69 ± 19.456 mcg/mL at the 40 mg once daily dose. The mean (± SD) AUC_0-24 was 262.18 ± 280.38 mcg*hr/mL at the 20 mg once daily dose and 246.78 ± 338.59 mcg*hr/mL at the 40 mg once daily dose.

All patients treated with pegvaliase in Studies 301 and 302 developed a sustained anti-drug antibody (ADA) response, with 91% of patients (235 of 258) developing this response by Week 4 of treatment. Mean overall ADA titers peaked two weeks after treatment initiation and remained elevated throughout the duration of the studies.

Neutralizing antibodies were detected in 88% of patients (249 of 284). Mean neutralizing antibody titers peaked and reached a plateau at 16 to 20 weeks of treatment, and remained present throughout the duration of the studies. Sixteen patients experienced acute systemic hypersensitivity (anaphylactic) reactions, and tested negative for pegvaliase-specific immunoglobulin E (IgE) antibodies at or near the time of the episode. The incidence and titer of anti-PEG IgE were not measured. The observed hypersensitivity reactions were most frequent during the induction and titration periods, and decreased during the maintenance phase of treatment. The antibody titers were not predictive of hypersensitivity reactions.

Although limited data are available in these patient populations, body weight, gender, and age were not associated with notable effects on pegvaliase pharmacokinetics. No clinical studies have been conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of pegvaliase.

For further details, please refer to the Palynziq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Palynziq was mainly evaluated in Study 302, which was conducted in patients who had previously participated in Study 301 (a safety and tolerability study, described in the Clinical Safety section). Both were Phase III studies and included patients with phenylketonuria (PKU) aged 16 years or older. Patients had a mean blood phenylalanine level greater than 600 micromol/L at screening and on average over the 6 months prior to screening. Dosing in Study 301 included induction, titration, and maintenance periods, while Study 302 was intended to demonstrate the efficacy and safety of maintenance treatment with Palynziq. Parts 1, 2, and 4 of Study 302 are described below. Part 3, which evaluated the pharmacokinetics and pharmacodynamics of Palynziq, is addressed in the Clinical Pharmacology section.

The eligibility period (Part 1) of Study 302 included 164 patients previously treated with Palynziq (152 patients from Study 301 and 12 patients from other studies), who continued treatment at maintenance doses of 20 mg or 40 mg once daily for up to 13 weeks. By the completion of 13 weeks of Part 1, 86 of the 164 patients had achieved a reduction of 20% or greater in mean blood phenylalanine level from their pre-treatment baseline while taking Palynziq at their assigned maintenance dose and continued to the randomized discontinuation trial (RDT; Part 2) period of the study. Twelve patients discontinued treatment, and 57 patients transferred directly to the open-label extension period (Part 4).

The 8-week RDT period (Part 2) of Study 302 was the primary focus of the clinical efficacy assessment, and the only part involving a formal statistical plan. There were 29 patients in each of the groups remaining on the maintenance regimens of 20 mg or 40 mg Palynziq once daily, and 14 patients in each of the groups receiving 20 mg or 40 mg placebo once daily. None of the patients who entered the RDT period of the study were less than 18 years of age.

The primary endpoint of Study 302 was the change in blood phenylalanine levels from baseline of the RDT to Week 8 of the RDT. The primary analysis was conducted by evaluating the actively treated pool of 58 patients (29 patients from each of the groups treated with 20 mg or 40 mg Palynziq once daily) against each of the two placebo groups. This was done due to statistically significant differences between the two placebo groups, and was acceptable as the poolability analyses were prespecified in the statistical analysis plan.

At baseline of the RDT period, the mean blood phenylalanine levels were 563.9 micromol/L in the group randomized to 20 mg placebo once daily, 508.2 micromol/L in the group randomized to 40 mg placebo once daily, and 503.9 micromol/L in the actively treated pool of patients. At Week 8, the mean blood phenylalanine levels were 1,509.0 micromol/L in the group receiving 20 mg placebo once daily, 1,164.4 micromol/L in the group receiving 40 mg placebo once daily, and 559.2 micromol/L in the actively treated pool. The least square mean differences in blood phenylalanine levels after 8 weeks of randomized blinded treatment were -923.25 micromol/L (95% confidence interval [CI]: -1,135.0, -711.5; p<0.0001) for the actively treated pool versus the group receiving 20 mg placebo once daily, and -638.3 micromol/L (95% CI: -859.0, -417.6; p<0.0001) for the actively treated pool versus the group receiving 40 mg placebo once daily. After 8 weeks, patients treated with Palynziq maintained their blood phenylalanine reductions, while patients who received the placebo returned to their pre-treatment baseline levels.

Along with the data from the RDT period, the efficacy assessment also focused on data from the induction/titration/maintenance (I/T/M) population. This population included 285 patients who received Palynziq in an I/T/M regimen in the Phase III Studies 301 (described in the Clinical Safety section) and 302, and the Phase II Studies 205 and PAL-003. The primary efficacy endpoint of interest was mean blood phenylalanine level, which was evaluated at multiple time points throughout the assessment.

At pre-treatment baseline, the mean blood phenylalanine level in the I/T/M population was 1,227.3 micromol/L (range: 285 to 2,330 micromol/L). The length of the titration period varied based on patient tolerability, and most patients achieved a maintenance dose of 20 to 40 mg per day within approximately 6 months. At this time, the mean blood phenylalanine level was 766.4 micromol/L, which is a reduction of approximately 40% relative to baseline. A continued treatment period followed, during which maintenance doses of 20 to 60 mg per day were tailored based on efficacy and patient tolerability. The mean blood phenylalanine levels were 546.6 micromol/L at one year of treatment and 390.3 micromol/L at 18 months. Mean levels remained stable between 300 and 400 micromol/L for up to four years for patients remaining in the study. Current clinical practice guidelines advise a target blood phenylalanine level of 120 to 360 micromol/L. In the I/T/M population, 190 patients (66.7%) achieved a blood phenylalanine level ≤360 micromol/L at any time during treatment. The mean time to achieve this target was 10.35 months (range: 0.5 to 57.1 months). Patients were generally able to maintain or increase their protein intake from intact food over the course of treatment and still achieve target blood phenylalanine levels.

The long-term extension period (Part 4) of Study 302 included 202 patients who continued treatment with Palynziq. Doses were adjusted by the physician (5 mg, 10 mg, 20 mg, 40 mg, or 60 mg once daily) to achieve further blood phenylalanine reductions and maintain previously achieved phenylalanine levels. The mean daily dose was 33.2 mg once daily and the mean duration of treatment was 1,034 days (range: 17 to 1,729 days).

Indication

The proposed indication was revised to more accurately represent the patient population in Studies 301 and 302. The recommended dosing regimen includes induction, titration, and maintenance phases intended to gradually acclimatize the patient’s immune response while building to therapeutic dose levels. The proposed maintenance doses range from 20 to 60 mg per day depending on individual patient blood phenylalanine response and tolerability. The recommended dosing table and comprehensive dosing and administration guidelines are provided in the Palynziq Product Monograph.

For more information, refer to the Palynziq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Palynziq was derived primarily from the two Phase III studies, 301 and 302, which included patients with PKU in the I/T/M population. Study 302 and the I/T/M population are described in the Clinical Efficacy section. Study 301, a safety and tolerability study, is described below.

Study 301 was an open-label and randomized (1:1) study conducted in 261 patients with PKU to evaluate the safety and tolerability of self-administered Palynziq in an I/T/M dose regimen. The patients ranged from 16 to 55 years of age (mean: 29 years). At baseline, patients had a mean blood phenylalanine level of 1,233 micromol/L, 149 patients (57%) were receiving part of their total protein intake from medical food, and 41 patients (16%) were on a phenylalanine-restricted diet (defined as receiving greater than 75% of total protein intake from medical food).

Patients initiated treatment with an induction regimen (2.5 mg once weekly for 4 weeks), followed by a stepwise titration to reach their randomized maintenance dose of either 20 mg or 40 mg once daily. The length of the titration period varied based on patient tolerability, with a maximum length of 30 weeks. The maintenance period was defined as a minimum of three weeks of dosing at the randomized maintenance dose, which was reached by 103 patients in the 20 mg once daily treatment arm and 92 patients in the 40 mg once daily treatment arm (in total, 195 of 261 patients; 75%). The median times to reach the maintenance dose were 10 weeks (range: 9 to 29 weeks) in the 20 mg once daily treatment arm and 11 weeks (range: 10 to 33 weeks) in the 40 mg once daily treatment arm. The mean total duration of dosing in Study 301 was 24.4 weeks. After Study 301, 152 patients continued to the eligibility period (Part 1) of Study 302, and 51 patients continued to the long-term extension period (Part 4) of Study 302.

Safety data from patients exposed to Palynziq were compiled into a safety database which included 299 patients exposed for 24 weeks, 209 patients exposed for one year, 181 patients exposed for two years, and 160 patients exposed for three years or longer. Collectively, the patients had 789 patient-years of exposure to pegvaliase. The safety database was limited by the lack of a comparator arm for all but the 8 weeks of treatment in the RDT period (Part 2) of Study 302.

The most frequently reported adverse events in patients treated with Palynziq were injection site reactions (93%), arthralgia (86%), and hypersensitivity reactions (>65%), including cutaneous reactions, serum sickness, angioedema, and acute systemic hypersensitivity reactions (i.e., anaphylaxis; 5.6%). Other frequently reported adverse events included headache (55%) and hypophenylalaninemia (46%). No fatal events attributed to treatment with Palynziq were reported.

The safety profile of Palynziq in patients 16 to less than 18 years of age was not considered to have meaningful differences from the safety profile in patients 18 years of age and older. However, the safety data provided in this population was limited to 12 patients.

A Serious Warnings and Precautions box was included in the Palynziq Product Monograph to highlight the risk of systemic hypersensitivity reactions, including anaphylaxis. These have been reported following the administration of Palynziq, and may occur at any time during treatment. The initial doses of Palynziq must be administered under the supervision of a health professional equipped to manage an acute systemic hypersensitivity (anaphylactic) reaction. Patients should be observed closely for at least one hour after injection. Additionally, auto-injectable epinephrine must be prescribed to the patient. Prior to the first self-administered or caregiver-administered dose, the patient or caregiver and a trained observer must be instructed on the appropriate use of epinephrine. The patient should also be instructed to carry auto-injectable epinephrine at all times during the course of treatment, and to seek immediate medical care in the case of epinephrine use. Finally, Palynziq should be discontinued in patients who experience a severe systemic hypersensitivity reaction and in patients who experience a recurrent mild to moderate anaphylactic reaction.

For more information, refer to the Palynziq Product Monograph, approved by Health Canada and available through the Drug Product Database.