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High-Cost Therapy Profile: March 2025

Pegzilarginase Intravenous (IV), Subcutaneous (SC) | Immedica 

Metabolic
March 14, 2025

Proposed indications 

Arginase 1 deficiency (ARG1-D)

United States (U.S.) Food and Drug Administration (FDA) approval timeline

May to July, 2025

  • Breakthrough Therapy
  • Fast Track
  • Orphan Drug
  • Priority Review 
  • Rare Pediatric Disease

Place in therapy 

Pegzilarginase is a recombinant, cobalt-substituted and pegylated human arginase 1 (ARG1) enzyme that lowers levels of arginine and its toxic metabolites in the plasma. The cobalt-substitution allows for increased catalytic activity compared to the natural arginase enzyme. 

  • If approved, pegzilarginase will be the first medicine that reduces geometric mean plasma arginine (pArg) to normal levels, fulfilling a large unmet need in treating ARG1-D.
  • Although pegzilarginase led to a significantly greater reduction in pArg levels compared to placebo in the PEACE trial, it did not demonstrate a statistically significant improvement in functional mobility at 24 weeks with pegzilarginase treatment.
  • Failure to meet statistical significance may have been influenced by differences among patients’ disease severity, disease duration and functional performance at baseline that may have led to variability in functional response.
  • Notably, data from the trial suggest that longer-term use of pegzilarginase may lead to clinical stabilization of patients with ARG1-D. 
  • Pegzilarginase is being evaluated in another Phase 3 clinical trial in pediatric patients less than 24 months old diagnosed with ARG1-D.

Understanding your data 

Pegzilarginase is a human enzyme therapy that addresses the underlying disease of ARG1-D. Clinical trial data on pegzilarginase demonstrated improved clinical outcomes and reduce disease manifestations in patients with ARG1-D. Pegzilarginase rapidly and sustainably reduced plasma arginine levels in patients with ARG1-D to normal levels and prevented disease progression. Studies evaluating pegzilarginase in ARG1-D include the following:

  • NCT03921541 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 ARG1-D.
  • NCT03378531: An open-label, multicentre extension study to evaluate the long-term safety, tolerability and effects of IV pegzilarginase in patients with ARG1-D who previously received treatment in study CAEB1102-101A.
  • NCT02488044: A Phase 1/2 open-label study in patients with ARG1-D to investigate the safety, pharmacokinetics and pharmacodynamics of IV pegzilarginase.
  • NCT06582524: A Phase 3 open-label study of safety, pharmacokinetics and activity of weekly SC pegzilarginase in subjects <24 months old with ARG1-D.

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria: 

  • Diagnosis of ARG1-D
  • Aged 2 years or older
  • Negative pregnancy test

Common measurable exclusion criteria:

  • Pregnancy or breastfeeding
  • Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
  • Previous liver or HSCT

Appendix

Category Procedure codes
ARG1-D International Classification of Diseases, Tenth Revision (ICD-10): E72.21
Pregnancy and lactation ICD-10: ICD-10: Z34.00, Z34.8, Z34.90, Z33.1, O09.00, O09.10, O09.291, O09.40, O09.211, O09.30, O09.511, O09.521, O09.611, O09.621, O09.819, O09.821, O09.822, O09.823, O09.829, O36.80x0, O09.891, O09.892, O09.893, O09.899, Z39.0, Z39.1, Z39.2, Z36, Z37, Z37.1, Z37.2, Z37.3, Z37.4, Z37.59, Z37.69, Z37.7, Z37.9, Z64.0, Z32.01, O30.009, O30.019, O30.039, O30.049, O30.099, O30.109, O30.119, O30.129, O30.199, O30.209, O30.219, O30.229, O30.299, O30.809, O30.819, O30.829, O30.899, O20.0, O44.01, O44.02, O44.03, O10.011, O10.012, O10.013, O10.02, O10.911, O10.912, O10.913, O10.92, O10.03, O21.0, O60.12X0, O60.13X0, O60.14X0, O48.0, O31.01X0, O31.02X0, O31.03X0, O98.111, O98.112, O98.113, O98.12, O98.13, O24.32, O24.911, O24.912, O24.913, O24.92, O24.93, O99.331, O99.332, O99.333, O99.334, O99.335, O80, O30.001, O30.002, O30.003, O32.0XX0, O33.0, O34.01, O34.02, O34.03, O34.01, O34.02, O34.03, O35.0XX0, O43.011, O36.0110, O36.0120, O36.0130, O36.0910, O36.0920, O36.0930, O36.1110, O36.1120, O36.1130, O36.1910, O36.1920, O36.1930, O68, O36.5110, O36.5120, O36.5130, O36.5910, O36.5920, O36.5930, O36.61X0, O36.62X0, O36.63X0, O43.101, O43.102, O43.103, O43.811, O43.812, O43.813, O43.91, O43.92, O43.93, O36.8910, O36.8920, O36.8930, O68, O77.0, O36.91X0, O36.92X0, O36.93X0, O40.1XX0, O40.2XX0, O40.3XX0, O41.01X0, O41.02X0, O41.03X0, O61.1, O64.9XX0, O62.0, O63.0, O70.0, O71.02, O71.03, O72.0, O43.211, O43.212, O43.213, O43.221, O43.222, O43.231, O43.232, O43.233, O73, O74.1, O89.09, O75.0, O86.89, O22.01, O22.02, O22.03, O87.4, O86.4, O88.011, O88.012, O88.013, O88.02, O88.03, O99.411, O99.412, O99.413, O99.42, O99.43, O91.011, O91.012, O91.013, O91.02, O92.011, O92.012, O92.013,O92.03, O35.8XX0, O36.8210, O36.8220, O36.8230, O75.89, Z37.0, Z37.2, Z37.3, Z37.59, Z37.69, O86.12, O85, O86.81, O86.89
HIV ICD-10: B20, B97.35, Z21
Hepatitis B ICD-10: B16.0, B16.1, B16.9, B17.0, B18.0, B19.10, B19.11, B16.2, B18.1
Hepatitis C ICD-10: B17.10, B17.11, B18.2, B19.20, B19.21
Liver transplant ICD-10: Z94.4 (Liver transplant status)
ICD-10 - Procedure Coding System (PCS): 0FY00Z0 (Transplantation of liver, allogenic, open approach), 0FY00Z1 (Transplantation of liver, syngeneic, open approach), 0FY00Z2 (Transplantation of liver, zooplastic, open approach)
HSCT ICD-10: Z94.84 (Stem cell transplant status), T86.5 (Complications of stem cell transplant)
Current Procedural Terminology (CPT) codes: 38241 (Transplantation and post-transplantation cellular infusion products), 38243 (Infusion of hematopoietic progenitor cells (HCP) into a patient who has previously received HPCs from the same donor during a transplant), 38205, 38206, 38230, 38240 (Other preparation codes)
ICD-10-PCS: 30230G2,30230G3, 30230Y2, 30230Y3, 30233G2, 30233G3, 30233Y2, 30233Y3, 30240G2, 30240G3, 30240Y2, 30240Y3, 30243G2, 30243G3, 30243Y2, 30243Y3, 30230C0, 30230G0, 30230Y0, 30233G0, 30233C0, 30233Y0, 30240C0, 30240G0, 30240Y0, 30243C0, 30243G0, 30243Y0, 30233Y1, 30243Y1, 30233Y1, 30263Y0, 30263Y1

Clinical deep dive 

Disease state overview

Arginase 1 deficiency is an ultra-rare, genetic, metabolic urea cycle disorder characterized by a lack of functional arginase enzyme in the liver and red blood cells. Arginase deficiency is caused by mutations in the ARG1 gene. This leads to high levels of arginine in the blood and cerebrospinal fluid. Excess accumulation of ammonia in the blood can also occur. The majority of patients present in early childhood; however, those with a partial enzyme deficiency may become symptomatic in later childhood or in adulthood. Frequent vomiting and poor appetite with food refusal and protein aversion are common. If left untreated, ARG1-D leads to spasticity, gait disorders, difficulty walking, developmental delay, failure to thrive and seizures. ARG1-D can be identified at birth through newborn screening.

Epidemiology 

Arginase 1 deficiency is estimated to occur in approximately 1 in 300,000 to 1,000,000 births.  In the U.S., there are an estimated 250 persons living with ARG1-D.

Treatment

Management of ARG1-D consists of a life-long severe protein restricted diet to reduce pArg levels and essential amino acids supplementation. Guidelines recommend lowering pArg to less than 200 μmol/L, but this is rarely achieved with dietary restriction due to endogenous arginine sources. Ammonia scavenger drugs (e.g., sodium phenylacetate, sodium benzoate) to clear accumulated ammonia from the blood may also be used. Arginine and ammonia levels should be monitored periodically and prompt treatment (e.g., IV fluids and ammonia scavengers, mannitol [for cerebral edema]) should be administered for excess levels. Even with current management approaches, most patients develop moderate to severe neurological damage, leading to poor quality of life and decreased lifespan.

Drug and clinical trial overview 

The double-blind, placebo-controlled, Phase 3 PEACE trial evaluated efficacy and safety of pegzilarginase added to standard of care (protein-restricted diet) in patients ≥ 2 years of age with ARG1-D. A total of 32 patients were randomized 2:1 to pegzilarginase or placebo. After 24 weeks, pegzilarginase led to a significantly greater reduction in pArg levels compared to placebo (76%; p<0.0001); notably, there were no meaningful changes in arginine levels reported with placebo. At 24 weeks, 90.5% of patients treated with pegzilarginase achieved a pArg level < 200 μmol/L (normal range, 100 to 200 μmol/L). In the pegzilarginase arm, the pArg was within normal range (40 to 115 μmol/L) by week 12. Key secondary outcomes of Gross Motor Function Measure part E (GMFM-E) and 2MWT showed numeric but not statistical improvements in functional mobility with pegzilarginase compared to placebo at week 24 (least squares mean [LSM] differences, +4.6 points and +5.5 meters, respectively). In addition, patients who continued pegzilarginase during the open-label, long-term extension phase maintained pArg levels within normal range and continued to experience meaningful improvements in mean GMFM-E and 2MWT through week 24 (48 weeks of total treatment). Treatment emergent adverse events (TEAEs) were generally mild and transient. The most common TEAEs (≥ 15%) were vomiting, pyrexia, cough and elevated ammonia levels during the double-blind period. 

In the PEACE trial, pegzilarginase was administered via a 30-minute IV infusion. Treatment was initiated with a dose of 0.1 mg/kg per week with dose adjustments as needed to achieve a pArg between 50 and 150 μmol/L at the end of the dosing interval (168 hours post-dose). The possible dosages ranged from 0.05 to 0.2 mg/kg per week. Patients could switch to SC administration given by a health care provider, using the same dose level, after the first eight weeks of the long-term extension phase. After the fourth SC dose, patients had the option for doses to be administered at home by a health care provider. 

Pipeline (late-stage development)

Drug name Route of administration Mechanism of action Proposed / studied indication Status
There are no other therapies under development for ARG1-D

The information provided has been developed based on available information as of March 3, 2025. This therapy is NOT FDA approved, and content may change as more information becomes available. Caution should be used when developing formulary and utilization management strategies.

By receipt of this report, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced or distributed to or disclosed to others at any time without the prior written consent of Prime Therapeutics. The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment.

All brand names are property of their respective owners. 

References 

  1. Aeglea BioTherapeutics announces sale of pegzilarginase to Immedica Pharma. Jul 27, 2023. Available at: https://www.prnewswire.com/news-releases/aeglea-biotherapeutics-announces-sale-of-pegzilarginase-to-immedica-pharma-301887231.html. Accessed February 12, 2025.
  2. BLA for pegzilarginase in the treatment of arginase 1 deficiency (ARG1-D) accepted for priority review by the U.S. FDA. November 5, 2024. Available at: https://www.immedica.com/en/press/bla-pegzilarginase-treatment-arginase-1-deficiency-arg1-d-accepted-priority-review-us-fda. Accessed February 12, 2025.
  3. ClinicalTrials.gov. NCT03921541. 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. Available at: https://clinicaltrials.gov/study/NCT03921541?cond=Hyperargininemia&intr=NCT03921541&rank=1. Accessed February 11, 2025.
  4. ClinicalTrials.gov. NCT03378531. An open-label, multicentre extension study to evaluate the long-term safety, tolerability and effects of intravenous AEB1102 in patients with arginase I deficiency who previously received treatment in study CAEB1102-101A. Available at: https://clinicaltrials.gov/study/NCT03378531?cond=Hyperargininemia&rank=5. Accessed February 11, 2025.
  5. Neurotech Pharmaceuticals, Inc. Announces Positive Phase 3 Topline  Results for NT-501 Implant in Macular Telangiectasia Type 2. Neurotech. November 2, 2022. Accessed January 2, 2025. https://www.neurotechpharmaceuticals.com/wp-content/uploads/Neurotech-Topline-PR__FINAL_11022022.pdf.
  6. ClinicalTrials.gov. NCT06582524. A Phase 3 open-label study of safety, pharmacokinetics, and activity of weekly subcutaneous pegzilarginase in subjects <24 months old with arginase 1 deficiency. Available at: https://clinicaltrials.gov/study/NCT06582524?cond=Hyperargininemia&rank=1. Accessed February 11, 2025. 
  7. ClinicalTrials.gov. NCT03371979. A Phase 1/2 study of pegzilarginase (AEB1102, Co-ArgI-PEG) in combination with pembrolizumab in the treatment of patients with extensive disease (ED) small cell lung cancer (SCLC). Available at:  https://clinicaltrials.gov/study/NCT03371979?intr=Co-ArgI-PEG&rank=3. Accessed February 11, 2025.
  8. ClinicalTrials.gov. NCT02561234, A multiple dose, dose escalation trial of AEB1102 (Co-ArgI-PEG) in patients with advanced solid tumors. Available at:  https://clinicaltrials.gov/study/NCT02561234?intr=Co-ArgI-PEG&rank=2. Accessed February 11, 2025.
  9. Experts implore FDA to accept biomarker evidence in ultra-rare diseases. October 13, 2023. Available at: https://www.biospace.com/experts-implore-fda-to-accept-biomarker-evidence-in-ultra-rare-diseases. Accessed February 12, 2025.
  10. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated Feb 24; Arginase deficiency; [updated 2024 Feb 13; cited 2025 Feb 12]. Available from: https://medlineplus.gov/genetics/condition/arginase-deficiency/#:~:text=The%20nervous%20system%20is%20especially,of%20the%20muscles%20(spasticity). Accessed February 12, 2025.
  11. National Organization for Rare Disorders (NORD). Last updated April 11, 2023. Arginase-1 Deficiency. Available at: https://rarediseases.org/rare-diseases/arginase-deficiency/. Accessed February 12, 2025.
  12. Russo RS, Gasperini S, Bubb G, et al. Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a Phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. EClinicalMedicine, 2024. Jan (68): 102405. DOI: 10.1016/j.eclinm.2023.102405. 
  13. Sawad AB, Jackimiec J, Bechter M, et al. Health care resource utilization in the management of patients with Arginase 1 Deficiency in the US: a retrospective, observational, claims database study. Journal of Medical Economics, 2022. 25(1): 848–856. https://DOI.org/10.1080/13696998.2022.2089517.
  14. Sawad AB, Pothukuchy A, Badeaux M, et al.  Natural history of arginase 1 deficiency and the unmet needs of patients: A systematic review of case reports. JIMD Rep, 2022. 63(4): 330–340. DOI: 10.1002/jmd2.12283.
  15. Sun A, Crombez EA, and Wong D. Arginase Deficiency. GeneReviews. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1159/. Accessed on February 7, 2025. 
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