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Indication: For the treatment of patients with phenylketonuria aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 µmol/L) on existing management
CADTH recommends that Palynziq should be reimbursed by public drug plans for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 µmol/L) on existing management if certain conditions are met.
Palynziq should only be covered to treat patients with PKU aged 16 years and older.
Palynziq should only be reimbursed for patients who demonstrate and maintain a response to treatment (blood phenylalanine levels less than 600 µmol/L), if the drug is prescribed by a clinician with expertise in treating genetic and metabolic disorders, and if the cost of Palynziq is reduced.
PKU is a genetic disorder in which both copies of the gene encoding phenylalanine hydroxylase are mutated, leading to high blood phenylalanine levels that can cause behavioural and psychiatric problems. PKU symptoms, as well as the low-protein PKU diet, negatively impact health-related quality of life. There are approximately 3,133 patients with PKU in Canada.
Dietary management on its own is not enough to control blood phenylalanine levels in most adults with PKU. Additional treatment options that can decrease blood phenylalanine levels and permit increased natural protein intake, with higher uptake and adherence, are needed.
Treatment with Palynziq is expected to cost approximately $130,410 to $443,475 per patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that pegvaliase be reimbursed for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 µmol/L) despite dietary management, only if the conditions listed in Table 1 are met.
One double-blind, randomized discontinuation trial (PRISM-2 RDT; N = 95) comparing pegvaliase with matching placebo in patients with PKU aged 16 to 70 years demonstrated that treatment with either 20 mg/day or 40 mg/day of pegvaliase (pooled active group) resulted in a statistically significant and clinically meaningful improvement in blood phenylalanine (Phe) concentration after 8 weeks. The least squares mean (LSM) change in blood Phe levels from the RDT entry to week 8 was 26.5 μmol/L (95% CI, −68.3 to 121.3) in the pooled active group, versus 949.8 μmol/L (95% CI, 760.4 to 1139.1) in the 20 mg/day placebo group, and 664.8 μmol/L (95% CI, 465.5 to 864.1) in the 40 mg/day placebo group. There were statistically significant differences in LSM change from baseline between the pooled active group and each of the 20 mg/day placebo (−923.25 µmol/L; 95% CI, −1135.04 to −711.46; P < 0.0001) and 40 mg/day placebo (−638.27 µmol/L; 95% CI, −858.97 to −417.57; P < 0.0001) groups.
CDEC acknowledged that there was a need for additional effective treatment options for patients with PKU. Patients identified an unmet need for treatments that allow them to have dietary flexibility, and improve mental health and quality of life outcomes. No differences in attention or mood symptoms were observed between the pegvaliase and placebo groups in PRISM-2 RDT; however, CDEC agreed with the clinical experts consulted by CADTH that differences in neurocognitive and neuropsychiatric function were unlikely to be detectable over the 8 week period of PRISM-2 RDT, given the high variability in the symptoms of adult patients with established PKU. Other outcomes important to patients, including health-related quality of life (HRQoL) and protein tolerance were not assessed in the trial.
The cost-effectiveness of pegvaliase is highly uncertain due to an absence of robust comparative evidence and the inappropriateness of the model structure. As such, a base-case cost-effectiveness estimate was unable to be determined in patients with PKU who are 16 years or older who have inadequate blood Phe control despite dietary management. CDEC considered exploratory analyses conducted by CADTH which determined the ICER was likely closer to $1,923,797 per QALY when compared to medical nutritional therapy (MNT) alone, therefore pegvaliase is not cost-effective at a $50,000 per QALY willingness-to-pay threshold. A price reduction of at least 99% would be required for pegvaliase to achieve an ICER of $50,000 per QALY.
Reimbursement Conditions and Reasons.
Phenylketonuria (PKU) is a monogenic autosomal recessive disorder and 1 of the most common inborn errors of metabolism. Patients with PKU have mutations in both alleles of the PAH gene encoding phenylalanine hydroxylase (PAH), an enzyme that catalyzes the conversion of phenylalanine (Phe) to tyrosine using tetrahydrobiopterin as a cofactor. PAH deficiency leads to uncontrolled blood Phe, which then crosses the blood-brain-barrier where it has neurotoxic effects. In adolescents and adults, uncontrolled Phe levels are associated with behavioural and psychiatric problems (inattentiveness and mood dysfunction, often collectively referred to as ‘executive dysfunction’). PKU symptoms, in conjunction with treatments, negatively impact patient health-related quality of life (HRQoL) of patients via difficulties with employment, social relationships, and mental health.
PKU is rare, with an incidence of approximately 1:12,000 to 1:15,000 live births in Canada (equivalent to approximately 300 new cases per year). According to the sponsor, there are approximately 3,133 PKU patients living in Canada at present, of whom approximately ||||| are being managed and approximately | || are at least old 16 years and currently being treated with sapropterin. The current cornerstone of PKU treatment is lifelong dietary control of Phe intake to curb blood Phe levels. This is principally accomplished by providing Phe-free foods and metabolic formulas with a small amount of complete Phe-containing protein allowed on top, sometimes collectively referred to as medical nutritional therapy (MNT). Adherence of adult patients with PKU to MNT is extremely challenging because low-protein medical food is very unpleasant to taste and smell. Other than dietary restriction, the only other approved medication is sapropterin, a cofactor of the deficient PAH enzyme in PKU. Approximately 25% of patients with milder PKU have a biochemically detectable response to sapropterin.
Pegvaliase has been approved by Health Canada to reduce blood phenylalanine concentrations in patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 μmol /L) despite dietary management. Pegvaliase is a recombinant enzyme substitution therapy. It is available as prefilled syringes (2.5 mg/0.5 mL [5 mg/mL], 10 mg/0.5 mL [20 mg/mL], and 20 mg/mL) and as recommended in the product monograph, dosing by self-administered daily subcutaneous injection should be titrated to a maintenance dose required to achieve blood Phe level lower than 600 μmol/L, with a maximum dose of 60 mg daily.
To make their recommendation, the CDEC considered the following information:
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from the clinical experts consulted by CADTH for the purpose of this review.
One submission, from the Canadian PKU and Allied Disorders (CanPKU), was received for this review. Between 30 November and 25 December 2021, CanPKU conducted online surveys (n = 68 PKU patients, n = 46 Canadian and n = 14 US) and telephone interviews (n = 5 patients experienced with pegvaliase, n = 1 Canadian and n = 4 US). Respondents narrated how PKU symptoms and the PKU protein-restricted diet had impacted their physical and mental health, employment, and social relationships. Almost all respondents (≥ 95%) had experience with low-protein medical foods and formulas, 65% had experience with Kuvan, while only 21% had experience with pegvaliase. Respondents described barriers to existing therapies including poor taste, lack of satiety, inconvenient preparation and administration, high cost, and limited availability.
The vast majority (≥ 85%) of respondents identified Phe control, reducing PKU symptoms, limiting long-term disease consequences, improving neurocognitive function, managing diet, reducing burden of treatment, improving HRQoL, and increasing natural protein intake as key outcomes of interest. Respondents experienced with pegvaliase reported that the drug limited long-term disease consequences, controlled Phe levels, reduced PKU symptoms, and had tolerable side effects such as injection site reactions, joint pain, and skin reactions.
Two clinical specialists with expertise in the diagnosis and management of pediatric and adult patients with PKU who have inadequate Phe control provided input for this review. The clinical experts relayed that currently available therapies (MNT with or without sapropterin) can in theory successfully meet treatment goals by decreasing Phe and preventing the neuropsychological complications of PKU. However, because adherence to MNT is generally low, MNT is not effective in most patients and only a minor population of patients with milder PKU will respond to sapropterin. Pegvaliase would be used as last line treatment following MNT and, if appropriate, sapropterin. Pegvaliase may shift the treatment paradigm for some adult patients with PKU by allowing liberalization of diet while maintaining Phe control.
There were differences of opinion between the 2 clinical experts consulted by CADTH for this review regarding the subset of PKU patients who would benefit most from pegvaliase. One clinical expert felt that patients with high and uncontrolled Phe are most in need of an intervention to improve metabolic control that will lead to a decrease in their Phe levels and improved Phe tolerance. The clinical expert could not rule out the possibility that patients who are poorly compliant with MNT could become more compliant to therapies (including pegvaliase) over time as Phe levels decrease and focus improves. A second clinical expert felt that PKU patients who are highly compliant with MNT and other therapy and have the most severe forms of PKU would be the most suitable for treatment with pegvaliase. These patients are generally able to achieve Phe levels within the control range but have the most unpalatable diets and experience large deviations in Phe levels. These patients can be identified by assessing compliance with MNT and other therapy (assessed via mean Phe values) and PKU severity (assessed by PAH genotyping, variability in Phe levels, and/or by degree of restriction of complete protein intake). This clinical expert indicated that patients who are non-compliant with therapy would be the least suitable for treatment with pegvaliase.
The clinical experts relayed that complete protein tolerance (or Phe tolerance) and blood Phe levels are the most convenient tests to assess response to treatment and are most often used in clinical trials. Clinically meaningful responses to treatment would be reflected by, in order of importance, increased complete protein tolerance (or Phe tolerance) and protein intake to levels in the general population, improvement in HRQoL, and improvement in psychological metrics (neurocognitive performance, mood, attention, and working memory). According to the clinical experts, high blood Phe levels can be used to show that pegvaliase treatment is ineffective, and in patients with low Phe who liberalize their diets to include natural foods, stability of Phe levels with the treatment range can demonstrate improvements in protein tolerance. Patients who cannot maintain good Phe levels (or whose levels are not monitored) with MNT and pegvaliase are non-compliant and should be discontinued from treatment, as should patients who experience significant adverse reactions.
A group of 3 physicians who care for adult patients with PKU in Canada provided input for this review. Although the clinician group echoed the challenges in adhering to the PKU diet and the limited proportion of patients who can benefit from sapropterin, views contrasting those of the clinical experts consulted by CADTH were presented on: (i) the connection between blood Phe levels and neurologic symptoms, diet liberalization, and associated impacts on HRQoL in adult PKU patients, which the clinician group felt were tightly and reversibly linked; (ii) the importance of Phe control as a treatment goal and marker of treatment response in and of itself; (iii) the patient subset most suitable for pegvaliase treatment, which the clinician group felt was patients non-compliant with dietary restriction who cannot benefit from sapropterin and thus have poor or no Phe control; (iv) the patient subset least suitable for pegvaliase treatment, which the clinician group felt was patients able to maintain Phe levels within target range on MNT with or without sapropterin; and (v) the risks of very low Phe levels (e.g., < 30 µmol/L) resulting from overtreatment with pegvaliase in patients who do not comply with Phe monitoring, which the clinician group felt were a potential concern. According to the clinician group, pegvaliase would be offered as last line treatment to adult PKU patients who have elevated Phe levels and neuropsychiatric symptoms and are able to self-administer the injection.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for pegvaliase. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
PRISM-2 was a phase III, 4-part, 4-arm, double-blind, placebo-controlled RDT with an extension period of open label (OL) treatment. The major feeder study for PRISM-2 was PRISM-1, a phase III, OL study to assess the safety and tolerability of 2 pegvaliase dose regimens (20 mg or 40 mg once daily; see Other Relevant Evidence); the main eligibility criteria for feeder studies were patients with PKU at least 16 years old with blood Phe levels of at least 600 µmol/L who were able to maintain a consistent diet. Dietary Phe control and adherence to MNT was not a requirement for participation in feeder studies or PRISM-2. Following enrolment and screening at 29 centers in the US, patients either entered part 1 (OL Phe assessment) or directly into part 4 (OL extension). In part 1 (N = 164), patients were randomized in a 1:1 ratio to receive OL pegvaliase (20 mg or 40 mg once daily, vial and syringe) for up to 13 weeks; blood Phe levels were measured every 2 weeks. Patients who achieved a mean blood Phe reduction of at least20% from treatment-naive baseline and were able to maintain their randomized pegvaliase dose were eligible for inclusion in the part 2 (i.e., RDT) modified intention to treat (mITT) set, while those who did not achieve this degree of Phe reduction or were unable to maintain their randomized pegvaliase dose due to AEs transitioned directly to part 4 (OL extension). In part 2 (RDT; N = 95), patients in each dose group (20 mg or 40 mg once daily, vial and syringe) were randomized 2:1 to either continue receiving their assigned dose of pegvaliase or to receive a matching-administration placebo over 8 weeks of double-blind treatment. In part 3 (N = 89), patients who completed part 2 received OL pegvaliase (dose as assigned in part 1) in 2 formats (vial and syringe or prefilled syringe) for 6 weeks and pharmacokinetics and pharmacodynamics (PK/PD) were compared. Part 4 (N = 202) was an OL extension in which patients received OL pegvaliase (up to 60 mg once daily, prefilled syringe) for up to 274 weeks. Only data for the Part 2 RDT of the PRISM-2 study are described in the Systematic Review section of this report.
The primary objective of the PRISM-2 study was to evaluate the efficacy of pegvaliase in decreasing blood Phe levels by observing changes from the RDT baseline to RDT week 8 in patients previously exposed to pegvaliase who were administered either pegvaliase (20 mg/day or 40 mg/day) or a matching-administration placebo in the RDT. Secondary objectives (all hierarchically tested) included comparing changes in Attention Deficit Hyperactivity Disorder Response Scale (Investigator-Rated) (ADHD RS-IV) Inattention subscale scores (among patients with drug-naive baseline scores > 9 as well as all patients), PKU-Specific Profile of Mood States (PKU POMS) (self-rated) Confusion subscale scores, PKU POMS (self-rated) total mood dysfunction (TMD) scores, and Profile of Mood States (POMS) (Self-Rated) TMD scores from part 2 baseline to Part 2 week 8 among patients previously exposed to pegvaliase who were randomized to receive either pegvaliase (20 or 40 mg/day) or a matching placebo in the RDT.
Almost all patients in PRISM-2 were White adults aged at least 18 years; the average age was approximately 30 years. According to the clinical experts consulted by CADTH for this review, baseline blood Phe, mood and inattention symptoms, and protein intake in the PRISM-2 study population were as expected for adult PKU patients with poor or no Phe control and limited adherence to MNT.
A poolability assessment of the 2 placebo groups (20 mg/day and 40 mg/day) indicated that the magnitude of blood Phe increase from part 2 baseline to part 2, week 8 differed between the 2 placebo groups; therefore, the primary and secondary efficacy analyses were conducted by comparing the pooled active group (patients who continued on their assigned dose of pegvaliase from part 1 in the part 2 RDT) versus the 20 mg/day placebo group and the 40 mg/day placebo group separately. At part 2 week 8 and in the mITT set, the least squares mean (LSM) change in blood Phe level from part 2 baseline was 26.50 µmol/L (95% confidence interval [CI], −68.26 to 121.26 µmol/L) in the pooled active group, 949.75 µmol/L (95% CI, 760.38 to 1,139.11 µmol/L) in the 20 mg/day placebo group, and 664.77 µmol/L (95% CI, 465.45 to 864.10 µmol/L) in the 40 mg/day placebo group. The difference in LSM change from baseline comparing the pooled active group to the 20 mg/day placebo group was −923.25 µmol/L (95% CI, −1135.04 to −711.46 µmol/L) (P < 0.0001). The difference in LSM change from baseline comparing the pooled active group to the 40 mg/day placebo group was −638.27 µmol/L (95% CI, −858.97 to −417.57 µmol/L) (P < 0.0001). A cumulative distribution function analysis showed that at part 2 week 8 in the pooled active group, ||||| of patients had blood Phe ≤ 120 µmol/L while approximately ||||||| ||| had blood Phe between 600 µmol/L and 1,200 µmol/L and approximately |||||| |||| had blood Phe at least 1,200 µmol/L. By contrast, in the placebo groups, no patients had blood Phe ≤ 120 µmol/L, while approximately |||| |||||| had blood Phe between 600 µmol/L and 1,200 µmol/L and approximately |||| ||||||||| had blood Phe of at least 1,200 µmol/L.
No statistically significant differences were observed between treatment groups in ADHD RS-IV Inattention subscale scores among patients with drug-naive baseline scores greater than 9 and further statistical testing for other neurocognitive or neuropsychiatric symptoms (ADHD RS-IV Inattention subscale scores among all patients, PKU POMS [Self-Rated] Confusion subscale scores, PKU POMS [Self-Rated] TMD scores, and POMS [Self-Rated] TMD scores) was halted due to the hierarchical testing procedure. Changes in protein intake and HRQoL were not evaluated in PRISM-2 RDT.
Adverse events (AEs) were reported for the pooled active group (patients who continued to receive either 20 mg/day or 40 mg/day pegvaliase during the RDT) and the pooled placebo group (patients who receive either 20 mg/day or 40 mg/day pegvaliase in part 1 and then switched to placebo during the RDT), as well as in some cases for individual dose groups. In PRISM-2 RDT, 83.3% of patients receiving active pegvaliase and 93.1% of patients receiving placebo experienced AEs. Common AEs in both the pooled active and pooled placebo arms were arthralgia (pooled active 13.6% and pooled placebo 10.3%), headache (pooled active 12.1% and pooled placebo 24.1%), fatigue (pooled active 10.6% and pooled placebo 10.3%), anxiety (pooled active 10.6% and pooled placebo 6.9%), and injection site bruising (pooled active 4.5% and pooled placebo 10.3%). Serious AEs (SAEs) occurred in 2 patients (3.0%) receiving active pegvaliase and 1 patient (3.4%) receiving placebo. AEs leading to dose reduction or interruption occurred in 1 patient (1.5%) receiving pegvaliase and 1 patient (3.4%) receiving placebo. No patients in PRISM-2 RDT had AEs leading to discontinuation of study drug. No deaths occurred during PRISM-2 RDT.
Several study protocol-defined adverse events of special interest occurred more frequently in patients receiving active pegvaliase than in those receiving placebo. These included hypersensitivity AEs (HAEs) (pooled active 39.4% and pooled placebo 13.8%), generalized skin reaction of at least 14 days in duration (pooled active 10.6% and pooled placebo 0%), and injection site skin reaction of at least 14 days in duration (pooled active 7.6% and pooled placebo 3.4%). Arthralgia and injection site reactions occurred at similar frequencies in patients receiving active pegvaliase (arthralgia: 13.6%; injection site reaction: 24.2%) and in those receiving placebo (arthralgia: 10.3%; injection site reaction: 24.1%). Among notable harms identified for this review, those occurring more frequently in patients receiving active pegvaliase than in those receiving placebo were rash (pooled active 7.6% and pooled placebo 3.4%), urticaria (pooled active |||| and pooled placebo | |), pruritis (pooled active 7.6% and pooled placebo 3.4%), injection site pruritis (pooled active |||| and pooled placebo | |), diarrhea (pooled active |||| and pooled placebo | |), injection site erythema (pooled active |||| and pooled placebo | |), and erythema (pooled active |||| and pooled placebo | |). No anaphylaxis events or systemic hypersensitivity reactions occurred during PRISM-2 RDT.
A major limitation of PRISM-2 RDT was the small size of the study and associated uncertainty. In addition, internal validity concerns included bias inherent to the RDT design (recruitment of a population of patients who did not discontinue treatment in feeder studies or PRISM-2 Part 1 due to AEs or patient preference, who were able to achieve target dose in feeder studies, and who achieved a decrease of at least 20% in blood Phe during PRISM-2 Part 1), baseline imbalances between treatment groups in gender, BMI, mean blood Phe level, protein intake, and inattention and mood symptoms, uncertainty regarding the measurement properties or minimal important differences of any of the efficacy outcomes used in the study (and associated uncertainty regarding the connection between changes in blood Phe at Part 2 week 8 and other outcomes including inattention and mood symptoms, protein tolerance, diet liberalization, and HRQoL), and uncertainty in adherence to pegvaliase and consistency in dietary protein intake, both of which were self-reported.
There was some uncertainty in the target population of adult PKU patients most appropriate for pegvaliase and the degree of generalizability of the PRISM-2 RDT results to this population. The study recruited patients with uncontrolled Phe who were willing and able to self-administer pegvaliase. Changes in blood Phe observed in the study would not be generalizable to patients with good Phe control, although the clinical experts consulted by CADTH for this review felt that these patients would still be likely to benefit from treatment. The primary analysis of blood Phe may also not be generalizable to the general population of adult patients with PKU, which according to the clinical experts, includes many patients who will not comply with any therapy including pegvaliase. The specific relevance of pegvaliase-induced changes in blood Phe levels in the PRISM-2 RDT, measured at 1 or a few time points, to improvements in dietary protein tolerance, neurocognitive and neuropsychiatric symptoms, and HRQoL, was uncertain. According to the clinical experts consulted by CADTH for this review, blood Phe measurements are highly variable in PKU patients, and the point estimate of Phe control associated with pegvaliase treatment at part 2 week 8 of PRISM-2 provided no randomized trial evidence on duration or consistency of Phe control in patients.
No indirect evidence was identified for this review.
PRISM-1 was a phase III, OL, randomized, multicenter study to assess the safety and tolerability of pegvaliase among drug-naive PKU patients (N = 261). PRISM-1 was the major feeder study for PRISM-2. The study is briefly summarized here to provide context for the patient population enrolled in PRISM-2, since 203/215 (94.4%) of patients participating in PRISM-2 entered from PRISM-1, as well as to contribute additional safety data. The primary objective of PRISM-1 was to characterize the safety and tolerability of induction, titration, and maintenance dosing in pegvaliase-naive PKU patients who self-administered pegvaliase up to 20 mg/day or 40 mg/day. PKU patients aged 16 years or older were eligible to participate if they have blood Phe of at least 600 µmol/L and had not been previously exposed to pegvaliase. Patients were randomized 1:1 to receive up to 20 mg/day or 40 mg/day pegvaliase for up to 36 weeks. Both randomized dose groups experienced reductions from baseline blood Phe levels. The mean (standard deviation [SD]) blood Phe concentration at baseline was 1232.7 (386.36) µmol/L in the ITT set and the mean (SD) reduction from baseline was ||||||||||||| µmol/L at week 28 (n = 133) and ||||||||||||| µmol/L at week 36 (n = 80). Almost all patients (99.6%) experienced AEs, most commonly arthralgia (65.1%), injection site reactions (56.7%), injection site erythema (45.2%), headache (31.4%), rash (25.7%), injection site pruritis (24.9%), and injection site pain (21.5%). SAEs occurred in 10.0% of patients; the most common SAE was anaphylaxis (3.1%). Anaphylaxis per the National Institute of Allergy and Infectious Diseases (NIAID)/Food Allergy and Anaphylaxis Network (FAAN) criteria occurred in 6.9% of patients and anaphylaxis per NIAID/FAAN criteria meeting Brown’s severe criteria occurred in 1.5% of patients. Most patients (88.1%) experienced HAEs including arthralgia (65.1%), generalized skin reaction of at least 14 days (22.6%), injection site reactions (86.2%), injection site skin reactions of at least 14 days (26.4%), serum sickness (3.1%), and angioedema (35.6%).
Evidence from the non-RDT portions of PRISM-2, including the Part 4 OL extension (N = 215), is briefly summarized here to provide insight into the long-term safety of pegvaliase treatment (including doses up to 60 mg/day in the Part 4 OL extension). In PRISM-2, patients were treated with OL pegvaliase in part 1 (20 mg/day or 40 mg/day, up to 13 weeks), part 3 (20 mg/day or 40 mg/day, 6 weeks), and part 4 (up to 60 mg/day, up to 274 weeks). In all parts of the study, self-reported adherence to pegvaliase was high with good exposure. In the overall PRISM-2 study, ||||| of patients receiving OL pegvaliase experienced AEs and ||||| of patients experienced SAEs, the majority of which occurred during the OL extension. No deaths occurred in the overall PRISM-2 study. Approximately ||||||||||| of patients experienced AEs leading to pegvaliase dose reduction or interruption but only |||| of patients experienced AEs leading to pegvaliase discontinuation. Most patients ||||||| experienced HAEs. Approximately ||||||||||||| of patients ||||||| experienced injection site reactions, approximately |||||||||||||||| experience arthralgia, and nearly |||| (||||| each) experienced generalized skin reactions of at least 14 days in duration and injection site skin reactions of at least 14 days in duration. Anaphylaxis reactions occurred in || || of patients, acute systemic hypersensitivity reactions occurred in || || of patients, and angioedema occurred in || || of patients.
PRISM-3 was an exploratory phase III substudy to evaluate executive function in adults with PKU participating in PRISM-2 (N = 9). Although the study addressed outcomes (executive function and self-perception) that were not evaluated in PRISM-2, interpretation was limited by small sample size.
Zori et al. conducted a retrospective observational cohort study of adolescent and adult PKU patients receiving pegvaliase with or without MNT, sapropterin plus MNT, or MNT alone. A cohort of patients who received pegvaliase plus MNT in the phase II 165 to 205 trial or phase III PRISM studies (PRISM-1 and PRISM-2) were compared using a propensity score matching (PSM) approach with a historical control of patients who received sapropterin plus MNT or MNT alone who participated in the PKU Demographics, Outcome, and Safety (PKUDOS) registry. The outcomes evaluated in the study included change in blood Phe and natural protein intake after 1 and 2 years of treatment. Greater decreases in blood Phe levels and increases in protein intake from natural food were observed for pegvaliase-treated patients compared with patients receiving sapropterin plus MNT or MNT alone. However, because of numerous limitations in study design involving comparison with a historic control cohort, potential bias due to the non-randomized study design and PSM approach, and statistical limitations (exploratory analysis only), no clear conclusions could be drawn concerning the comparative effectiveness of pegvaliase, sapropterin plus MNT, and MNT alone.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis:
CADTH reanalysis included incorporating a titration year and adherence for pegvaliase patients, incorporating adherence for sapropterin patients, and removing the cost of MNT from the base case. In the CADTH reanalysis, for patients with PKU 16 years of age or older and who have blood Phe levels above 600 µmol/L despite previous treatment with sapropterin, the estimated budget impact for pegvaliase was $3,646,043 in year 1, $6,501,441 in year 2, and $8,587,322 in year 3, for a 3-year total incremental cost of $18,734,806.
The sponsor filed a Request for Reconsideration for the draft recommendation for pegvaliase (Palynziq) for the treatment of patients with PKU aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 µmol/L) despite dietary management. In their request, the sponsor identified 4 issues:
In the meeting to discuss the sponsor’s request for reconsideration, CDEC considered the following information:
All stakeholder feedback received in response to the draft recommendation from patient and clinician groups and the public drug programs is available on the CADTH website.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Regrets: None
Conflicts of interest: None
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Regrets: One
Conflicts of interest: None
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Indication: For the treatment of patients with phenylketonuria aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 µmol/L) on existing management
Sponsor: BioMarin Pharmaceutical Canada Inc.
Recommendation: Reimburse with conditions
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