Reimbursement Review

Pegzilarginase (Loargys)

Sponsor: Immedica Pharma AB

Therapeutic area: Arginase 1 deficiency

What Is Arginase 1 Deficiency?

• Arginase 1 deficiency (ARG1-D) is a rare, inherited, and progressive metabolic disease caused by a defective arginase 1 enzyme. This leads to the accumulation of toxic metabolites affecting the nervous system. While some patients survive into adulthood, ARG1-D is generally associated with premature mortality. The natural history of the disease comprises a multitude of severe clinical manifestations. Patients are increasingly impacted by neurologic complications and have challenges caring for themselves due to deteriorating mobility, including wheelchair dependence, and increasing intellectual disability.

• The estimated prevalence of ARG1-D in Canada is approximately 1 per million based on modelling from genetic population databases. Input from clinical experts suggests there are approximately 20 patients currently living with ARG1-D in Canada.

What Are the Treatment Goals and Current Treatment Options for ARG1-D?

• The patient group identified controlling arginine levels and preventing neurologic progression as important treatment goals. To these goals, the clinician group added increasing or normalizing ornithine levels, decreasing the frequency of hyperammonemia episodes, and improving cognitive and motor outcomes.

• Current management of ARG1-D primarily consists of best supportive care (BSC) with nitrogen scavenger therapy, protein-restricted and high-calorie diets, supplementation with essential amino acids, liver transplant, and symptomatic treatments. Only liver transplant corrects the underlying disease mechanism.

What Is Loargys and Why Did Canada’s Drug Agency Conduct This Review?

• Loargys is a synthetic arginase 1 that is administered by IV infusion or subcutaneous injection. Subcutaneous administration by the patient or caregiver may be considered after at least 8 weeks of treatment, once a stable maintenance dose has been established and the risk for hypersensitivity reactions is assessed as low. Health Canada reviewed Loargys for the treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with ARG1-D, in conjunction with dietary protein restriction.

• Canada’s Drug Agency (CDA-AMC) reviewed Loargys to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with ARG1-D, in conjunction with dietary protein restriction.

How Did CDA-AMC Evaluate Loargys?

• The clinical evidence was identified through systematic searches for available studies.

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, as well as the economic evidence, of Loargys versus other treatments used in Canada for the treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with ARG1-D, in conjunction with dietary protein restriction. In the absence of other disease-modifying therapies, treatments involved in BSC were considered as relevant to compare with Loargys when reviewing the clinical evidence. These included nitrogen scavengers (glycerol phenylbutyrate, sodium benzoate, and sodium phenylbutyrate), protein-reduced diet, antiepileptic drugs, and antispasmodic drugs.

• CDA-AMC identified equity and ethical considerations relevant to Loargys and the treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with ARG1-D, in conjunction with dietary protein restriction.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 1 patient group submission and 1 clinician group submission in response to the call for input by CDA-AMC, and by input from the participating public drug programs regarding issues that may impact their ability to implement a recommendation.

• Three clinicians with expertise in the diagnosis and management of ARG1-D were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed the following clinical evidence:

  • 1 phase III, double-blind, randomized controlled trial, the PEACE study, comparing Loargys plus individualized disease management with placebo plus individualized disease management in 32 patients with ARG1-D

  • 1 open-label, long-term extension (LTE) study, the PEACE LTE study, in the 31 patients who completed the 24-week treatment period of the PEACE trial

  • 1 phase I/II, open-label, randomized controlled trial, Study 101A, in 16 patients evaluating the safety, pharmacokinetics, and pharmacodynamics of pegzilarginase

  • 1 phase I/II, open-label, LTE study, Study 102A, in 14 patients who completed Study 101A, providing long-term efficacy and harms data and assessing motor function outcomes

  • 1 early access program real-world evidence study assessing effectiveness of Loargys in 16 patients.

• The following is a comparison of Loargys versus placebo at week 24 based on the PEACE study.

  • Loargys results in a clinically important reduction in plasma arginine levels and in a clinically important increase in the proportion of patients experiencing a response resulting in arginine levels within the normal range (40 μM to 115 μM) when compared with placebo. The clinical experts indicated that the proportion of patients experiencing arginine levels within the normal range may represent the most clinically meaningful outcome for clinical decision-making.

  • Loargys may result in little to no difference in neurologic and neuromotor function, as measured by the 2-minute walk test and Gross Motor Function Measure-88 (GMFM-88) Dimension D and Dimension E; however, the clinical experts indicated that a 24-week follow-up period was insufficient to detect clinically meaningful changes.

  • Loargys may also result in little to no difference in adaptive behaviour, based on the Vineland Adaptive Behavior Scales II, although a 24-week follow-up period was insufficient to detect clinically meaningful changes according to the clinical experts.

  • Loargys likely results in a clinically important increase in health-related quality of life as measured by the PedsQL overall score when compared with placebo at 24 weeks.

  • Loargys may result in little to no difference in hyperammonemic episodes compared with placebo.

  • No new safety signals were identified; according to the experts consulted, harms were considered manageable in clinical practice, and were consistent with the known expected safety profile of Loargys.

• The open-label, noncomparative LTE phase of the PEACE trial partially addressed an evidence gap by providing data on the efficacy and safety of Loargys beyond week 24. The following is based on the LTE phase of the PEACE trial.

  • Pegzilarginase treatment descriptively resulted in sustained reductions in plasma arginine.

  • Neuromotor and mobility outcomes demonstrated variable and inconsistent changes over time, with some indication of maintenance or improvement up to week 96, with a small number of patients remaining in follow-up (N ranges from 2 to 10). As such, substantial uncertainty remains due to small and decreasing sample sizes and variability in outcomes. Results for health-related quality of life were inconclusive.

• Study 101A and Study 102A were open-label, single-arm studies that partially addressed an evidence gap from the PEACE trial by providing additional supportive evidence in patients aged 2 years and older with confirmed ARG1-D; however, findings are limited by small sample sizes (N = 16 for Study 101A and N = 14 for Study 102A), descriptive analyses, and the absence of a comparator group. The following are based on Study 101A and Study 102A.

  • Reductions in plasma arginine were observed across the 192 weeks of follow-up with a reasonable number of patients remaining in the study, consistent with findings from the PEACE study and its LTE period.

  • Changes in functional outcomes, including the 6-minute walk test and GMFM Dimension D and GMFM Dimension E had some improvement across 144 weeks of follow-up; however, these changes were modest and associated with substantial variability, and their clinical relevance remains uncertain.

  • No new safety signals were identified during the study.

• The French Early Access Program study addressed an evidence gap by providing noncomparative real-world evidence on the effectiveness of Loargys in treated patients; however, interpretation is limited by its observational design which precludes causal inference, and small sample size (N = 16). The following results are based on the French Early Access Program study.

  • Mean plasma arginine levels at 3 months were reduced. A proportion of patients experienced target thresholds (93.8% < 200 μmol/L; 81.3% < 170 μmol/L; 62.5% < 115 μmol/L).

  • Mean dietary protein intake increased from 0.66 g/kg/day to 0.89 g/kg/day over 12 months, while essential amino acid intake decreased from 0.33 g/kg/day to 0.26 g/kg/day (n = 3; variability not reported). These findings suggest potential dietary liberalization; however, interpretation is limited by the very small sample size and lack of reported variability.

  • Changes in patient-reported and caregiver-reported PedsQL total scores over 12 months were modest and not statistically significant.

  • No new safety signals were identified during the study.

Economic Evidence

• Loargys is available as a solution for subcutaneous injection and IV infusion (5 mg/mL). At the submitted price of $7,271.55 per 0.4 mL vial, the annual cost of Loargys is expected to range from $379,419 to $758,838 for pediatric patients weighing 13 kg, depending on the dose (0.1 mg/kg to 0.2 mg/kg). The annual cost of Loargys is expected to range from $1,897,095 to $3,414,772 for adult patients weighing 85 kg, depending on the dose (0.1 mg/kg to 0.2 mg/kg).

• Key efficacy outcomes (transitions between Gross Motor Function Classification System levels) in the economic model were informed by using patient-level count data on a small sample size (n = 32) from the PEACE trial data. Evidence submitted by the sponsor suggested little to no difference in neurologic, neuromotor, and neurocognitive function, as measured using the 2-minute walk test, GMFM Dimension E, and GMFM Dimension D, as well as little to no difference in adaptive behaviour based on the Vineland Adaptive Behavior Scales II, when compared with placebo at 24 weeks. However, the follow-up period was considered insufficient to detect meaningful changes. There was also no robust evidence to support the modelled long-term impact of Loargys plus BSC on Gross Motor Function Classification System transitions, neurocognitive function, and overall survival. Evidence submitted by the sponsor showed that Loargys results in a clinically important reduction in plasma arginine levels and in a clinically important increase in the proportion of patients experiencing a response resulting in arginine levels within normal range (40 μM to 115 μM) when compared with placebo. The clinical experts indicated that the proportion of patients experiencing arginine levels within the normal range may represent the most clinically meaningful outcome for clinical decision-making; however, arginine plasma was not modelled in the submitted cost-utility analysis. While observational evidence suggests that reductions in plasma arginine at the individual patient level may be associated with longer-term, patient-relevant clinical outcomes, the relationship between change in arginine levels and improvements in hard clinical outcomes has not been formally validated.

• The sponsor’s base case predicted that Loargys plus BSC is associated with higher costs and higher quality-adjusted life-years (QALYs) compared with BSC alone, resulting in an incremental cost-effectiveness ratio of $2,805,316 per QALY gained. In this analysis, costs were driven by treatment acquisition costs for people treated with Loargys (approximately $72 million in additional treatment costs per patient over a lifetime). Health benefits were driven by a substantial reduction in mortality (approximately 28 life-years gained over a lifetime). There is no robust evidence on functional, cognitive, and survival outcomes to support these findings. The predicted benefits are based on the assumption that stabilizing plasma arginine will impact functional and cognitive outcomes for patients by completely stopping disease progression. Therefore, the economic analysis may not accurately assess the impact on health and health care resources, and the cost-effectiveness estimates are highly uncertain.

• Results from the sponsor’s analyses suggest that with substantial price reductions (i.e., 90%), the incremental cost-effectiveness ratio for Loargys plus BSC remains greater than $375,000 per QALY gained. This is a result of the estimated prolonged survival for patients treated with Loargys plus BSC, which results in increased nondrug costs (e.g., disease management costs) and drug costs associated with the ongoing use of BSC.

• CDA-AMC identified a number of issues with the sponsor’s estimated budget impact that could not be addressed. Although the sponsor estimated that the budget impact of reimbursing Loargys plus BSC for use in the indicated population will be approximately $22 million over the first 3 years (estimated expenditure = $25 million), the impact of reimbursing Loargys plus BSC is highly uncertain. The actual budget impact would depend on the number of patients with ARG1-D in Canada.

Background

Introduction

Context for the Review

The objectives of this report are as follows:

• This report reviews and critically appraises the evidence submitted by the sponsor on the beneficial and harmful effects of pegzilarginase 5 mg/mL solution for IV infusion and subcutaneous (SC) injection in the treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with arginase 1 deficiency (ARG1-D), in conjunction with dietary protein restriction. The focus will be placed on comparing pegzilarginase to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence, and this focus is outlined in Table 1.

• This report reviews and critically appraises the economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis. The focus of the Economic Review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, a base case is developed by Canada’s Drug Agency (CDA-AMC), informed by the available clinical evidence, clinical expert input, and the best interpretation of the economic evidence based on the information provided by the sponsor.

The application was submitted by the sponsor before receiving a Notice of Compliance from Health Canada. This report has been updated to reflect the final indication and recommended dosage for pegzilarginase, because the Notice of Compliance was received during the CDA-AMC review period.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

AE = adverse event; CDA-AMC = Canada's Drug Agency; NOC = Notice of Compliance.

^aThe Economic Review aligns with the scope of the Clinical Review, unless otherwise stated.

^bCDA-AMC has previously issued a reimbursement recommendation for this drug for the same indication or a similar indication.

Submission History for the Drug Under Review

CDA-AMC has not previously reviewed pegzilarginase through the Reimbursement Review process.

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input received from interested parties (patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each Reimbursement Review. One patient group submission from the Canadian Organization for Rare Disorders and 1 clinician group submission from the Garrod Association were received. Input from the patient group was collected from patients with lived experience and caregivers through a survey distributed to the Arginase 1 Deficiency Foundation, individual interviews, and written testimonials. Inputs from the clinician group were collected from metabolic physicians across Canada treating patients with ARG1-D, a review of the literature of clinical trials with pegzilarginase, and discussions with metabolic colleagues in Canada. The full submissions received are available on the project landing page in the consolidated input document.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections.

The drug programs provide input on each drug being reviewed through the Reimbursement Review process by identifying issues that may impact their ability to implement a recommendation. The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, in the Summary of Drug Program Input and Clinical Expert Responses table in Appendix 1.

Each review team includes at least 1 clinical expert with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process. Three clinical experts with expertise in the diagnosis and management of ARG1-D participated as part of the review team.

Disease Background

ARG1-D is a rare, progressive, autosomal recessive metabolic disorder within the urea cycle disorders. The condition is caused by deficiency of the arginase 1 enzyme, which catalyzes the final step of the urea cycle converting arginine to urea and ornithine.^1-3 Impaired enzyme activity results in accumulation of arginine and its neurotoxic metabolites, leading to progressive neurologic manifestations including spasticity, mobility impairment, developmental delay, seizures, and cognitive dysfunction.⁴ ARG1-D is caused by pathogenic variants in the ARG1 gene, resulting in reduced or absent arginase 1 enzyme activity and elevated plasma arginine levels, which serve as a key biochemical marker of the disease.^1,3

In a mathematical modelling study using genetic population databases, the global birth prevalence for ARG1-D was estimated at 2.8 cases per million live births (country-specific estimates ranged from 0.92 to 17.5) and population prevalence to be 1.4 cases per million people (approximately 1 in 726,000 people).⁵ In the same study, the authors estimated the birth prevalence and population prevalence for Canada to be 1.94 per million and 0.97 per million, respectively.⁵ The clinical experts consulted by CDA-AMC estimate that there are currently 20 patients in Canada living with ARG1-D. The prognosis and long-term outcomes of patients with ARG1-D are not well established. While data from the literature report that some patients survive into adulthood, the natural history of the disease comprises a multitude of severe clinical manifestations, such as developmental delay, intellectual disability, lower limb spasticity, impaired mobility, and seizures. Although systematic studies on survival in patients with ARG1-D are lacking, available data show that ARG1-D is generally associated with premature mortality. In a cohort of 140 individuals, the median age at death was reported as 17 years. Patients who survive into adulthood are increasingly impacted by neurologic complications and have challenges caring for themselves due to deteriorating mobility, including wheelchair dependence, and increasing intellectual disability.

ARG1-D is typically diagnosed by identifying elevated plasma arginine levels, with confirmation through arginase enzyme activity testing in erythrocytes or genetic testing for pathogenic variants in the ARG1 gene, with supportive findings such as increased urinary orotic acid excretion.⁶

Patient group input: Input from the Canadian Organization for Rare Disorders notes that ARG1-D has a substantial impact on patients’ daily functioning and quality of life, with early-onset neurologic and physical symptoms including muscle stiffness (approximately 66%), impaired mobility (33%), developmental delays (33%), seizures or cognitive difficulties (17%), and metabolic crisis with hospitalization (33%). Many patients experience initial misdiagnoses (42%), as well as progressive functional decline despite strict dietary management and supportive care. The condition also imposes significant ongoing burdens related to mobility limitations, strict dietary restrictions (low protein), and frequent medical monitoring, often leading to social isolation and intensive caregiving needs.

Current Management

Treatment Goals

Patient group input: Treatment goals noted by patient groups include controlling arginine levels and preventing the neurologic deterioration associated with ARG1-D. Patients and caregivers desire improvements or stabilization in mobility, cognitive function, and overall daily functioning, which includes participating in school and/or work and social activities. In addition, they emphasized the importance of reducing symptoms such as spasticity, seizures, and fatigue, and reducing reliance on strict dietary restrictions, which would lessen the overall disease burden.

Clinician input: The clinical experts indicated that the primary goals of treatment for ARG1-D include reducing or normalizing plasma arginine levels, as well as reducing or normalizing guanidine compounds, increasing or normalizing ornithine levels, decreasing the frequency of hyperammonemia episodes, preventing the progression of neurologic disease, and improving existing neurologic disease. Additional treatment goals include preventing or mitigating psychiatric conditions, improving cognitive and motor outcomes, supporting normal development in asymptomatic individuals, reducing seizure frequency, and ensuring normal growth without nutritional deficiencies. Input from the clinician group noted additional important goals such as improving mobility, reducing spasticity, and limiting adverse events (AEs).

Current Treatment Options

The current management of ARG1-D primarily involves best supportive care (BSC), including the use of nitrogen scavenger therapy, protein-restricted and calorie-enriched diets, supplementation with essential amino acids, and ornithine supplementation to help reduce plasma arginine levels and mitigate hyperammonemia. However, these treatments do not address the underlying disease pathway dysregulation that drives disease progression. The clinical experts indicated that in Canada, the treatment of ARG1-D is largely guided by international expert consensus and current guidelines due to the absence of disease-specific therapies and randomized controlled trials (RCTs) informing the use of these supportive care treatment options.

The clinical experts indicated that nitrogen scavenger therapy (e.g., sodium benzoate, sodium phenylbutyrate, and/or glycerol phenylbutyrate) may help reduce the risk of hyperammonemia and may also lower the formation of arginine. Protein-restricted (i.e., arginine-restricted) diets may reduce plasma arginine levels, although supplementation with specialized metabolic formulas (e.g., essential amino acids) may be required to maintain adequate nutritional status. In addition, pharmacological symptomatic treatments targeting disease manifestations, such as antiepileptic and antispasmodic medications, may be used to manage seizures and other symptoms. However, the clinical experts noted that these treatments do not modify the underlying disease mechanism and thus, cannot be considered comparators of pegzilarginase. Only liver transplant addresses the pathophysiology of the disease according to clinical experts, as arginase 1 is predominantly expressed in periportal hepatocytes. Nonetheless, they indicated that this intervention is associated with significant risks and morbidity and may not be accessible to all patients.

Key characteristics of pegzilarginase are summarized with other treatments available for ARG1-D in the Supplemental Material document (available on the project landing page), in the Key Characteristics table in Appendix 1.

Unmet Needs and Existing Challenges

Patient group input: Patient group input highlighted the need for treatments that prevent disease progression. Current approaches such as strict low-protein diets and supportive therapies, do not address the underlying disease mechanism, have limited efficacy, and may be burdensome. Patients and caregivers reported ongoing neurologic decline, mobility impairment, seizures, and cognitive difficulties despite adherence to dietary management. In addition to strict dietary monitoring, managing the condition imposes substantial additional daily burdens, including frequent medical care, and high caregiving demands. Delayed diagnosis and misdiagnosis were also highlighted as a significant concern.

Clinician input: The clinical experts noted significant unmet need for therapies that are both effective and tolerable, and that have meaningful impacts on reducing plasma arginine levels and burden of the disease. According to the experts, the treatment landscape in Canada is insufficient, given that there are no approved therapies preventing the progressive neurologic and cognitive impairments of ARG1-D. The clinical experts noted that while symptomatic treatments may help manage certain manifestations, they do not meaningfully reduce the overall burden of disease for patients, families, and society. Likewise, they indicated that dietary protein restriction may decrease plasma arginine levels but is generally insufficient to achieve the goal of normalization. In addition, they mentioned that these diets are difficult to maintain; adherence is often poor and typically declines as patients reach adulthood. Similarly, the clinical experts mentioned that ammonia scavenger therapies may reduce the risk of hyperammonemia, which is clinically important, but they do not substantially affect arginine levels.

Input from the clinician group was consistent with that of the clinical experts consulted for this review. The clinician group emphasized that ARG1-D is a rare disease associated with a poor prognosis and a high disease burden despite the currently available treatment options.

Considerations for Using the Drug Under Review

Contents within this section have been informed by input from the clinical expert(s) consulted for the purpose of this review and from clinician groups, as well as the reimbursement conditions proposed by the sponsor (refer to the Initiation, Renewal, Discontinuation, and Prescribing Conditions Proposed by the Sponsor table in Appendix 1 in the Supplemental Material document available on the project landing page). The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, in the Summary of Drug Program Input and Clinical Expert Responses table in Appendix 1. The following has been summarized by the review team.

Place in Therapy

The clinical experts anticipate pegzilarginase to cause a paradigm shift in the management of ARG1-D. The clinical experts agreed that pegzilarginase should be considered a first-line therapy because it directly targets the underlying disease mechanism. By converting arginine to ornithine, pegzilarginase can reduce hyperargininemia, which drives the disease symptoms and progression. The clinical experts emphasized that with adequate arginine control, dietary protein restriction may be reduced or potentially not required anymore; this could substantially reduce the burden of disease management. However, clinicians may still concomitantly use dietary management and ammonia scavengers in some patients to reduce the risk of hyperammonemia.

Input from the clinician group was consistent with the insights offered by the clinical experts.

Patient Population

The clinical experts and input from the clinician group agree that all patients with ARG1-D are in high need of intervention, and all would be adequately suited for treatment with pegzilarginase. The clinical experts noted that treatment should be initiated as early as possible, given that ARG1-D is a progressive condition leading to irreversible damage. They also noted that disparities in access to diagnosis and specialized care may negatively affect patient outcomes.

The sponsor’s proposed initiation criteria include pediatric and adult patients (aged ≥ 2 years), with a confirmed diagnosis of ARG1-D. Pegzilarginase should be given in conjunction with individualized disease management such as dietary protein restriction, amino acid supplements, and pharmacological treatment including nitrogen scavengers, at the discretion of the treating physician. The clinical experts considered these criteria to be appropriate, noting that confirmation of ARG1-D should involve 2 of the following methods: elevated plasma arginine level, markedly decreased arginase 1 enzyme activity, or genetic assessment of biallelic mutation of the ARG1 gene, as determined by the treating physician. They noted that genetic testing should be conducted for all patients and, given their increased accessibility, these tests may replace measurement of arginase 1 enzyme activity, which is not readily accessible.

The clinical experts noted that there is no point in the disease course at which treatment would be expected to provide no benefit or should not be used. However, they suggested that patients with a history of severe hypersensitivity reactions to pegylated products may be unsuitable for pegzilarginase treatment. Finally, because pegzilarginase is administered SC and can be given at home, patients do not need to be in close proximity to specialized metabolic centres once the IV administration period is completed.

Input from the clinician group was consistent with that of the clinical experts, including in terms of characteristics of patients who may or may not benefit from treatment with pegzilarginase.

Assessing the Response to Treatment

The clinical experts indicated that treatment response in ARG1-D is primarily assessed using objective measures, in particular, reductions in plasma arginine levels. They noted that improvements in development, cognitive function, mobility, and spasticity should also be evaluated; however, these outcomes may require several months, and often years, to see meaningful improvement. Where available, objective assessments, such as psychoeducational testing or validated spasticity and mobility scales, may be used to support evaluation, although these tools may not be accessible in all jurisdictions and may be challenging to use. The experts also indicated that incorporating motor function assessment into the physical examination could impose substantial additional workload for clinicians.

The clinical experts noted that due to the progressive nature of ARG1-D, improvements in clinical outcomes may be subtle and are likely to become apparent in the long term. This is why, in clinical practice, even slowing or stabilizing disease progression is considered a clinically meaningful response. The experts noted that a meaningful response may be based on reduction of plasma arginine levels to within the normal range; stabilization of spasticity, seizures, and cognition or development; reduction of hyperammonemic crises in patients at risk; and absence of new neurologic symptoms. They noted that treatment response should typically be assessed at least every 3 months, depending on the patient’s age and proximity to a treatment centre.

The sponsor’s proposed renewal criteria include: a reduction in predose arginine concentration that is considered clinically meaningful according to the treating clinician, without developing unacceptable toxicities requiring discontinuation; and, for subsequent renewal, maintained arginine levels can be reassessed every 6 to 12 months, as determined by the treating physician. The clinical experts considered these criteria to be appropriate.

Input from the clinician group was consistent with the treatment response measures suggested by the clinical experts.

Discontinuing Treatment

The sponsor’s proposed discontinuation criteria include patients who develop unacceptable toxicities or hypersensitivity. Clinical experts generally considered these criteria to be appropriate; however, they indicated that discontinuation of pegzilarginase should also be considered in the absence of reduction in plasma arginine levels, increase in hyperammonemic events or crises, lack of treatment adherence, continued disease progression, or inability to ensure regular monitoring.

Input from the clinician group was consistent with the criteria suggested by the clinical experts.

Prescribing Considerations

The sponsor’s proposed prescribing criterion is that treatment should be initiated and supervised by a physician experienced in the management of patients with inherited metabolic diseases. The clinical experts indicated that the sponsor’s proposed prescribing conditions align well with clinical practice and are considered readily implementable without significant challenges. The experts noted that diagnosis of ARG1-D, as well as prescribing and monitoring of pegzilarginase, should be restricted to geneticists or metabolic geneticists in specialized metabolic centres, although patient care can be managed in collaboration with other specialists, such as neurologists. They noted that patients living in remote areas may require transportation support to access specialized metabolic centres. Input from the clinician group highlighted that the care team for patients with ARG1-D may also include dietitians and genetic counsellors, with ongoing communication and coordination with the patient’s primary care physician.

Additional Considerations

Treatment with pegzilarginase can be initiated as either IV infusion or SC injection. The clinical experts noted that an initial IV administration period as per the trial procedures may temporarily limit accessibility, particularly for patients living far from a metabolic centre. Due to the increased risk of hypersensitivity reactions including anaphylaxis, the product monograph states that pegzilarginase must be administered by a health care professional for at least the first 8 weeks, regardless of whether the drug is administered as an IV infusion or SC injection. The clinical experts noted that for this initial observation period, administration may likely occur in a hospital setting. For the longer term, the product monograph recommends that SC injections be considered instead of IV administration after at least 8 weeks to reduce the risk of hypoargininemia.

Clinical Review

Methods

The CDA-AMC review considered inclusion studies in the sponsor’s systematic review (pivotal studies and RCTs), sponsor-submitted long-term extension (LTE) studies, indirect treatment comparisons, and studies addressing gaps in the evidence. Eligible studies in the sponsor-submitted systematic review included published and unpublished pivotal studies and phase III RCTs. Relevant patients and interventions were defined by the indication or reimbursement request and the recommended dosage in the product monograph. Relevant comparators were treatments used as BSC in clinical practice in Canada to treat patients described in the indication under review. These included nitrogen scavengers (glycerol phenylbutyrate, sodium benzoate, and sodium phenylbutyrate), protein-reduced diet, antiepileptic drugs, and antispasmodic drugs. LTEs of included pivotal studies and RCTs were included in the systematic review, regardless of whether there was a comparison group. Studies addressing gaps submitted by the sponsor were included when they filled an identified gap in the systematic review evidence (e.g., longer follow-up time, evaluating motor function outcomes). No indirect treatment comparisons were included in the review.

The review team selected outcomes (and follow-up times) for review considering the sponsor’s Summary of Clinical Evidence, clinical expert input, and patient and clinician group input. Included outcomes are those considered relevant to expert committee deliberations, and they were selected in consultation with committee members. Evidence from the systematic review for the most important outcomes at week 24 was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These outcomes address important treatment goals for ARG1-D, are considered important to patients and clinicians according to patient group input and clinician input, and provide the source for a key input in the sponsor’s pharmacoeconomic model. The selected outcomes include:

• plasma arginine levels

• proportion of patients experiencing a response after 24 weeks (i.e., arginine value within the normal range [40 μM to 115 μM])

• 2-minute walk test (2MWT)

• Gross Motor Function Measure (GMFM)-88, Dimension E

• GMFM-88, Dimension D

• Vineland Adaptive Behavior Scales II (VABS-II)

• Pediatric Quality of Life Inventory (PedsQL)

Methods for data extraction, risk of bias appraisal, and certainty of evidence assessment are in the Supplemental Material document in Appendix 2.

Outcomes not assessed using GRADE but pertinent to the review and appearing in the report include change from baseline in ornithine at 24 weeks, proportion of patients who achieved response to composite mobility (2MWT, GMFM Dimension D, and GMFM Dimension E) at 24 weeks, change from baseline in functional mobility scales at 24 weeks, Wechsler Intelligence Scales at 24 weeks, growth assessments at 24 weeks, and diets/dietary disease management at 24 weeks. Results for these outcomes were considered less critical to decision-making but were nevertheless included as supportive outcomes for contextual interpretation and/or pharmacoeconomic modelling. Detailed results of these outcomes can be found in Appendix 4 in the Supplemental Material document.

In this report, the following sources of evidence submitted by the sponsor are reviewed and appraised:

• 1 phase III, double-blind, RCT, the PEACE study, comparing pegzilarginase plus individualized disease management with placebo plus individualized disease management in 32 patients with ARG1-D

• 1 open-label, LTE study, PEACE LTE, in the 31 patients who completed the 24-week treatment period of the PEACE trial

• 1 phase I/II, open-label, RCT, Study 101A, in 16 patients evaluating the safety, pharmacokinetics, and pharmacodynamics of pegzilarginase

• 1 phase I/II, open-label, LTE study, Study 102A, in 14 patients who completed Study 101A, providing long-term efficacy and harms data and assessing motor function outcomes

• 1 early access program real-world evidence study assessing effectiveness of pegzilarginase in 16 patients.

Systematic Review

Description of Studies

Study Characteristics

Characteristics of the PEACE study are summarized in Table 2. Details pertaining to study objectives, design, eligibility criteria, and relevant outcome measures are in the Supplemental Material document in Appendix 3.

The PEACE study was a phase III, multicentre, double-blind, placebo-controlled RCT evaluating the safety and efficacy of pegzilarginase plus individualized disease management compared to placebo plus individualized disease management in pediatric patients (aged ≥ 2 years) and adult patients with ARG1-D. In the 24-week double-blind period, patients were randomized in a 2:1 ratio to receive either pegzilarginase (n = 21) or placebo (n = 11). Randomization was conducted using a central computer-generated randomization schedule and stratified by severity of prior history of hyperammonemia. Pegzilarginase or volume-adjusted placebo was administered as weekly IV infusions with a starting dose of 0.1 mg/kg, to be optimized during the double-blind period based on arginine levels. Dose modifications were implemented by an unblinded pharmacist and/or physician, and laboratory results were not disclosed to blinded individuals. Patients were enrolled from 19 sites across Austria, Canada, France, Germany, Italy, the UK, and the US.

All patients received individualized disease management, which involves a common framework of severe protein restriction and essential amino acid supplementation with or without the use of ammonia scavengers. These facets of disease management are individualized for each patient by titration of the different components to reduce plasma arginine levels and ensure an adequate intake of protein for proper growth and development while avoiding hyperammonemia.

The double-blind period was followed by up to approximately 150 weeks of an open-label LTE period in which all patients received active pegzilarginase plus individualized disease management. All eligible patients began the LTE phase with an 8-week blinded follow-up treatment period for the purpose of data integrity. Patients initially randomized to pegzilarginase received the optimized dose they received during the double-blind period. Patients initially randomized to placebo began the 8-week period at a dose of 0.10 mg/kg, to be adjusted during the LTE period based on arginine levels. After the first 8 weeks of the LTE period, patients had the option to switch from pegzilarginase IV administration to SC administration once weekly. The initial SC dose was the same as the IV dose unless adjustments were required based on arginine levels.

The main body of this report presents data from the double-blind period of the PEACE study up to 24 weeks.

Table 2: Characteristics of Studies Included in the Systematic Review

2MWT = 2-minute walk test; ARG1-D = arginase 1 deficiency; EAA = essential amino acid; GFAQ = Gillette Functional Assessment Questionnaire; GMFM-88 = Gross Motor Function Measure-88; LTE = long-term extension; PedsQL = Pediatric Quality of Life Inventory; RBC = red blood cell; RCT = randomized controlled trial; SC = subcutaneous.

Sources: PEACE Clinical Study Report (2024).⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Statistical Testing and Analysis Populations

A sample size of 30 patients provided at least 95% power at a 2-sided alpha of 0.05 under the following assumptions based on data from the phase I/II Study 101A and Study 102A: reduction of 77% from baseline in plasma arginine levels at 24 weeks, corresponding to −2.13 on the log₂ scale, for those receiving pegzilarginase; and a reduction of 0 at 24 weeks for placebo.^8,9

In addition to the primary end point, power calculations were also performed for the 2 key secondary end points (2MWT and GMFM Dimension E) using simulated data. Baseline and 24-week data were sampled from a joint distribution of the 2MWT and GMFM Dimension E based on effect sizes estimated from preliminary data (Study 101A and Study 102A). Patients treated with placebo were assumed to have 0 mean change from baseline. It was shown that there was more than 90% power to show statistical significance in at least 1 of the key secondary end points.

Details pertaining to the multiple testing procedure are in the Supplemental Material document in Appendix 3. To control for type I error, the primary, key secondary, and other secondary end points were tested in the following sequence:

1. primary end point: change from baseline in log-transformed plasma arginine after 24 weeks

2. key secondary:

   • comparison of mean change from baseline at week 24 in the 2MWT

   • comparison of change from baseline at week 24 in the GMFM Dimension E score

3. additional secondary: comparison of response (arginine < 200 μM after 24 weeks of study treatment)

4. additional secondary: comparison of response (arginine 40 μM to 115 μM after 24 weeks of study treatment)

5. additional secondary: comparison of mean change from baseline in the GMFM Dimension D score at week 24.

Efficacy and safety analyses were performed primarily using the full analysis set, which included all patients who were randomized and received a least 1 dose of blinded study treatment.

Patient Disposition

A total of 44 patients with ARG1-D were screened; among them, 32 patients were eligible and randomized 2:1 to receive pegzilarginase (n = 21) or placebo (n = 11). Most patients who did not meet the study inclusion criteria either had plasma arginine levels inferior to 250 μM, were not able to perform clinical assessments for at least 1 secondary outcome, or experienced an hyperammonemic episode within the 6 weeks before the first dose of study drug. One patient (4.8%) discontinued from the study in the pegzilarginase group due to their personal decision, compared to none in the placebo group. All 31 patients who completed the double-blind period continued to the LTE portion of the study.

At study completion, 90.6% of patients experienced at least 1 important protocol deviation. Of these, 18 patients (85.7%) were in the pegzilarginase group and 11 (100%) were in the placebo group. A total of 11 patients (34.4%) experienced important protocol deviations that were related to COVID-19. Most of these deviations involved a screening pause (12.5%), study suspension (9.4%), and visit schedule criteria (9.4%). There were 29 patients (90.6%) who experienced non-COVID-19–related important protocol deviations; 85.7% (n = 18) in the pegzilarginase group and 100% (n = 11) in the placebo group. The majority involved study procedure criteria (62.5%) and investigational product compliance (50%).

Details of patient disposition and major protocol deviations for the PEACE trial are summarized Appendix 4 in the Supplemental Material.

Baseline Characteristics

Detailed baseline characteristics for patients in the PEACE trial are available in the Supplemental Material. The mean age of all study patients was 10.7 years with a standard deviation (SD) of 6.47 years. Patients in the pegzilarginase group had a mean age of 9.6 years (SD = 6.16 years), while those in the placebo group were an average age of 12.9 years (SD = 6.77 years). Overall, the majority of patients were aged between 6 and 12 years (37.5%), and there were only 3 patients (9.4%) aged older than 18 years. There was a greater proportion of males included in the study (59.4%) than females (40.6%). The age at diagnosis of ARG1-D was lower in the pegzilarginase group (2.8 years; SD = 4.06 years) compared to the placebo group (4.2 years; SD = 3.07 years). Likewise, patients in the pegzilarginase group had better motor function abilities on average. Overall, 14 patients (43.8%) had a Gross Motor Function Classification System (GMFCS) level of I at baseline, 13 patients (40.6%) had a GMFCS level of II, and 5 patients (15.6%) had a GMFCS level of IV. Twelve patients (57.1%) in the pegzilarginase group and 10 patients (90.9%) in the placebo group had cognitive delays.

Table 3: Summary of Baseline Characteristics From Studies Included in the Systematic Review

ARG1-D = arginase 1 deficiency; GMFCS = Gross Motor Function Classification System; IDM = individualized disease management; SD = standard deviation.

Sources: PEACE Clinical Study Report (2024).⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Treatment Exposure and Concomitant Medications

During the placebo-controlled, double-blind period, 95.2% of patients in the pegzilarginase group and 100% of patients in the placebo group had a dosing adherence of 80% or higher. Pegzilarginase was administered IV once weekly at doses ranging from 0.05 mg/kg to 0.20 mg/kg. In the pegzilarginase group, 90.5% of patients (n = 19) had a treatment duration of at least 24 weeks compared to 81.8% (n = 9) in the placebo group. Dose interruptions due to AEs were reported in 38.1% of patients (n = 8) in the pegzilarginase group and 9.1% (n = 1) in the placebo group. There was no discontinuation of study treatment due to treatment-emergent AEs.

All 32 patients enrolled in the study received concomitant medications. The most frequently used included ammonia scavengers, received by 20 patients in the group receiving pegzilarginase (95.2%) and 9 patients in the placebo group (81.8%). During the study, 15 patients (46.9%) received glycerol phenylbutyrate, 15 (46.9%) sodium benzoate, and 10 (31.3%) sodium phenylbutyrate.

Details of patients’ treatment exposure, compliance, and use of concomitant medications during the double-blind period in the PEACE study are in Appendix 4 in the Supplemental Material document.

Critical Appraisal

Internal Validity

Randomization was conducted using an interactive web/voice response system, supporting adequate allocation concealment. Stratification by prior hyperammonemia history was prespecified and clinically relevant. The stratification categories were defined as: 1 or more hyperammonemic episodes within 90 days before consent or 2 or more episodes within 365 days before consent; and no hyperammonemic episodes within 365 days before consent, or 1 episode occurring more than 90 days before consent. This approach was clinically relevant to minimize potential imbalance in baseline risk across treatment groups but did not account for underlying disease severity.

Because results of arginine, ornithine, and guanidine compound laboratory tests could reveal treatment allocation, they were withheld from blinded individuals, including investigators and other study site personnel until formal unblinding. Dose modifications based on these tests results were implemented by an unblinded pharmacist and/or physician. However, a quality finding was discovered by the sponsor indicating that unblinded information was sent to blinded site staff, including the amount of each vial type (placebo and active drug) included in the shipment to study site. This poses a potential of patient unblinding; however, the impact is expected to be limited due to the objective nature of the primary outcome (change in plasma arginine) and because neuromotor assessments were carried out by assessors independent of study site staff. Unblinding could nevertheless increase the risk of bias for subjective, patient-reported outcomes and dietary management by site investigators.

Several imbalances were observed in baseline demographic and disease characteristics between treatment groups. These differences may reflect sampling variability due to the small sample size, which increases the risk that prognostic balance was not fully achieved. Overall, patients in the pegzilarginase group had characteristics that were consistent with less severe clinical status at baseline compared with the placebo group. Patients in the pegzilarginase group were younger, with a higher proportion having received newborn screening and a younger age of diagnosis. In these patients, baseline mean arginine and historic arginine was lower. Conversely, patients in the placebo group appeared to have somewhat greater impairment in walking short to moderate distances, higher levels of spasticity, and more frequent cognitive delays documented in their medical history. For most of these measures, baseline range is wide, indicating the variability in clinical presentation within the groups.

The imbalance in arginine at baseline is not expected to bias the findings for plasma arginine, as the analyses involved adjustment for historical arginine, and the effect sizes were large. The imbalances in mobility, spasticity, and cognitive function could potentially favour the pegzilarginase group, as motor improvements may be more pronounced in younger patients according to the clinical experts; whereas, patients who reach adolescence may have experienced irreversible damage. However, the clinical experts noted that a clinically meaningful response would be achieved if treatment was able to even stabilize the decline in mobility and cognitive function; considering the aforementioned, the experts did not expect that the imbalances in baseline values would create a clinically meaningful bias in the assessment of these outcomes.

The sample size of the PEACE trial was considered adequate for the primary analysis based on the assumptions outlined in the statistical analysis plan; however, it may be insufficient for the key secondary and other secondary clinical outcomes, potentially resulting in unstable effect estimates and imprecision. Likewise, patient heterogeneity in disease duration and clinical presentation may further broaden the overall variance.

The clinical experts, as well as patient and clinician group input, noted that reduction in plasma arginine levels is the primary assessment of treatment response in clinical practice; an optimal response would be to reduce arginine levels to within the normal range. Arginine level has not been formally validated as a surrogate for clinical outcomes in a controlled trial. The evidence supporting the clinical effectiveness of reducing and ideally normalizing plasma arginine is based on understanding of the disease pathophysiology and observational clinical evidence. ARG1-D leads to accumulation of high levels of arginine and metabolites of arginine; therefore, normalization of arginine levels is expected to slow or halt the motor and neurologic deterioration associated with the condition. At the present time, the mechanism of toxicity and the responsible metabolites have yet to be fully defined. In the absence of disease-modifying therapy, standard of care involves strict dietary control and ammonia-salvaging agents, which show modest benefits in most patients according to the clinical experts. Observational evidence in the form of case reports, case series, and longitudinal studies suggests that reductions in plasma arginine, including through restoration of normal liver enzyme function by liver transplant in the eligible few may be associated with improved motor, cognitive, and developmental outcomes at the individual patient level.^10-16

As for clinical outcomes, the clinical experts indicated that the trial duration and follow-up period of 24 weeks were too short to detect clinically meaningful changes in neurologic and neuromotor function (e.g., GMFM-88), adaptive behaviour (VABS-II), neurocognitive outcomes, and dietary management. The 2MWT is validated in both children and adults with cerebral palsy, while GMFM Dimension D and GMFM Dimension E are validated for children and adolescents with cerebral palsy. Spasticity is a prominent symptom of both ARG1-D and cerebral palsy. Also, VABS-II has been validated in children with autism spectrum disorder, typically developing children, and children with other neurodevelopmental disorders such as attention-deficit/hyperactivity disorder and specific learning disabilities. Neither of the key secondary outcomes have been validated on patients with ARG1-D. The health-related quality of life (HRQoL) measure, PedsQL, has been validated in cerebral palsy and other neurologic conditions, but not in ARG1-D.

Methods for missing data imputation were appropriate, and there were limited missing data for the primary and secondary end points. Changes to end points and analyses made after the start of patient accrual were made following regulatory input, and were not considered a threat to validity.

Multiplicity was adequately controlled across the primary and key secondary end points using a prespecified hierarchical testing procedure. However, the statistical hierarchy failed after the key secondary end points as neither were statistically significant. Consequently, formal hypothesis testing was not conducted for subsequent end points to control the risk of type I error (i.e., incorrectly rejecting the null hypothesis). As a result, findings for these end points should be interpreted as supportive rather than confirmatory evidence.

As of the study completion, 85.7% of patients (n = 18) in the pegzilarginase group and 100% (n = 11) in the placebo group experienced at least 1 important protocol deviation. During the COVID-19 pandemic, dosing was paused in 4 patients and restarted after the pandemic restrictions ended. However, these protocol deviations are unlikely to adversely impact the interpretation of the findings.

External Validity

Overall, the estimands, end points, and outcome measures in the PEACE trial were appropriate and aligned with the study objectives, and several are commonly used in clinical practice. For the primary end point, the use of log-transformed plasma arginine levels was appropriate to address skewness and reduce the influence of extreme values. Nevertheless, these results may be less readily interpretable for clinicians. The reporting of geometric means and relative reduction, as well as the proportions of patients who met the outcome of arginine level normalization, support a more clinically meaningful interpretation of treatment effects.

The PEACE study excluded patients with extreme mobility deficits (i.e., inability to be assessed using the Gillette Functional Assessment Questionnaire or a score of 1 on the Gillette Functional Assessment Questionnaire), those with plasma arginine levels less than 250 µM during screening, and patients aged younger than 2 years. These exclusions may limit the generalizability of the findings to these populations. The clinical experts noted that patients with plasma arginine levels less than or close to 250 µM would be expected to have fewer symptoms; however, treatment would still be pursued to achieve normalization of arginine levels and prevent disease progression. Similarly, the exclusion of patients with very severe disease (e.g., extreme mobility deficits) was considered to further limit generalizability, because these patients would still receive treatment in clinical practice. All in all, the clinical experts noted that by requiring that baseline arginine level to be high, the PEACE trial excluded patients with a less severe enzyme defect; however, by excluding patients who had severe motor and cognitive effects, the trial excluded those with a severe clinical picture. Furthermore, clinical experts consulted by CDA-AMC noted that newborn screening was not evaluated as a subgroup. Patients identified through newborn screening may represent a higher proportion of milder cases and may experience better outcomes due to earlier initiation of supportive treatment. The clinical experts also indicated that, although patients may be identified as having ARG1-D through newborn screening, the risk and timing of subsequent symptom development remain uncertain.

The small overall sample size may further limit generalizability to the broader population of patients with ARG1-D. However, the CDA-AMC review team acknowledges that larger trials may not be feasible given the rarity of the condition. In addition, the 24-week double-blind phase assessed short-term response, whereas patients are expected to remain on treatment long term. As such, extended follow-up is required to fully characterize long-term efficacy and safety.

Results

The key efficacy and harms results and findings from the GRADE assessment are presented in this section. Detailed efficacy and harms results can be found in Appendix 4 in the Supplemental Material document. Although overall survival was considered important to this review, it was not assessed in the PEACE study.

Efficacy

Key results include the following.

Change From Baseline in Log-Transformed Plasma Arginine

• The geometric mean change in log-transformed plasma arginine from baseline to week 24 was 0.244 μM (SD = 1.635 μM) in the pegzilarginase group, and 0.918 μM (SD = 1.371 μM) in the placebo group. The geometric least squares mean difference on the log scale was −1.457 μM (standard error = 0.170 μM; P < 0.0001), corresponding to a relative reduction of 76.7% (95% confidence interval [CI] −67.1% to −83.5%) with pegzilarginase compared to placebo.

Proportion of Patients With Plasma Arginine Levels Between 40 μM and 115 μM

• A total of 19 patients (90.5%) in the pegzilarginase group and no patients in the placebo group experienced arginine levels within normal range (40 μM to 115 μM) at week 24. This end point was not formally tested due to earlier failure of the statistical hierarchy.

Mean Change From Baseline in 2MWT, GMFM Dimension D Score, and GMFM Dimension E Score

• The mean change in 2MWT from baseline to week 24 was 7.3 m (SD = 30.64 m) in the pegzilarginase group, and 2.7 m (SD = 19.66 m) in the placebo group. The least squares mean difference was 5.5 (95% CI, −15.6 to 26.7; P = 0.5961).

• The mean change in the GMFM Dimension E score from baseline to week 24 was 4.2 (SD = 7.69) in the pegzilarginase group, and −0.4 (SD = 6.20) in the placebo group. The least squares mean difference was 4.6 (95% CI, −1.1 to 10.2; P = 0.1087).

• The mean change in the GMFM Dimension D score from baseline to week 24 was 2.7 (SD = 3.88) in the pegzilarginase group, and 0.4 (SD = 0.97) in the placebo group. The least squares mean difference was 2.2 (95% CI, −0.4 to 4.9; P = 0.0904). This end point was not formally tested due to earlier failure of the statistical hierarchy.

Mean Change From Baseline in Parent Report Transformed PedsQL Domain Scores

• The mean change in parent report transformed PedsQL physical functioning score at week 24 was −0.22 (SD = 30.806) in the pegzilarginase group, and −4.69 (SD = 16.396) in the placebo group.

• The mean change in parent report transformed PedsQL emotional functioning score at week 24 was 7.86 (SD = 19.973) in the pegzilarginase group, and −11.04 (SD = 19.404) in the placebo group.

• The mean change in parent report transformed PedsQL social functioning score at week 24 was 4.23 (SD = 19.984) in the pegzilarginase group, and −8.33 (SD = 22.061) in the placebo group.

• The mean change in parent report transformed PedsQL school functioning score at week 24 was −4.99 (SD = 17.058) in the pegzilarginase group, and −13.33 (SD = 18.619) in the placebo group.

• The mean change in parent report transformed PedsQL overall score at week 24 was 3.33 (standard error = 3.294) in the pegzilarginase group, and −13.89 (standard error = 5.257) in the placebo group. The between-group difference was 17.23 (95% CI, 4.13 to 30.33).

Mean Change From Baseline in VABS-II Scores

• The mean change in VABS-II composite score from baseline to week 24 was 1.4 (SD = 16.54) in the pegzilarginase group, and −1.6 (SD = 8.78) in the placebo group. The least squares mean difference was 4.9 (95% CI, −3.8 to 13.7; P = 0.2557).

• The mean change in VABS-II communication domain score from baseline to week 24 was −2.4 (SD = 6.29) in the pegzilarginase group, and −4.7 (SD = 8.43) in the placebo group. The least squares mean difference was 2.2 (95% CI, −3.0 to 7.4; P = 0.3858).

• The mean change in VABS-II daily living skills domain score from baseline to week 24 was −1.1 (SD = 6.90) in the pegzilarginase group, and −0.8 (SD = 10.76) in the placebo group. The least squares mean difference was 0.3 (95% CI, −6.4 to 6.9; P = 0.9390).

• The mean change in VABS-II socialization domain score from baseline to week 24 was −4.9 (SD = 12.31) in the pegzilarginase group, and −0.2 (SD = 10.56) in the placebo group. The least squares mean difference was −0.5 (95% CI, −9.6 to 8.7; P = 0.9171).

• The mean change in VABS-II motor skills domain score from baseline to week 24 was 21.6 (SD = 72.42) in the pegzilarginase group, and 6.5 (SD = 9.19) in the placebo group. The least squares mean difference was 16.0 (95% CI, −133 to 165.2; P = 0.8012).

Results for the following supportive outcomes are in Appendix 4 in the Supplementary Material document: change from baseline in ornithine at 24 weeks, proportion of patients who achieved response to composite mobility (2MWT, GMFM Dimension D, and GMFM Dimension E) at 24 weeks, change from baseline in functional mobility scales at 24 weeks, Wechsler Intelligence Scales at 24 weeks, growth assessments, and diets/dietary disease management.

Harms

Key results include the following.

• At least 1 AE was reported for 86% (18 of 21) of patients in the pegzilarginase group and 100% (11 of 11) of patients in the placebo group. The most common AEs were vomiting (29% in the pegzilarginase group versus 27% in the placebo group); infections and infestations (38% in the pegzilarginase group versus 0% in the placebo group); nervous system disorders (24% in the pegzilarginase group versus 27% in the placebo group); respiratory, thoracic, and mediastinal disorders (24% in the pegzilarginase group versus 18% in the placebo group); and general disorders and administration site conditions (33% in the pegzilarginase group versus 0% in the placebo group).

• At least 1 serious AE was reported for 19% of patients in the pegzilarginase group and 36% in the placebo group. The most common serious AEs in both groups were hyperammonaemia (10% in the pegzilarginase group versus 27% in the placebo group), hyperammonemic encephalopathy (5% in the pegzilarginase group versus 9% in the placebo group), and vomiting (5% in the pegzilarginase group versus 0% in the placebo group).

• No patients reported an AE that led to study drug discontinuation.

• No patients had a fatal AE during the double-blind phase of the PEACE study.

• The clinical experts consulted by CDA-AMC and/or the sponsor identified the following AEs of special interest for the treatment with pegzilarginase.

• Hypersensitivity reactions (defined as the occurrence of symptoms, as assessed by the investigator, that are considered consistent with a hypersensitivity reaction related to study drug administration) occurred in 10% of the pegzilarginase group versus 0% of the placebo group.

• Hyperammonemic episodes (defined as a patient with a confirmed ammonia level ≥ 100 μM and ≥ 1 symptoms related to hyperammonemia requiring hospitalization or emergency department management, with or without admission to the hospital) occurred in 14% of the pegzilarginase group versus 36% of the placebo group. The absolute between-group risk difference for pegzilarginase versus placebo was −22.08 (95% CI, −54.20 to 10.05).

• No injection site reactions were reported in either group.

• Details of the results can be found in Appendix 4 in the Supplemental Material document.

Summary of Findings and Certainty of the Evidence

Literature-based minimum important difference (MID) estimates were used as the thresholds for the outcome of change from baseline in VABS-II composite score at 24 weeks (MID = ≥ 7.5-point improvement; details of the summary of outcome measures can be found in Appendix 3 of the Supplemental Material document). The clinical experts were unable to suggest a specific threshold for a clinically important effect for change from baseline in plasma arginine at 24 weeks and proportion of patients with arginine levels of 40 μM to 115 μM at 24 weeks. However, with their input, the review team judged whether the point estimates and relevant bounds of the CI represented clinically important effects. In the absence of a known threshold, the certainty in the presence of a non-null effect was rated for change from baseline in 2MWT at 24 weeks; change from baseline in GMFM-88, Dimension E score at 24 weeks; change from baseline in GMFM-88, Dimension D score at 24 weeks; change from baseline in PedsQL overall score at 24 weeks; and incidence of hyperammonemic episodes at 24 weeks.

Table 4: Summary of Findings for Pegzilarginase vs. Placebo for Patients With ARG1-D

2MWT = 2-minute walk test; ARG1-D = arginase 1 deficiency; CDA-AMC = Canada's Drug Agency; CI = confidence interval; GMFCS = Gross Motor Function Classification System; GMFM = Gross Motor Function Measure; HRQoL = health-related quality of life; MID = minimal important difference; NA = not available; NR = not reported; RCT = randomized controlled trial; RR = risk ratio; SE = standard error; VABS-II = Vineland Adaptive Behavior Scales II; vs. = versus.

^aThere is no established between-group MID for any of the measurements used in the trial to assess change in plasma arginine, and the clinical experts consulted by CDA-AMC could not suggest thresholds of importance. Although no formal threshold exists, experts agreed that even the lower bound of the 95% CI for both the between-group difference in change from baseline to week 24 in log-transformed plasma arginine (67.1%) and the proportion of patients experiencing a response with arginine levels within normal range (670 more per 1,000) would be considered clinically meaningful, supporting the conclusion that the observed treatment effects are clinically important. Although the sample size was small and the estimates are likely unstable, the magnitude of the benefits observed with pegzilarginase on plasma arginine in the PEACE trial was large and constant, and showed objective biomarker improvement over 24 weeks that was absent in patients receiving placebo and that is typically not observed in the natural disease trajectory of ARG1-D. Plasma arginine level is a surrogate outcome that is indicative of treatment response in clinical practice; the relationship between arginine levels and improvements in hard clinical outcomes has not been formally validated. The proportion of patients experiencing a response with arginine levels within normal range was not formally tested due to failure of the statistical hierarchy.

^bRated down 2 levels for very serious imprecision. There is no established between-group MID for the 2MWT at week 24, and the clinical experts consulted by CDA-AMC could not suggest a threshold of importance. The certainty of evidence assessment focused on whether there was any effect relative to the null. The 95% CI for the difference between groups included benefit, harm, and no difference. Given the small sample size (N = 29), the effect estimate is likely unstable.

^cRated down 2 levels for serious imprecision and serious indirectness. There is no established between-group MID for the GMFM Dimension E score at week 24, and the clinical experts consulted by CDA-AMC could not suggest a threshold of importance. The sponsor provided MID values of change of 4.0, 2.8, and 1.8 points in GMFCS I, II, and III, respectively; however, the MID value for the overall population was not available. The certainty of evidence assessment focused on whether there was any effect relative to the null. The 95% CI for the difference between groups included benefit, harm, and no difference. Given the small sample size (N = 31), the effect estimate is likely unstable. Moreover, the certainty of the evidence was downgraded by 1 level for serious indirectness, as clinical experts consulted by CDA-AMC indicated that the follow-up duration was insufficient to detect a meaningful difference in the outcome.

^dRated down 2 levels for serious imprecision and serious indirectness. There is no established between-group MID for the GMFM Dimension D score at week 24, and the clinical experts consulted by CDA-AMC could not suggest a threshold of importance. The sponsor provided MID values of change of 2.4, 3.3, and 1.5 points in GMFCS I, II, and III, respectively; however, the MID value for the overall population was not available. The certainty of evidence assessment focused on whether there was any effect relative to the null. The 95% CI for the difference between groups included benefit, harm, and no difference. Given the small sample size (N = 30), the effect estimate is likely unstable. Moreover, the certainty of the evidence was downgraded by 1 level for serious indirectness, as clinical experts consulted by CDA-AMC indicated that the follow-up duration was insufficient to detect a meaningful difference in the outcome. This outcome was not formally tested due to failure of the statistical hierarchy.

^eRated down 2 levels for serious imprecision and serious indirectness. The sponsor provided an MID value of a ≥ 7.5-point improvement. Certainty was rated down 1 level for imprecision because the point estimate and upper bound of the 95% CI for the difference between groups included a clinically important benefit, and the lower bound included no difference based on a 7.5-point threshold. Given the small sample size (N = 28), the effect estimate is likely unstable. Moreover, the certainty of the evidence was downgraded by 1 level for serious indirectness, as clinical experts consulted by CDA-AMC indicated that the follow-up duration was insufficient to detect a meaningful difference in the outcome.

^fRated down 1 level for serious imprecision. There is no established between-group MID for the PedsQL overall score at week 24. The sponsor provided an MID value of change of 4 to 5 points in pediatric patients with chronic health conditions based on previous CDA-AMC reimbursement reviews. Certainty was rated down 1 level given that the lower bound of the 95% CI for the difference between groups (4.13 points) included the possibility of no difference based on the more stringent threshold. Given the small sample size (N = 29), the effect estimate is likely imprecise and unstable, as reflected by the wide CI.

^gRated down 2 levels for very serious imprecision. There is no established between-group MID for the incidence of hyperammonemic episodes at week 24, and the clinical experts consulted by CDA-AMC could not suggest a threshold of importance. The certainty of evidence assessment focused on whether there was any effect relative to the null. The 95% CI for the difference between groups included benefit, harm, and no difference. Given the small sample size (N = 32), the effect estimate is likely imprecise and unstable, as reflected by the wide CI. Also, the number of events does not meet the optimal information size.

Source: PEACE Clinical Study Report (2024).⁷

LTE Studies

The PEACE trial included an LTE period that directly followed the 24-week double-blind randomized phase. The LTE period from the PEACE study, conducted over a study period of 150 weeks, has been summarized to provide evidence regarding long-term efficacy and harms outcomes.

Eligible participants were patients with a documented diagnosis of ARG1-D and elevated plasma arginine levels (≥ 250 µM), who demonstrated assessable clinical deficits during the double-blind period, maintained a prescribed diet, and were on stable doses of concomitant medications. Thirty-one patients who completed the double-blind phase entered the LTE period, including 20 patients previously treated with pegzilarginase and 11 patients previously treated with placebo. During the LTE, all patients received pegzilarginase, administered weekly. Patients previously treated with pegzilarginase continued their optimized dose from the double-blind phase. Patients previously receiving placebo transitioned to pegzilarginase at 0.10 mg/kg, with dose adjustments based on predose plasma arginine levels. Treatment was initially administered IV with the option to transition to SC administration after an initial blinded treatment period of 8 weeks. The outcomes of the LTE, assessed 168 hours post dose every 1 week and 12 weeks for blood chemistry (arginine and ornithine) and motor function outcomes, respectively, were the same as those evaluated during the double-blind database phase.

Results were reported descriptively without formal statistical testing. There was no imputation of missing data.

Patient Disposition

All 31 patients completing the double-blind period continued into the LTE period (20 in the pegzilarginase-to-pegzilarginase group, 11 in the placebo-to-pegzilarginase group) and were still receiving treatment by the time the study was terminated. There were no study discontinuations during the LTE period.

Baseline Characteristics

Baseline characteristics were not reassessed during the LTE phase; however, baseline values for disease-specific outcome measures evaluated in the LTE are reported within the results section.

Exposure to Study Treatments

Study Treatments

The median treatment exposure and duration in the LTE phase were 94.0 weeks and 96.9 weeks, respectively, and similar in both groups. More than 90% of patients had dosing compliance of 80% or higher. Treatment-emergent AE–related dose interruptions were reported in 45.2% of patients in total; however, there was no discontinuation of study treatment due to treatment-emergent AEs in the LTE period.

Details of patients’ treatment exposure and adherence in the included study are in Appendix 5 of the Supplemental Material document.

Concomitant Medications and Cointerventions

All patients (100%) received at least 1 concomitant medication. The most frequently reported category was various alimentary tract and metabolism products (90.6%). Nutritional and metabolic supportive therapies were commonly used, including combinations of amino acids, carbohydrates, minerals, and vitamins (65.6%); multivitamins with minerals (28.1%); general nutrients (25.0%); amino acids and derivatives (12.5%); and combinations of fat, carbohydrates, proteins, minerals, and vitamins (9.4%). Analgesics (anilides) were reported in 40.6% of patients, including acetaminophen and paracetamol. Other commonly reported medications included antiepileptics (25.0%), centrally acting agents (21.9%), and antihistamines for systemic use (12.5%).

The use of concomitant medications throughout the double-blind and LTE study phases of the PEACE trial is described in Appendix 4, Table 10.

Critical Appraisal

Internal Validity

The study population consisted of patients who completed the double-blind phase and were considered by investigators to have derived clinical benefit from pegzilarginase. Consequently, patients who did not experience a response or who experienced unacceptable toxicity were systematically excluded, resulting in a reduced sample size and the introduction of selection bias.

Outcomes were reported descriptively, and no formal hypothesis testing was conducted, limiting the ability to assess statistical significance of observed changes. Substantial missing data further limited the reliability and interpretability of long-term outcomes, particularly for key efficacy and safety end points. Indeed, the number of patients contributing data decreased to less than 10 at later follow-up time points (particularly after weeks 96 and 120) due to varying durations of follow-up before study closure, which may limit the interpretability of longer-term outcomes.

The single-arm design of the LTE study does not allow for causal inferences regarding the effect of pegzilarginase, as there is no comparator group to contextualize observed outcomes. Knowledge of treatment received may introduce bias in the perception of treatment benefit, particularly for outcomes that are subjective in measurement and interpretation (e.g., patient-reported outcomes and subjective AEs).

External Validity

Concomitant medications used during the study were generally consistent with standard supportive care therapies in clinical practice in Canada. Finally, the limitations to generalizability identified during the double-blind phase of the PEACE study remain applicable to the open-label extension period.

Results

Efficacy

Key results include the following.

Plasma arginine:

• In the pegzilarginase-to-pegzilarginase group, the mean change from baseline in plasma arginine was −268.7 μM (SD = 81.38 μM; n = 18) at LTE week 24, −289.5 μM (SD = 101.56 μM; n = 16) at LTE week 48, and −270.2 μM (SD = 138.05 μM; n = 7) at LTE week 96. The number of patients included beyond LTE week 96 was small, and results were not reported.

• In the placebo-pegzilarginase group, following the switch to pegzilarginase in LTE week 1, the mean change in plasma arginine was −350.9 μM (SD = 80.38 μM; n = 9) at LTE week 24, −354.2 μM (SD = 79.78 μM; n = 11) at LTE week 48, and −373.7 μM (SD = 77.75 μM; n = 4) at LTE week 96.

Ornithine:

• In the pegzilarginase-to-pegzilarginase group, mean change in ornithine levels was 36.3 μM (SD = 45.40 μM; n = 13) at LTE week 24, 39.8 μM (SD = 38.16 μM; n = 11) at LTE week 48, and 47.7 μM (SD = 17.71 μM; n = 6) at LTE week 96.

• In the placebo-to-pegzilarginase group, mean change in ornithine levels was 58.1 μM (SD = 13.57 μM; n = 7) at LTE week 24, 60.1 μM (SD = 44.06 μM; n = 9) at LTE week 48, and 66.9 μM (SD = 46.59 μM; n = 4) at LTE week 96.

2MWT:

• In the pegzilarginase-to-pegzilarginase group, the mean change in 2MWT was 7.32 m (SD = 30.64 m) at the end of the double-blind period, 22.78 m (SD = 36.69 m; n = 18) at LTE week 24, 20.24 m (SD = 33.81 m; n = 17) at LTE week 48, and 13.90 m (SD = 29.26 m; n = 10) at LTE week 96.

• For the placebo-to-pegzilarginase group, the mean change in 2MWT was −1.13 m (SD = 14.61 m; n = 8) at LTE week 24, 7.50 m (SD = 19.06 m; n = 8) at LTE week 48, and 10.60 m (SD = 19.01 m; n = 5) at LTE week 96.

Mean Change in GMFM Dimension D and GMFM Dimension E Scores:

• In the pegzilarginase-to-pegzilarginase group, the mean change in GMFM Dimension D score from baseline was 2.7 points (SD = 3.88 points) at the end of the double-blind period, 4.21 points (SD = 5.13 points; n = 19) at LTE week 24, 4.89 points (SD = 4.39 points; n = 18) at LTE week 48, and 5.00 points (SD = 4.81 points; n = 10) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean change in GMFM Dimension D score was 1.22 points (SD = 3.19 points; n = 9) at LTE week 24, −1.00 points (SD = 2.06 points; n = 9) at LTE week 48, and 0.67 points (SD = 4.55 points; n = 6) at LTE week 96.

• In the pegzilarginase-to-pegzilarginase group, the mean change in GMFM Dimension E score from baseline was 4.2 points (SD = 7.69 points) at the end of the double-blind period, 7.68 points (SD = 8.63 points; n = 19) at LTE week 24, 8.28 points (SD = 10.32 points; n = 18) at LTE week 48, and 6.80 points (SD = 10.75 points; n = 10) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean change in GMFM Dimension E score was 0.44 points (SD = 4.22 points; n = 9) at LTE week 24, 0.89 points (SD = 2.37 points; n = 9) at LTE week 48, and 4.83 points (SD = 12.43 points; n = 6) at LTE week 96.

Mean Change From Baseline in Parent Report Transformed PedsQL Domain Scores:

• In the pegzilarginase-to-pegzilarginase group, the mean PedsQL physical functioning score at baseline was 70.11 (SD = 27.393; n = 16). The mean change from baseline was −6.24 (SD = 38.736; n = 13) at LTE week 24, −3.81 (SD = 39.419; n = 9) at LTE week 48, and 18.75 (SD = 4.426; n = 2) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean PedsQL physical functioning score at baseline was 55.47 (SD = 13.120; n = 8). The mean change from baseline was −2.61 (SD = 34.648; n = 6) at LTE week 24, −5.75 (SD = 26.171; n = 5) at LTE week 48, and no data were available at LTE week 96.

• In the pegzilarginase-to-pegzilarginase group, the mean PedsQL emotional functioning score at baseline was 65.31 (SD = 16.680; n = 16). The mean change from baseline was 4.62 (SD = 25.533; n = 13) at LTE week 24, −13.33 (SD = 29.686; n = 9) at LTE week 48, and 10.00 (SD = 0.0; n = 2) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean PedsQL emotional functioning score at baseline was 57.34 (SD = 21.655; n = 8). The mean change from baseline was 9.38 (SD = 26.830; n = 6) at LTE week 24, 8.25 (SD = 17.491; n = 5) at LTE week 48, and no data were available at LTE week 96.

• In the pegzilarginase-to-pegzilarginase group, the mean PedsQL social functioning score at baseline was 69.69 (SD = 22.765; n = 16). The mean change from baseline was 2.31 (SD = 20.373; n = 13) at LTE week 24, −8.89 (SD = 24.721; n = 9) at LTE week 48, and 7.50 (SD = 3.536; n = 2) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean PedsQL social functioning score at baseline was 56.88 (SD = 17.513; n = 8). The mean change from baseline was 4.17 (SD = 18.280; n = 6) at LTE week 24, −5.00 (SD = 15.000; n = 5) at LTE week 48, and no data were available at LTE week 96.

• In the pegzilarginase-to-pegzilarginase group, the mean PedsQL school functioning score at baseline was 70.66 (SD = 20.610; n = 15). The mean change from baseline was −2.63 (SD = 24.895; n = 12) at LTE week 24, −3.95 (SD = 17.508; n = 8) at LTE week 48, and −7.50 (SD = 3.536; n = 2) at LTE week 96.

• In the placebo-to-pegzilarginase group, the mean PedsQL school functioning score at baseline was 43.13 (SD = 11.319; n = 8). The mean change from baseline was 11.67 (SD = 24.221; n = 6) at LTE week 24, 18.00 (SD = 22.249; n = 5) at LTE week 48, and no data were available at LTE week 96.

Harms

• All patients in both groups experienced at least 1 treatment-emergent AE (100.0%). Treatment-emergent AEs leading to dose interruption occurred in 40.0% of patients in the pegzilarginase-to-pegzilarginase group and 54.5% in the placebo-to-pegzilarginase group, while dose reductions were infrequent (5.0% and 9.1%, respectively).

• No treatment-emergent AEs led to treatment discontinuation or death.

• AEs of special interest occurred in 20.0% and 45.5% of patients, respectively. Hyperammonemic episodes were reported in 5 patients in the placebo-to-pegzilarginase group (45.5%) and in 2 patients in the pegzilarginase-to-pegzilarginase group (10.0%), while injection site reactions occurred in 2 (10.0%) and 1 (9.1%) patients, respectively. No hypersensitivity reactions were reported.

Detailed results for harms are presented in Appendix 5 in the Supplemental Material document.

Indirect Evidence

No indirect treatment comparisons were provided by the sponsor. In Canada, the current standard of care treatment for patients with ARG1-D includes BSC therapies including the use of nitrogen scavenger therapy, protein-restricted and calorie-enriched diets, supplementation with essential amino acids, and ornithine supplementation. Their use is largely guided by international expert consensus and current guidelines. The PEACE trial evaluated pegzilarginase versus placebo in a population where nearly all patients were receiving background therapy with BSC as concomitant medications. Based on the current evidence and expert opinion, pegzilarginase is a novel disease-modifying therapy; there are no other drugs in Canada approved for the treatment of ARG1-D.

Studies Addressing Gaps in the Systematic Review Evidence

Studies addressing gaps in the systematic review include 1 phase I/II open-label and single-arm study, the open-label extension of this study, and 1 observational study These studies were summarized to provide additional evidence on the long-term efficacy and safety of pegzilarginase, its effects on motor function outcomes, and its real-world effectiveness. The following table (Table 5) summarizes these studies and the evidence gaps they aim to address.

Table 5: Summary of Gaps in the Systematic Review Evidence

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

Table 6: Characteristics of Studies Addressing Gaps in Systematic Review Evidence

6MWT = 6-minute walk test; ADA = antidrug antibody; ARG1-D = arginase 1 deficiency; BBS = Berg Balance Scale; GMFM = Gross Motor Function Measure; MAS= Modified Ashworth Scale; PEG = polyethylene glycol; QoL = quality of life; RBC = red blood cell; SC = subcutaneous.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Study 101A and Study 102A

Patient Disposition

In Study 101A, 17 patients were screened and of these, 16 were eligible and received up to 24 weeks of treatment in part 1. More than 93% who completed treatment in part 1 went on to receive up to 13 weeks of treatment in part 2 for a total follow-up of 37 weeks. A total of 14 patients (87.5%) completed both parts of Study 101A; 2 withdrawals from the studies were not related to treatment and consent was withdrawn for personal reasons (i.e., focusing on high school and unexpected death of a family member).

All 14 patients who completed Study 101A were enrolled and treated in Study 102A. Thirteen patients completed Study 102A; 1 patient discontinued after their parent reported being dissatisfied with the medical care received from the hospital. Patients in Study 102A were followed up for up to 144 weeks.

Baseline Characteristics

The mean age of patients was 15 years, and the median age at diagnosis was 1.0 year (mean not reported). Limb spasticity was reported in 12 (75%) of patients and the symptom was considered moderate or severe in 9 (56%) patients. Developmental delays were evident in 9 (56%) patients. At baseline, 14 (88%) patients had a baseline deficit in the 6-minute walk test, 8 (50%) patients had a baseline deficit in GMFM Dimension D, and 9 (56%) had a baseline deficit in GMFM Dimension E. Plasma arginine levels were elevated in all patients (median = 389 μM). Seven (44%) patients had abnormal ammonia. A history of hyperammonemic episodes was present in 7 (44%) patients. Seven (44%) patients had a history of seizures. All patients were managed with dietary protein restriction and essential amino acid supplementation, and 14 (88%) patients were taking ammonia scavengers. There were 2 patients taking antiepileptic therapy and 4 patients receiving baclofen. Detailed baseline characteristics are presented in Appendix 6 in the Supplemental Material document.

Exposure to Study Treatments

Study 101A was a dose-finding study. Of the planned dose levels in part 1 (0.015 mg/kg, 0.03 mg/kg, 0.06 mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, and 0.30 mg/kg), all patients received the lowest dose of 0.015 mg/kg and no patients received 0.15 mg/kg or the highest dose of 0.30 mg/kg. In part 2 of the study, 13 of the 15 enrolled patients had doses administered without interruption; 2 patients had a dose interruption due to AEs. The goal of part 2 was to establish a dose regimen that achieved plasma arginine levels between 40 µM and 115 µM during repeat-dose administration, with emphasis on maintaining predose levels between 150 µM to 200 µM.

Doses in Study 102A ranged from 0.03 mg/kg to 0.2 mg/kg, with most participants maintaining their initial dose or remaining within 0.03 mg/kg of their initial Study 102A dose throughout the treatment period. The mean exposure to pegzilarginase IV and SC administration was 212 weeks. No dose reduction was required due to AEs. Detailed treatment exposure for 102A is presented in Appendix 6 in the Supplemental Material document.

Critical Appraisal

Internal Validity

Both Study 101A and Study 102A were open-label, single-arm studies without a comparator group, which limits the ability to attribute observed effects to pegzilarginase. The sample size was small (N = 16 in Study 101A and N = 14 in the extension study), reducing the precision of estimates. In addition, the studies were not designed to formally test hypotheses and results were reported descriptively, limiting the ability to draw definitive conclusions regarding treatment effects based on the collected data. The lack of blinding may also introduce performance and outcome assessment bias, particularly for functional end points.

Similar to the PEACE trial, additional limitations relate to the validity and interpretation of study end points. Although the primary outcome (change in plasma arginine) is an objective biochemical measure, its validity as a surrogate for clinically meaningful outcomes has not been established, and the relationship between arginine levels and patient-relevant outcomes remains uncertain. While some functional outcomes (e.g., 2MWT, GMFM, VABS-II) are validated in other populations, none have been validated in patients with ARG1-D, limiting confidence in their applicability.

External Validity

The studies included a small number of patients and were conducted in specialized clinical trial settings, which may limit generalizability to routine clinical practice. In addition, eligibility criteria and study requirements, such as stable dietary management and absence of recent hyperammonemic episodes, may select for a more stable patient population than patients who are in high need of treatment for ARG1-D in clinical practice. Study 102A also included only patients who completed Study 101A, which may further limit the representativeness of the study population.

Results

Efficacy: Study 101A Part 1 — Plasma Arginine

• The mean arginine level decreased from baseline by −74.4 μM (SD = 82.41 μM; n = 16) after dose 1, −95.5 μM (SD = 97.39 μM; n = 15) after dose 2, −168.0 μM (SD = 102.99 μM; n = 10) after dose 3, −220.7 μM (SD = 49.42 μM; n = 4) after dose 4, and −301.2 μM (n = 1) after dose 5.

• The proportion of patients with plasma arginine less than 200 μM ranged from 18.8% (3 of 16) after dose 1 to 26.7% (4 of 15) after dose 2, 30.0% (3 of 10) after dose 3, 25.0% (1 of 4) after dose 4, and 100.0% (1 of 1) after dose 5. Similarly, the proportion of patients with plasma arginine levels less than 115 μM was 13.3% (2 of 15) after dose 2, 10.0% (1 of 10) after dose 3, and 100.0% (1 of 1) after dose 5.

Efficacy: Study 101A Part 2

• Across doses in part 2, mean arginine levels decreased from baseline by −166.2 μM (SD = 120.11 μM; n = 14) after dose 1, −194.0 μM (SD = 129.68 μM; n = 15) after dose 2, −167.7 μM (SD = 136.44 μM; n = 14) after dose 3, −228.2 μM (SD = 118.92 μM; n = 14) after dose 4, −249.3 μM (SD = 99.89 μM; n = 14) after dose 5, −233.3 μM (SD = 150.27 μM; n = 14) after dose 6, −234.2 μM (SD = 114.83 μM; n = 14) after dose 7, and −253.5 μM (SD = 106.52 μM; n = 14) after dose 8.

• The proportion of patients with arginine levels between 40 μM and 115 μM was 7.1% (1 of 14) after dose 1, 33.3% (5 of 15) after dose 2, 21.4% (3 of 14) after dose 3, 28.6% (4 of 14) after dose 4, 42.9% (6 of 14) after dose 5, 35.7% (5 of 14) after dose 6, 50.0% (7 of 14) after dose 7, and 42.9% (6 of 14) after dose 8.

Efficacy: Study 102A

• Mean plasma arginine change from baseline was −186.7 μM (SD = 88.56 μM; n = 12) at week 144, −147.1 μM (SD = 100.60 μM; n = 9) at week 168, and −186.9 μM (SD = 84.20 μM; n = 9) at week 192. Detailed results from all time points are presented in Appendix 6 in the Supplemental Material document.

Efficacy: Study 102A Part 1 — 6-Minute Walk Test, GMFM Dimension D Score, and GMFM Dimension E Score

• The mean 6-minute walk test distance change from baseline was 58.2 m (SD = 73.81 m; n = 12) at week 144 and 63.8 m (SD = 87.37 m; n = 12) at final follow-up. Detailed results from all time points are presented in Appendix 6 in the Supplemental Material document.

• The mean GMFM Dimension D score change from baseline was 3.9 points (SD = 7.34 points; n = 12) at week 144 and 4.5 points (SD = 7.59 points; n = 12) at final follow-up. Detailed results from all time points are presented in Appendix 6 in the Supplemental Material document.

• The mean GMFM Dimension E score change from baseline was 4.9 points (SD = 21.82 points; n = 12) at week 144 and 6.4 points (SD = 22.60 points; n = 12) at final follow-up. Detailed results from all time points are presented in Appendix 6 in the Supplemental Material document.

Harms

• All patients (100%) experienced at least 1 treatment-emergent AE. The most commonly reported treatment-emergent AEs (≥ 15% of patients) were cough (78.6%); vomiting (57.1%); headache (50.0%); and abdominal pain upper, ammonia increased, COVID-19, hyperammonemia, nasopharyngitis, and nausea (each 42.9%). Other frequently reported events included constipation and upper respiratory tract infection (35.7% each); gastroenteritis and pyrexia (28.6% each); and arthralgia, decreased appetite, and diarrhea (21.4% each).

• Serious treatment-emergent AEs were reported in 8 (57.1%) patients. Reported serious treatment-emergent AEs included hyperammonemia in 5 patients (35.7%); gastroenteritis and respiratory syncytial virus infection in 2 patients (14.3% for each); and posttraumatic headache, vomiting, ammonia increased, liver function test increased, aspartate aminotransferase increased, abdominal pain, pain, and respiratory tract infection in 1 patient each (7.1% each).Treatment-emergent AEs leading to dose interruption were reported in 57.1% of patients (46 events), while no treatment-emergent AEs led to dose reduction, discontinuation of pegzilarginase, or death.

French Early Access Program

Patient Disposition

A total of 16 patients were enrolled in the French Early Access Program, including 10 patients who were naive to treatment and 6 patients who had previously participated in the PEACE clinical trial. One treatment-naive patient discontinued pegzilarginase after 69 weeks due to lack of efficacy, while all other patients continued receiving treatment at the time of reporting.

Baseline Characteristics

The mean age was 11.5 years (range = 3.0 years to 29.3 years). All patients followed a protein-restricted diet, and 87.5% received nitrogen scavenger therapy. At baseline, 60% of patients were shorter than normal for their age and sex (≤ −2 SD). Severe height deviations (≤ −3 SD) were seen in 44.4% of patients who were naive to treatment but none in the patients who had previously participated in the PEACE clinical trial. No patient was taller than the median height for their age and sex. Body mass index was normal for 87.5% of patients, with 12.5% underweight. Despite a therapy gap where patients who had previously participated in the PEACE clinical trial discontinued pegzilarginase for 4 to 6 weeks, baseline plasma arginine levels remained low in these patients (mean = 168 μmol/L), while it was higher in patients who were naive to treatment (mean = 430 μmol/L; P < 0.001). Detailed baseline characteristics are presented in Appendix 6 in the Supplemental Material document.

Exposure to Study Treatments

The mean pegzilarginase dose remained stable over time. At 12 months, the mean dose was 0.14 mg/kg/week (range = 0.05 mg/kg/week to 0.23 mg/kg/week). All patients who had previously participated in the PEACE clinical trial had transitioned from IV to SC administration during the PEACE study and continued with SC injections upon restarting treatment. Patients who are naive to treatment began with IV administration and transitioned to SC administration within 2 to 12 months. Detailed treatment exposures are presented in Appendix 6 in the Supplemental Material document.

Critical Appraisal

Internal Validity

This prospective cohort study was uncontrolled and lacked a comparator group, which limits the ability to attribute observed changes directly to pegzilarginase. The sample size was small (N = 16), reducing the precision of estimates. In addition, treatment decisions, follow-up assessments, and concomitant therapies were not based on standardized criteria and were determined at the discretion of the treating physician, which may introduce variability in outcome assessment and potential confounding. The study population also included both patients who were naive to treatment and patients previously enrolled in the PEACE clinical trial, which may introduce heterogeneity in baseline characteristics and treatment exposure.

External Validity

The external validity of this study may be limited by the small sample size and the fact that it was conducted within a single country through a French Early Access Program. Patients enrolled through early access programs may not be fully representative of the broader population with ARG1-D in Canada. In addition, the study included both patients who were naive to treatment and patients previously treated in the PEACE clinical trial, which may limit the generalizability of findings to a uniform treatment-naive population. However, as treatment and follow-up were conducted according to routine clinical practice, the study may provide insights into the real-world use of pegzilarginase.

Results

Efficacy

Mean Change in Plasma Arginine

• Efficacy results for plasma arginine levels were reported at 3 months. Mean plasma arginine was 120 μmol/L. Patients with plasma arginine levels less than 200 μmol/L were 93.8% of the population; 81.3% of patients had plasma arginine levels less than 170 μmol/L, and 62.5% of patients had plasma arginine levels less than 115 μmol/L.

Change in Dietary Intake

• Mean dietary protein intake increased from 0.66 mg/kg to 0.89 g/kg/day over 12 months. Essential amino acid intake decreased from 0.33 to 0.26 g/kg/day (n = 3; variability not reported).

Change in PedsQL Score

• Patient-reported PedsQL total score changed from 74.9 to 78.4 in 12 months (n = 6; variability not reported). Caregiver-reported total score changed from 60.4 to 64.5 (n = 11; variability not reported). School and work functioning changed from 63.5 to 84.0, and physical functioning changed from 54.8 to 63.1 (n = 11; variability not reported).

Harms

• Five adverse drug reactions, defined as AEs suspected to be related to pegzilarginase, were reported in 4 patients; no serious adverse drug reactions were reported. One case of vomiting resolved following dose reduction.

• One patient experienced hyperammonemia (plasma ammonia = 125 μmol/L) requiring hospitalization; the event was resolved.

Discussion

Efficacy

The PEACE trial evaluated the effects of pegzilarginase on plasma arginine levels; neurologic, neuromotor, and neurocognitive function; adaptive behaviour; HRQoL; growth; and evolution of dietary management. These efficacy outcomes align with patient-identified priorities, including controlling plasma arginine levels; preventing neurologic deterioration; improving or stabilizing the decline in mobility, cognitive function, and overall daily functioning; reducing symptoms such as spasticity, seizures, and fatigue; and decreasing reliance on strict dietary restrictions. In the current absence of disease-modifying therapy, standard of care involves strict control of dietary arginine and other amino acids, an approach that is burdensome for patients and caregivers and associated with modest reductions in arginine levels and limited impact on disease manifestations.

The primary end point of the trial (change in plasma arginine levels) is a surrogate end point that is indicative of treatment response in clinical practice rather than a direct clinical outcome. According to the clinical experts, an optimal response would be to reduce arginine levels to within the normal range; because ARG1-D is driven by a toxic accumulation of arginine and its neurotoxic metabolites due to arginase 1 enzyme deficiency, normalization of arginine levels is expected to halt disease progression and prevent further neurologic deterioration. To that effect, the clinical experts noted that slowing disease progression is in itself a treatment goal, as ARG1-D is known to cause irreversible neuromotor and neurocognitive damage. Observational evidence suggests that reductions in plasma arginine at the individual patient level may be associated with longer-term, patient-relevant clinical outcomes; however, the relationship between arginine levels and improvements in hard clinical outcomes has not been formally validated.¹⁰ Although surrogate measures are commonly used in rare disease trials due to feasibility constraints, where it is not practical to enrol large cohorts and follow them for many years to capture hard clinical outcomes, they highlight an evidence gap regarding how patients feel, function, or survive.

Based on results of the PEACE trial, pegzilarginase results in a clinically important reduction in plasma arginine levels when compared with placebo. There is no established between-group MID for log-transformed plasma arginine or relative reduction. The clinical experts agreed that even the lower bound of the 95% CI for the between-group difference (67.1%) would be considered clinically meaningful, suggesting a clinically important benefit. The experts noted, however, that the proportion of patients experiencing arginine levels within the normal range may represent a more clinically meaningful outcome for decision-making. Findings from the PEACE trial suggest that pegzilarginase results in a clinically important increase in the proportion of patients experiencing a response resulting in arginine levels within normal range (40 μM to 115 μM) at week 24 when compared with placebo. A total of 19 patients (90.5%) in the pegzilarginase group and no patients in the placebo group experienced this level of response; the absolute between-group risk difference for pegzilarginase versus placebo was 84.5% (95% CI, 67.0% to 100.0%). This end point was not formally tested due to earlier failure of the statistical hierarchy. The relatively small sample size may introduce some uncertainty regarding the true magnitude of effect, as small studies may yield unstable estimates and may also overestimate treatment effects due to chance.¹⁷ However, the CDA-AMC review team acknowledges the challenges of recruiting larger cohorts given the rarity of ARG1-D. In addition, the magnitude of the benefits observed with pegzilarginase on plasma arginine in the PEACE trial was large and constant, showing a marked improvement over 24 weeks that is typically not observed in the natural disease trajectory of ARG1-D and as such, could not be achieved in patients receiving placebo.

Pegzilarginase may result in little to no difference in neurologic, neuromotor, and neurocognitive function, as measured using the 2MWT, GMFM Dimension E, and GMFM Dimension D, as well as little to no difference in adaptive behaviour based on the VABS-II, when compared with placebo. Notably, small sample size and patient heterogeneity result in small changes accompanied by large SDs and/or standard errors, making it difficult to detect subtle differences. Most importantly, for these clinical outcomes, the clinical experts indicated that the trial duration and follow-up period of 24 weeks were too short to detect a clinically meaningful change. The experts noted that meaningful improvements in development, cognitive function, mobility, and spasticity may require several months and often years to be observed. However, findings from the PEACE trial showed that pegzilarginase likely results in a clinically important increase in the PedsQL overall score when compared with placebo, based on a change of 4 to 5 points in pediatric patients with chronic health conditions that was used in previous CDA-AMC reimbursement reviews. Patients indicated that they desired improved HRQoL and that it was an important treatment goal. The clinical experts noted that any improvement or no decline of the PedsQL score would be considered clinically meaningful.

Findings from additional outcomes included as supportive evidence were generally consistent with those for the most clinically important outcomes. Ornithine levels appeared to be increased in patients receiving pegzilarginase. A higher proportion of patients in the pegzilarginase group experienced at least a 1-level improvement in the composite clinical outcome (comprising 2MWT, GMFM Dimension D, and GMFM Dimension E) at week 24. Relatively more patients had an increase in the total amount of consumed calories and total protein in the pegzilarginase group than the placebo group at 24 weeks, despite the clinical experts considering 24 weeks to be a short period to observe a meaningful change in diet. Improvements in functional mobility were generally greater in the pegzilarginase group at both the 5-metre and 50-metre thresholds. However, patients in the placebo group seemed to experience a greater change from baseline at the 500-metre threshold, as well as a greater increase from baseline in combined full-scale IQ score at week 24. Several of these outcomes were assessed as exploratory end points and were not powered to show a difference between groups; therefore, results should be interpreted with caution.

The PEACE trial included a noncomparative LTE phase providing data on the long-term efficacy and safety of pegzilarginase beyond 24 weeks. In the absence of formal hypothesis testing, findings are limited to descriptive interpretation. Sustained reductions in plasma arginine were observed following pegzilarginase exposure across both treatment sequences, which is consistent with the results from the double-blinded phase. Improvements in functional outcomes, including 2MWT and GMFM Dimension D and Dimension E domains, were reported; however, the magnitude and consistency of these changes varied across time points. Although the LTE follow-up extended up to more than 2 years, the small and decreasing sample size at later time points and variability in observed changes limit confidence in whether the duration of follow-up was sufficient to demonstrate sustained and clinically meaningful functional improvement beyond LTE week 96. Similarly, VABS-II and PedsQL scores suggested variable and generally modest changes, with no consistent pattern favouring continued pegzilarginase exposure across the 96 weeks of follow-up with a reasonable sample size of patients. Growth parameters and nutritional intake also fluctuated over time without clear trends. Overall, stabilizing the decline in function is an important treatment goal according to the clinical experts; therefore, some signals of potential benefit were observed with pegzilarginase over 96 weeks, especially because there is uncertainty as to how much of the impairment may be reversible. However, the absence of a comparative design does not support causal interpretation of the findings. In addition, the heterogeneity and inconsistent magnitude of changes across multiple end points in a small number of patients limit confidence in the robustness and clinical significance of these findings.

Additional evidence was submitted by the sponsor to provide long-term and supportive evidence for improvement in motor function, as well as real-world evidence regarding effectiveness of pegzilarginase. Evidence from Study 101A and Study 102A is limited to descriptive findings, as no formal hypothesis testing was conducted. Reductions in plasma arginine were observed, including sustained reductions over time in the Study 102A extension. These descriptive findings are consistent with the results of the pivotal trial. However, the absence of a comparator group limits the ability to determine the magnitude of treatment effect relative to standard care or natural disease progression. Improvements in functional outcomes were variable and characterized by fluctuations across time points. The results for the 6-minute walk test were directionally positive across Study 101A and Study 102A. However, these results are limited by substantial variability across outcomes, reflected by large SDs. Confidence in the consistency and reliability of the observed effects is thus limited. Overall, while trends toward functional improvement were reported descriptively, the clinical significance of these findings remains uncertain. Evidence from Study 101A and Study 102A was limited by small sample sizes (N = 14) and variable duration of follow-up. With this sample size, it is not possible to confidently separate true treatment effects from chance findings resulting from random statistical variation. Although the LTE and supportive studies are limited by their design and by uncertainty, they provide supportive evidence in the context of a rare, progressive disease where prolonged placebo-controlled follow-up is constrained by feasibility and ethical considerations.

Findings from the French Early Access Program provided evidence of pegzilarginase effectiveness in a real-world setting, but are limited to descriptive and exploratory analyses, given the absence of a comparator group and small sample size. Reductions in plasma arginine were observed in a high proportion of patients, with many achieving clinically relevant thresholds (i.e., < 200 μmol/L, < 170 μmol/L, and < 115 μmol/L). Changes in nutritional parameters, including increased dietary protein intake and decreased essential amino acid supplementation, were observed over time and may suggest improved metabolic control. However, these findings should be interpreted cautiously due to potential confounding from uncontrolled variables in the real world, systematic biases from the uncontrolled and unblinded design, and small sample sizes. Overall, while the results suggest potential biochemical and patient-reported benefits, the clinical significance remains uncertain.

Harms

Overall, clinical experts concluded that pegzilarginase is considered to have an acceptable and tolerable safety profile, and that there were no major safety concerns identified with pegzilarginase. However, they noted an increased risk of hyperammonemic episodes in this patient population, as evidenced by the results from the PEACE trial. Nonetheless, they indicated that these episodes are typically manageable in clinical practice, and that hyperammonemic episodes are inherent to the disease. The experts also noted that treatment with pegzilarginase would likely be discontinued in the event of an increase in treatment-refractory hyperammonemia. The findings suggest that pegzilarginase may result in little to no difference in the incidence of hyperammonemic episodes when compared with placebo. The estimated difference in incidence between hyperammonemic episodes was 22% less for pegzilarginase, but the CIs incorporated both greater and lesser differences (54% less to 10% more).

The safety profile of pegzilarginase in the longer-term follow-up was consistent with the previously reported data from the double-blind phase of the PEACE trial; no new safety concerns for pegzilarginase were identified with the additional follow-up period. Studies that were submitted to address evidence gaps were very small and therefore could only capture very common harms. The open-label design and absence of a comparator group limit the ability to contextualize the safety profile of pegzilarginase or attribute observed AEs directly to treatment. As such, conclusions regarding long-term safety remain uncertain.

Ethics and Equity Considerations

No information was available in any of the inputs regarding whether any racial or ethnic groups experience a higher prevalence of ARG1-D. In addition, there was limited description of racially and ethnically diverse population groups in the PEACE trial as well as in the additional evidence submitted. Clinical experts consulted by CDA-AMC indicated that findings from these studies are expected to be generalizable to the overall population in clinical practice; however, CDA-AMC notes that the uncertainty regarding this lack of data on the safety and efficacy of pegzilarginase in diverse population groups should be accounted for in clinical decision-making when considering treatment with pegzilarginase in populations or groups not represented in the trials.

In addition, inequities exist, including limited access to metabolic centres and specialized care for people in rural and remote regions, which may delay diagnosis for some patients. Access considerations also include the feasibility of at-home SC administration: while most patients and/or caregivers can self-administer with appropriate training, those with young age, disability, severe visual impairment, or developmental delay may require structured supports (e.g., patient support programs, home nursing, pharmacy-based injection assistance), alongside clear pathways for troubleshooting and safety monitoring.

Given the rarity of ARG1-D, evidence generation is inherently constrained, and it is neither feasible nor ethical to hold these conditions to evidentiary standards typical of common diseases (e.g., large hard-outcome trials). ARG1-D can substantially compromise patients’ autonomy and dignity by limiting their ability to maintain independence and control over daily activities. Persistent symptoms coupled with the demands of strict dietary restrictions, complex medication regimens, and frequent medical appointments, impose significant physical and emotional burdens. These factors often disrupt social engagement and routine responsibilities, diminishing quality of life and contributing to a loss of personal agency. The at-home SC administration of pegzilarginase would potentially reduce travel and time-related burdens for all patients, especially for patients who live in rural and remote areas.

Finally, the potentially high cost of pegzilarginase should be weighed against avoided downstream costs (costs of health care for patients with severe clinical manifestations and early mortality) and the broader impacts on autonomy, dignity, and caregiver burden (time off work, income loss, stress). Funding policies that acknowledge rare disease constraints and support home-based care with adequate training and monitoring are essential to ensure appropriate use and equitable uptake across Canada.

Conclusion

One phase III, randomized, double-blind, placebo-controlled trial (PEACE) provided evidence for the efficacy and safety of pegzilarginase plus individualized disease management in patients aged 2 years and older with ARG1-D. Evidence from the PEACE trial showed that pegzilarginase resulted in a clinically important reduction in plasma arginine levels at 24 weeks compared with placebo. There was a clinically important increase in the proportion of patients experiencing a response resulting in arginine levels within normal range, which, when achieved, is expected to halt disease progression and prevent further neurologic deterioration based on clinician input and observational evidence. The magnitude of the benefits was large and constant, a marked improvement from the natural disease trajectory of ARG1-D. However, the relationship between arginine levels and clinical outcomes has not been formally validated. This remains an evidence gap, and reliance on surrogate measures is common in rare diseases and reflects feasibility challenges in generating evidence. Pegzilarginase likely results in a clinically important increase in HRQoL as measured by the PedsQL overall score when compared with placebo, which was an important treatment goal according to the patient input. In contrast, pegzilarginase may result in little to no difference in neurologic, neuromotor, and neurocognitive function, as measured using the 2MWT, GMFM Dimension E, and GMFM Dimension D, as well as in little to no difference in adaptive behaviour based on the VABS-II, when compared with placebo at 24 weeks. This was anticipated by the clinical experts who noted that meaningful differences between groups in development, cognitive function, mobility, and spasticity could require years of follow-up to be observed. The study population was broadly representative of patients seen in clinical practice in Canada; however, some categories of patients who may benefit from pegzilarginase were excluded according to the clinical experts. Patients in both groups received individualized disease management, which does not address the underlying pathophysiology of the disease.

Results from the LTE phase of the PEACE trial suggested sustained reductions in plasma arginine beyond 24 weeks, and signals of potential benefits in terms of neurologic, neuromotor, and neurocognitive function, as well as in adaptive behaviour; however, the absence of a comparative design does not support causal interpretation of the results and uncertainty limits the robustness of these findings. Study 101A, Study 102A, and the French Early Access Program provided limited supportive evidence of potential efficacy of pegzilarginase for motor outcomes and longer-term efficacy and safety.

Compared with placebo, pegzilarginase may result in little to no difference in the incidence of hyperammonemic episodes at 24 weeks; there was uncertainty due to imprecision and few patients with events. The LTE phase of the PEACE trial supports a consistent safety profile for pegzilarginase during extended follow-up. Studies submitted to address evidence gaps were very small and therefore unlikely to detect harms that are not common. Overall, clinical experts concluded that pegzilarginase is considered to have an acceptable and tolerable safety profile.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of pegzilarginase plus BSC compared to BSC alone for treatment of hyperargininemia in adult and pediatric patients aged 2 years and older with ARG1-D. Pegzilarginase is being reviewed by CDA-AMC through the complex review pathway (scenario 1); as such, CDA-AMC has appraised 2 cost-effectiveness analyses submitted by the sponsor, 1 adopting a publicly funded health care payer perspective and 1 adopting a societal perspective.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of pegzilarginase plus BSC from the perspective of a public health care payer in Canada and from a societal perspective over a lifetime horizon (89 years). The modelled population comprised patients aged 2 years and older diagnosed with ARG1-D, which is aligned with the Health Canada–approved indication and reimbursement request, and was based on the participants in the PEACE trial. The sponsor’s base-case analysis included costs related to drug acquisition, administration, monitoring, health-state–specific health care resource use, hyperammonemic crisis, and 1-time mobility aid cost. The sponsor’s societal base case included additional costs associated with patient and caregiver productivity loss.

In the sponsor’s base case, which adopted a health care payer perspective, pegzilarginase plus BSC was associated with incremental costs of $71,697,531 and 25.56 incremental quality-adjusted life-years (QALYs) relative to BSC alone. This resulted in an incremental cost-effectiveness ratio (ICER) of $2,805,316 per QALY gained. From a societal perspective, the ICER was $2,805,842 per QALY gained. Of the incremental benefit compared to BSC alone (25.56 incremental QALYs), the entirety of the predicted benefit was accrued after the observation period of the PEACE trial (maximum follow-up = 24 weeks). Additional information about the sponsor’s submission is summarized in Appendix 9 of the Supplemental Materials.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 7; full details are provided in Appendix 10 of the Supplemental Materials).

Table 7: Key Issues With the Sponsor’s Economic Submission

BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; GMFCS = Gross Motor Function Classification System; HAC = hyperammonemia crisis; SMR = standardized mortality ratio.

Note: Full details of the issues identified by CDA-AMC are provided in Appendix 10 of the Supplemental Materials.

CDA-AMC Assessment of Cost-Effectiveness

Based on the CDA-AMC Clinical Review, 1 phase III, double-blind RCT (PEACE) provided evidence for the efficacy and safety of pegzilarginase in adults, adolescents, and children aged 2 years and older with ARG1-D. Evidence from the PEACE trial showed that pegzilarginase resulted in a reduction in plasma arginine levels at 24 weeks compared with placebo, and likely increased the proportion of patients experiencing arginine levels within the normal range. While there was little to no difference between pegzilarginase and placebo on functional outcomes such as 2MWT, GMFM Dimension E, GMFM Dimension D, and VABS-II, clinical experts indicated that the trial duration was too short to capture changes in these outcomes. Pegzilarginase likely increased PedsQL overall scores compared with placebo. The trial population was broadly representative of patients seen in clinical practice in Canada; however, some categories of patients who may benefit from pegzilarginase were excluded according to the clinical experts. Although the LTE study suggested potential for sustained efficacy beyond 24 weeks, the absence of a comparative design does not support causal interpretation of the results and uncertainty limits the robustness of these findings. Additional supportive evidence from Study 101A and Study 102A and the French Early Access Program provided limited descriptive evidence of potential efficacy and real-world effectiveness on motor outcomes, reduction of plasma arginine, and long-term safety, but was insufficient to infer any causality due to the uncontrolled and single-arm nature of the studies, as well as limited sample size. While observational evidence suggests that reductions in plasma arginine at the individual patient level may be associated with longer-term, patient-relevant clinical outcomes, the relationship between arginine levels and improvements in hard clinical outcomes has not been formally validated.

Given the degree of uncertainty in the submitted analysis, no base-case cost-effectiveness analysis was considered reliable. This is driven by substantial uncertainty in the clinical evidence, particularly the lack of robust evidence linking treatment to sustained improvements in key outcomes such as motor function and neurocognitive outcomes, and the absence of long-term comparative data to support durability of effect and impact on survival. As a result, the magnitude of the modelled long-term clinical benefit is highly uncertain. In addition, treatment costs are highly uncertain and driven by assumptions on dosing, patient weight distribution, adherence, and vial wastage. In the sponsor’s base case, the incremental costs were primarily driven by the drug acquisition cost of pegzilarginase, and even if the price of pegzilarginase is substantially lowered, treatment with pegzilarginase is still associated with high costs to the health care system due to ongoing disease management and BSC costs during the period of life extension.

Uncertainty and Sensitivity

Uncertainty was explored in the scenario analyses outlined in Table 7. Uncertainty around assumptions regarding duration of treatment effect and hyperammonemia crisis-related mortality had minimal impact on cost-effectiveness (refer to Appendix 9 and Appendix 10 of the Supplemental Materials). Across all scenarios presented by the sponsor and by CDA-AMC, the ICER of pegzilarginase plus BSC compared to BSC alone exceeded $2.6 million per QALY gained.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis to estimate the 3-year (2026 to 2029) budget impact of reimbursing pegzilarginase plus BSC for use in the treatment of ARG1-D, also known as hyperargininemia, in adults, adolescents, and children aged 2 years and older. The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach. The price of pegzilarginase was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Appendix 11 of the Supplemental Materials.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact that could not be addressed. Although the sponsor estimated that the budget impact of reimbursing pegzilarginase plus BSC for use in the indicated population will be approximately $22 million over the first 3 years (estimated expenditure = $25 million), the impact of reimbursing pegzilarginase plus BSC is highly uncertain. The actual budget impact would depend on the number of patients with ARG1-D who would be considered for treatment.

Conclusion

Based on the sponsor’s base case, pegzilarginase plus BSC would be considered cost-effective at the submitted price compared to BSC alone if the public health care system was willing to pay at least $2,805,316 for each additional QALY gained. If the public health care system is not willing to pay that amount, a price reduction should be considered (full details of the impact of price reductions on the ICER are presented in Appendix 10 of the Supplemental Materials). The estimated cost-effectiveness of pegzilarginase plus BSC compared to BSC alone is uncertain due to substantial uncertainty in the clinical evidence supporting long-term impacts on motor and neurocognitive outcomes, as well as duration of treatment effect.

The budget impact of reimbursing pegzilarginase plus BSC to the public drug plans in the first 3 years is estimated to be approximately $22 million. The 3-year expenditure on pegzilarginase plus BSC (i.e., not accounting for current expenditure on comparators) is estimated to be $25 million. The estimated budget impact is highly uncertain due to uncertainty in the number of patients with ARG1-D who will be treated in clinical practice.

References

1.Schlune A, Vom Dahl S, Haussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47(9):1751-62. doi:10.1007/s00726-015-2032-z PubMed

2.Keshavan N, Wood M, Alderson LM, et al. Clinical status, biochemical profile and management of a single cohort of patients with arginase deficiency. JIMD Rep. 2022;63(2):123-130. doi:10.1002/jmd2.12266 PubMed

3.Burlina A, Ardissone A, Battini R, et al. Arginase 1 deficiency: a treatable form of spastic paraplegia. Neurol Sci. 2025;46(9):4219-4228. doi:10.1007/s10072-025-08153-3 PubMed

4.Diaz GA, Bechter M, Cederbaum SD. The role and control of arginine levels in arginase 1 deficiency. J Inherit Metab Dis. 2023;46(1):3-14. doi:10.1002/jimd.12564 PubMed

5.Catsburg C, Anderson S, Upadhyaya N, Bechter M. Arginase 1 Deficiency: using genetic databases as a tool to establish global prevalence. Orphanet J Rare Dis. 2022;17(1):94. doi:10.1186/s13023-022-02226-8 PubMed

6.Haberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. doi:10.1186/1750-1172-7-32 PubMed

7.Immedica Pharma AB. Clinical Study Report: CAEB1102-300A, final. PEACE (pegzilarginase effect on arginase 1 deficiency clinical endpoints): a randomized, double-blind, placebo-controlled phase 3 study of the efficacy and safety of pegzilarginase in children and adults with arginase 1 deficiency [internal sponsor's report]. March 15, 2024.

8.Immedica Pharma AB. CAEB1102-102A, final. An open-label, multicenter study to evaluate the long-term safety, tolerability, and efficacy of AEB1102 in patients with arginase 1 deficiency [internal sponsor's report]. February 20, 2024.

9.Aeglea BioTherapeutics Inc. Clinical Study Report: CAEB-1102-101A, final. A phase 1/2 open-label study in patients with arginase 1 deficiency to investigate the safety, pharmacokinetics, and pharmacodynamics of intravenous AEB1102 [internal sponsor's report]. July 29, 2019.

10.Immedica Pharma AB. Comprehensive review of the literature outlining the relationship between arginine and disease manifestations and progression in arginase 1 deficiency [sponsor supplied reference].

11.Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV. Argininemia. J Pediatr. 1977;90(4):563-8. doi:10.1016/s0022-3476(77)80367-3 PubMed

12.Lambert MA, Marescau B, Desjardins M, et al. Hyperargininemia: intellectual and motor improvement related to changes in biochemical data. J Pediatr. 1991;118(3):420-4. doi:10.1016/s0022-3476(05)82161-4 PubMed

13.Cederbaum SD, Moedjono SJ, Shaw KN, Carter M, Naylor E, Walzer M. Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet. J Inherit Metab Dis. 1982;5(2):95-9. doi:10.1007/bf01800000 PubMed

14.Brockstedt M, Smit LM, de Grauw AJ, van der Klei-van Moorsel JM, Jakobs C. A new case of hyperargininaemia: neurological and biochemical findings prior to and during dietary treatment. Eur J Pediatr. 1990;149(5):341-3. doi:10.1007/bf02171562 PubMed

15.Silva ES, Cardoso ML, Vilarinho L, Medina M, Barbot C, Martins E. Liver transplantation prevents progressive neurological impairment in argininemia. JIMD Rep. 2013;11:25-30. doi:10.1007/8904_2013_218 PubMed

16.Cui B, Wei L, Sun LY, et al. The effect of liver transplantation for argininemia-the largest experiences in a single center. Transl Pediatr. 2022;11(4):495-504. doi:10.21037/tp-21-576 PubMed

17.Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial sample size on treatment effect estimates: meta-epidemiological study. BMJ. 2013;346:f2304. doi:10.1136/bmj.f2304 PubMed