New Weekly Enzyme Treatment for Arginase-1 Deficiency

Loargys (pegzilarginase-nbln) is a weekly recombinant human arginase-1 enzyme replacement. It is not a gene therapy, not a liver transplant, and not a substitute for the protein-restricted diet. It converts plasma arginine to urea and ornithine. ARG1-D (hyperargininemia) is an ultra-rare urea-cycle disorder: the body’s own arginase-1 does not work, arginine stays high, and over years that is associated with spasticity, seizures, developmental delay, and metabolic decompensation.

The FDA granted accelerated approval on 23 February 2026. Health Canada issued a Notice of Compliance on 29 May 2026 — a full NOC, not a Notice of Compliance with Conditions. The European Commission authorised Loargys under exceptional circumstances on 15 December 2023; the UK MHRA followed on 20 December 2023. United States and Canada are the 2026 doors. Europe was already labelled.

This is not a cure. US continued approval depends on a confirmatory trial (PMR 4966-1). EU/UK exceptional circumstances means complete information could not be obtained because the disease is so rare; the agencies review new data every year.

Where this is taking place

Commercial labelled supply (age 2+, metabolic clinic): United States (accelerated), Canada (NOC), European Union (exceptional circumstances), United Kingdom (MHRA). Funding is a separate question everywhere.

PEACE / Trial 1 — NCT03921541 (CAEB1102-300A) — Phase 3, randomised, double-blind, placebo-controlled, COMPLETED. Sponsor: Immedica Pharma AB (Aeglea listed as collaborator / original study sponsor). 32 people, ages 2–29 at enrolment, 2:1 Loargys vs placebo, weekly IV for 24 weeks plus individualised disease management (protein restriction, essential amino acids, ammonia scavengers when used). Open-label extension up to ~150 weeks; after 8 weeks of the extension, subcutaneous dosing was allowed. Canadian site on CT.gov: McGill University Health Center, Montreal, Quebec. That site is completed, not recruiting. Other countries with sites: United States, United Kingdom, Italy, Austria, France, Germany.

NCT02488044 (CAEB1102-101A, Phase 1/2) and NCT03378531 (CAEB1102-102A extension) — COMPLETED. USPI Trial 2 / Trial 3. Canadian site: The Hospital for Sick Children, Toronto, Ontario. Completed, not recruiting.

NCT06582524 (CAEB1102-301A) — Phase 3 open-label in children younger than 24 months. COMPLETED (17 Jun 2025). Sites: Graz (Austria), Lisbon (Portugal), Bradford (United Kingdom). No Canadian sites. Not the labelled indication in the US, Canada, EU, or UK.

There is no recruiting labelled-age ARG1-D pegzilarginase trial on the records checked for this draft. The US confirmatory trial (PMR 4966-1) does not yet have a public NCT on documents retrieved.

Ultra-rare: the practical door is the inherited-metabolic / urea-cycle clinic that already manages the diet, ammonia scavengers, and arginine labs — not a general paediatrician and not Special Access Programme paperwork for a labelled DIN.

Approval matrix (accelerated vs exceptional circumstances, and diet clause, are not the same)

Access by country

• United States: Inherited-metabolic / urea-cycle clinic. FDA-labelled 23 Feb 2026 for hyperargininemia in people 2 years and older with ARG1-D, with dietary protein restriction. Start 0.1 mg/kg once weekly as an IV infusion over at least 30 minutes, in a healthcare setting that can treat anaphylaxis (CPR equipment on hand). After eight weeks of weekly IV, the same milligram dose may move to subcutaneous (abdomen, thigh, or upper arm). Home SC only if maintenance SC is tolerated, still under a healthcare provider. Baseline plasma arginine before the first dose; titrate toward a pre-dose arginine near the upper limit of normal (normal range on the USPI: 40–115 µmol/L); max 0.2 mg/kg weekly. US arginine labs must use Immedica Nor-NOHA tubes and the LOARGYS Arginine Assay — the USPI says the product is only available if the patient is enrolled in Study IMM-PEG-005. Immedica US: 1-844-627-4687 (USPI). No copay dollars here. Prior authorization still applies. Children under 2 are not labelled. This is accelerated approval — clinical benefit is still being confirmed.
• Canada (zoom): Authorized (full NOC) 29 May 2026. DIN 02568713. Ask the metabolic clinic (urea-cycle / inherited metabolic disease) for a prescription — the same clinics that already run the diet. Authorized ≠ funded. CDA-AMC (August 2026) recommended public-plan reimbursement with conditions (age 2+, confirmed ARG1-D, plasma arginine ≥ 250 µmol/L, specialist prescriber, price reduction, 24-week initial authorization). That is a recommendation, not a provincial formulary listing. pCPA status unknown / not confirmed. B.C. PharmaCare: Under Review. Other provinces, territories, NIHB, and RAMQ: listing unknown. SAP is the wrong door for a labelled DIN. Innomar Strategies is the Canadian importer on the PM. Canada medical information on the PM extract: 1-844-576-2707 — medical information, not a copay program. Do not mail-order a US bottle. First sale unknown; DHPP status is Approved, Marketed status not confirmed.
• United Kingdom: MHRA authorised 20 Dec 2023. NICE HST35 (4 Mar 2026) recommends use within the licence if the commercial arrangement is in place; NHS England had a 90-day funding clock from that date. Scotland: SMC2813 is not recommended (non-submission). Ask the metabolic clinic; do not assume NHSScotland funding from an English HST. Start under a physician experienced in inherited metabolic disease. Home injection only after ≥ 8 weeks, stable dose, and low assessed hypersensitivity risk (GB SmPC).
• European Union: EC licence 15 Dec 2023, exceptional circumstances. Metabolic clinic experienced in inherited metabolic diseases. First doses where allergic reactions can be treated. Diet, amino-acid supplements, and nitrogen scavengers continue. Member-state reimbursement is not the EC licence — reimbursement status outside local HTA is unknown. Named-patient import is not a DIY order from a US vial.
• Japan: Orphan designation only (company, 25 Aug 2026). No marketing authorisation / licence confirmed on sources used here.
• Australia: Company TGA filing under evaluation. Not ARTG. Specialist + local special-access / trial only if those programs apply.
• China / Switzerland / other regulators: Authorisation unknown / not confirmed. Do not import on your own.

If your regulator has not authorised it: do not import on your own.

Who is eligible (from the labels — they are not the same)

This is an enzyme-replacement + diet conversation. Diet does not stop because Loargys starts.

United States (USPI):

• Adult or child 2 years of age and older.
• Arginase 1 Deficiency (ARG1-D) with hyperargininemia.
• Used in conjunction with dietary protein restriction.
• Start 0.1 mg/kg actual body weight IV once weekly; titrate by 0.05 mg/kg after two consecutive weekly pre-dose arginine values are outside the desired range (reduce if <50 µmol/L; increase if >150 µmol/L); maximum 0.2 mg/kg weekly.
• Initiate in a monitored healthcare setting (boxed warning).
• Enrolment in Study IMM-PEG-005 for the required arginine assay tubes.
• Not established under age 2. Geriatric: no patients ≥65 in the trials.
• Contraindications: none.

Canada (SBD / Product Monograph indication):

• Adults and pediatric patients aged 2 years and older.
• Hyperargininemia with arginase 1 deficiency (ARG1-D).
• In conjunction with dietary protein restriction.
• DIN 02568713, 5 mg/mL, IV after dilution or SC.
• NOC is a full authorisation, not conditional. Funding is separate.
• Full PM hypersensitivity / contraindication wording: ask the clinic to read the monograph, not this article, for Canadian contraindications.
• CDA-AMC reimbursement recommendation (not the label) would further restrict public coverage to confirmed ARG1-D with plasma arginine ≥ 250 µmol/L and a metabolic specialist — that is HTA, not Health Canada’s indication.

European Union and United Kingdom (SmPC 4.1):

• Adults, adolescents and children aged 2 years and older.
• Arginase 1 deficiency (ARG1-D), also known as hyperargininemia.
• Intended for chronic management in conjunction with individualised disease management (protein restriction, amino-acid supplements, nitrogen scavengers) — that sentence sits in posology.
• Same starting dose 0.1 mg/kg weekly; increments of 0.05 mg/kg; doses above 0.2 mg/kg/week not studied.
• Contraindication: severe hypersensitivity to pegzilarginase or any excipient (this is not the US line).
• Not recommended in pregnancy or in women of childbearing potential not using contraception (EU/UK SmPC). Not established ≥65 years. Not established under 2 years.
• Home SC only after at least 8 weeks, stable maintenance dose, and hypersensitivity risk assessed as low, with training.

Not labelled:

• Children younger than 2 years (NCT06582524 is a completed under-2 trial, not a label).
• ARG1-D without continuing individualised diet (US/Canada indication requires dietary protein restriction).
• A “walking cure” or proven survival benefit at 24 weeks.

What the pivotal study showed (label vs journal)

Use the label of the country that will prescribe. Do not mix cuts. Motor function at 24 weeks was not a statistical win.

FDA / USPI Trial 1 (NCT03921541), 24-week double-blind:

• 32 randomised (21 Loargys / 11 placebo); ages 2–29; 90% were 2–17 (median pediatric age 9); 19 male / 13 female.
• Primary: change in plasma arginine at Week 24. Loargys mean (SD) baseline 365 (94) → Week 24 92 (51) µmol/L vs placebo 472 (80) → 449 (86). Treatment difference −312 (95% CI −384, −239). Mean percent change difference −72% (95% CI −89, −55).
• 90% of Loargys-treated patients reached target <200 µM and normalised levels vs 0% on placebo.
• Patients stayed on prior diet and ammonia scavengers.
• Extension: 31 completers; placebo-switch patients reached similar arginine reductions. Median extension exposure 94 weeks (range 62–152), excluding the 24-week double-blind.

EMA / MHRA SmPC (same trial, different emphasis):

• Geometric-mean arginine reduction vs placebo 76.7% (95% CI 67.1%, 83.5%), p<0.0001.
• 90.5% vs 0% below 200 µM and within the trial’s normal range.
• GMFM-E LS-mean difference 4.6 (95% CI −1.1, 10.2); 2MWT 5.5 m (95% CI −15.6, 26.7) — not statistically significant. Longer-term mobility signals in the open-label extension are uncontrolled.

Journal (Russo et al., EClinicalMedicine 2024;68:102405): same PEACE trial. Not a preprint. Do not copy journal secondary endpoints onto a prescription if the label of the prescribing country does not carry them.

This is arginine lowering on a 24-week trial. US accelerated approval says clinical benefit still has to be verified. EU exceptional circumstances says complete information was not obtainable.

How it is taken (labelled)

Start 0.1 mg/kg actual body weight once weekly. IV infusion over at least 30 minutes after dilution in 0.9% sodium chloride (maximum concentration 0.5 mg/mL). Flush the line. Do not mix other drugs in the same line.

After eight weeks of weekly IV, the same dose may be given subcutaneous, undiluted, into abdomen (not around the navel), lateral thigh, or side/back of upper arm. Rotate sites. If more than one injection is needed, USPI: sites at least 1 inch apart; EU/UK SmPC: at least 3 cm apart. Do not inject into scar, red, inflamed, or swollen skin.

Home SC: only after maintenance SC is tolerated (US) / after ≥8 weeks, stable dose, and low hypersensitivity risk plus training (EU/UK). Missed or delayed home doses may need to go back to a supervised clinic.

Missed dose: give as soon as possible. Do not give two doses the same day or within four days. Minimum four days between doses.

Refrigerate 2–8 °C in the original carton. Do not freeze. Do not shake. After preparation: 2 hours at room temperature or 4 hours refrigerated, then discard.

US-only lab rule: ordinary arginine tubes will read falsely low because leftover enzyme keeps eating arginine after the blood is drawn. USPI requires Immedica Nor-NOHA tubes and the Loargys arginine assay via Study IMM-PEG-005. EU/UK SmPC: use validated methods / CE-marked nor-NOHA tubes; tell the lab the patient is on an arginine-metabolising enzyme.

Safety (from the labels)

United States — BOXED WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS

Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred early in enzyme replacement and after extended duration.

Initiate Loargys in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g. anaphylaxis) occurs, discontinue Loargys and immediately start appropriate medical treatment, including epinephrine. Tell patients the symptoms of life-threatening hypersensitivity and to seek immediate care.

USPI 5.1: hypersensitivity that was mild to moderate occurred in 13% (6/48) of Loargys-treated patients in clinical trials (facial swelling, rash, flushing, dyspnea). Reactions generally occurred with the first few doses but may occur later. ADA-positive patients had more hypersensitivity (42% (5/12) vs 3% (1/36) ADA-negative). Consider antihistamine premedication; corticosteroids can be considered after a prior reaction.

US most common adverse reactions (>10%) in Trial 1 vs placebo: vomiting 33% vs 27%, pyrexia 19% vs 9%, infusion-associated reactions 14% vs 9%, constipation 14% vs 9%. Also (Loargys, ≥2 patients and higher than placebo): dizziness, fall, hypersensitivity, nasopharyngitis, rhinorrhoea, ALT increased, AST increased (each 10%). Injection-site reactions after SC: 14% (6/44) in open-label extensions.

US contraindications: None.

EU / UK SmPC (no boxed warning):

• Contraindication: severe hypersensitivity to pegzilarginase or excipients.
• Hypersensitivity very common (12.5%, 6/48) with IV; injection-site reactions very common (13.6%, 6/44) after SC.
• Initial administrations under medical observation. Severe cases: stop and give adrenaline. Home injectors need a plan for hives, chest tightness, wheezing, hypotension.
• Not recommended in pregnancy. Animal data: fetal growth effects at maternally toxic doses; male reproductive findings in rats. Breastfeeding: unknown; a decision is required.
• Pegzilarginase does not directly target ammonia. Hyperammonaemic episodes still happened in PEACE (serious hyperammonaemia: 2/21 Loargys vs 3/11 placebo on CT.gov).

Canada: walk the Product Monograph with the metabolic clinic. Do not assume the US boxed-warning text is printed the same way on the Canadian PM.

Report suspected reactions: Immedica 1-844-627-4687 (USPI) or FDA 1-800-FDA-1088; Canada via the clinic / PM contact 1-844-576-2707; UK Yellow Card.

No copay dollars in this article.

Research team (source-only)

Names and roles as they appear on primary sources — not a clinic directory.

• Immedica Pharma AB, Stockholm — MAH (EU, UK, Canada); BLA holder (US License 2342); current PEACE sponsor.
• Immedica Pharma US Inc., Chicago — US marketer (USPI).
• Aeglea Biotherapeutics — original PEACE / Phase 1/2 sponsor (CT.gov collaborator on NCT03921541; lead sponsor on NCT02488044 and NCT03378531).
• Mattias Rudebeck, PhD MSc BMedSc — CT.gov study director, NCT03921541 and NCT06582524 (Immedica Pharma AB).
• Innomar Strategies Inc., Milton, Ontario — Canadian importer/distributor (Product Monograph).
• Russo RS; Gasperini S; Diaz GA; Enns GM (and PEACE Investigators) — EClinicalMedicine 2024 PEACE paper. Not listed as “overall official” on CT.gov.
• Josie Gayton — CT.gov overall official, NCT02488044 (name only; no title/phone on the record retrieved).
• Cortney Caudill — CT.gov overall official, NCT03378531 (name only).
• CT.gov results point of contact (PEACE): Vice President, Head of Global Integrated Evidence / Global Head of Genetic and Metabolic Diseases, Immedica Pharma AB — Clinical@immedica.com, +46 8 533 39 500.
• GB eMC: medicalinfo@immedica.com, +46 (0)8 533 39 500.

No named Canadian principal investigator is printed on the CT.gov facility rows for McGill or SickKids.

How to talk to a doctor

Bring the NCT numbers and the label of the country you are in. The door is the metabolic / urea-cycle clinic.

1. “I / my child has ARG1-D (hyperargininemia) and is 2 or older. Is Loargys (pegzilarginase) the labelled next step with the protein-restricted diet — not instead of it?”
2. “The US label has a boxed warning for anaphylaxis. Where will the first doses be given, and is epinephrine and CPR equipment in the room?”
3. “Starting dose is 0.1 mg/kg IV weekly, max 0.2 mg/kg. After eight weeks, can we switch to subcutaneous? Who teaches home injection, and when would a missed home dose come back to clinic?”
4. “Which arginine tube do we use? Ordinary labs can read falsely low. In the US, is Study IMM-PEG-005 the enrolment path for Nor-NOHA tubes?”
5. “What is the plan for hypersensitivity (antihistamine premed, when to stop, when to use epinephrine) and for hyperammonaemia? This drug does not replace ammonia scavengers on its own.”
6. “Under 2 years is not labelled. Is there anything else, or is that a wait?”
7. Canada: “This is a full NOC, DIN 02568713, not NOC/c. SAP is the wrong door. CDA-AMC said reimburse with conditions (arginine ≥250 µmol/L, metabolic specialist). What is actually funded in this province? Provincial listing is unknown.”
8. UK: “MHRA yes. NICE HST35 is a yes with a commercial arrangement. SMC2813 is not recommended (non-submission). Which nation am I in?”
9. EU: “EC licence under exceptional circumstances. Which centre infuses it, and is it reimbursed here?”
10. Pregnancy, contraception (EU/UK: not recommended without contraception), breastfeeding unknown.

Canada zoom: authorized, not funded-by-default

Health Canada has already authorised Loargys with a full NOC. That is not a compassionate-access story and it is not NOC/c. The remaining Canadian questions are who pays (CDA-AMC said yes-with-conditions; pCPA status unknown; provinces unknown except B.C. under review) and which metabolic clinic will start weekly IV in a setting that can treat anaphylaxis. Do not call asking for SAP. Do not assume a provincial drug plan has listed it because a DIN exists. Ultra-rare: there are on the order of ~20 people with ARG1-D in Canada on the CDA-AMC clinical-expert input — the clinic that already knows the family is the door.

Bottom line

Pegzilarginase is a labelled weekly enzyme replacement for hyperargininemia in ARG1-D, age 2 and older, used with dietary protein restriction, in the United States (accelerated, boxed anaphylaxis warning, IMM-PEG-005 arginine tubes), Canada (full NOC, DIN 02568713), the EU and the UK (exceptional circumstances since Dec 2023). NICE HST35 is a yes for NHS England with a commercial arrangement; Scotland’s SMC is a no (non-submission). Japan is orphan designation, not a licence. Australia is a company TGA filing. China and Switzerland: authorisation not confirmed. Canada’s NOC is authorised, not a funding decision. SAP is the wrong door. The pivotal trial NCT03921541 is completed; Canadian sites (McGill, SickKids) are not recruiting. Under 2 is not labelled. Authorized is not funded. The metabolic clinic is the door.

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Primary sources

1. FDA Novel Drug Approvals for 2026 (Loargys row 4, 23 Feb 2026) — https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2026
2. FDA accelerated-approval letter, BLA 761211, 23 Feb 2026 — https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/761211Orig1s000Approv.pdf
3. DailyMed LOARGYS (pegzilarginase-nbln), setid d5ceabf2-43a0-4746-9371-d98a39cf6cfc — https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d5ceabf2-43a0-4746-9371-d98a39cf6cfc
4. FDA orphan designation 16 Mar 2015 / marketing 23 Feb 2026 — https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=466614
5. FDA ongoing accelerated-approval table (PMR 4966-1, 30 Jun 2035) — https://www.fda.gov/drugs/accelerated-approval-program/ongoing-non-malignant-hematological-neurological-and-other-disorder-indications-accelerated
6. Health Canada SBD for Loargys (DIN 02568713; NOC 2026-05-29; SBD issued 2026-08-14) — https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1786728777024
7. Health Canada DHPP product page (Approved; DIN 02568713) — https://dhpp.hpfb-dgpsa.ca/dhpp/resource/107101
8. Canadian Product Monograph (HRES 00085011; Date of Authorization 2026-05-29; control 302066) — https://pdf.hres.ca/dpd_pm/00085011.PDF
9. CDA-AMC SR0923, August 2026, Reimburse with conditions — https://www.canjhealthtechnol.ca/index.php/cjht/article/download/SR0923/SR0923/13957
10. EMA EPAR Loargys (EC MA 15 Dec 2023, exceptional circumstances) — https://www.ema.europa.eu/en/medicines/human/EPAR/loargys
11. EMA EPAR product information (SmPC) — https://www.ema.europa.eu/en/documents/product-information/loargys-epar-product-information_en.pdf
12. EMA public assessment report EMA/485896/2023 — https://www.ema.europa.eu/en/documents/assessment-report/loargys-epar-public-assessment-report_en.pdf
13. MHRA / eMC SmPC, PLGB 53487/0007, first authorisation 20 Dec 2023 — https://www.medicines.org.uk/emc/product/15382/smpc
14. NICE HST35, published 4 Mar 2026 — https://www.nice.org.uk/guidance/hst35
15. SMC2813 non-submission, 9 Jun 2025 — https://scottishmedicines.org.uk/medicines-advice/pegzilarginase-loargys-nonsub-smc2813/
16. ClinicalTrials.gov PEACE NCT03921541 — https://clinicaltrials.gov/study/NCT03921541
17. ClinicalTrials.gov NCT02488044 — https://clinicaltrials.gov/study/NCT02488044
18. ClinicalTrials.gov NCT03378531 — https://clinicaltrials.gov/study/NCT03378531
19. ClinicalTrials.gov NCT06582524 (under 24 months; not labelled) — https://clinicaltrials.gov/study/NCT06582524
20. Russo RS, Gasperini S, Bubb G, et al. Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE). EClinicalMedicine. 2024;68:102405. DOI 10.1016/j.eclinm.2023.102405 (journal; not the label)
21. B.C. PharmaCare Your Voice drug information sheet, pegzilarginase (Under Review) — https://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/your-voice-drug-info/pegzilarginase_tbc_4171_dis.pdf
22. INESSS continuous-evaluation table, pegzilarginase INESSSid 29501 (en cours, 13 Apr 2026) — https://www.inesss.qc.ca/thematiques/medicaments/medicaments-evaluation-aux-fins-dinscription/evaluation-en-mode-continu.html
23. Immedica Japan ODD, 25 Aug 2026 (company; not PMDA licence) — https://news.cision.com/immedica-pharma-ab/r/immedica-receives-orphan-drug-designation-for-pegzilarginase-in-japan,c4387406
24. Immedica TGA filing, 9 Dec 2025 (company; not ARTG) — https://www.immedica.com/en/press/immedica-submits-pegzilarginase-application-australian-therapeutic-goods-administration-tga
25. Immedica Health Canada NOC, 1 Jun 2026 (company overlay on the SBD) — https://www.immedica.com/en/press/loargysr-pegzilarginase-injection-approved-canada-treatment-arginase-1-deficiency-arg1-d