CAEB1102-300A PEACE Pegzilarginase Effect on Arginase 1 Deficiency

• Research type

  Research Study

• Full title

  Protocol Title: 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

• IRAS ID

  262991

• Contact name

  Dr Reena Sharma

• Contact email

  reena.sharma@srft.nhs.uk

• Sponsor organisation

  Aeglea BioTherapeutics

• Eudract number

  2018-004837-34

• Clinicaltrials.gov Identifier

  127774, IND

• Duration of Study in the UK

  3 years, 5 months, 19 days

• Research summary

  Arginase 1 deficiency (ARG1-D) is a rare disease caused by a defect in a specific gene that causes a deficiency of the enzyme called arginase I. This enzyme’s job is to help break down an amino acid called arginine. When arginase is not working, arginine can build up in the blood which can cause serious effects on growth, learning, and health. The aim of this study is to see whether a new drug, pegzilarginase (the study drug), is safe and to find out if the study drug can lower arginine levels in patients with arginase 1 deficiency better than placebo (an inactive substance). We hope this study drug will help with some of the symptoms and signs of this disease.

  Participants will be randomised to treatment or placebo in a ratio of 2:1 receiving either weekly intravenous (IV) infusions of the study drug (pegzilarginase) plus individualised disease management (IDM) which includes severe protein restriction, essential amino acid supplementation, and the use of ammonia scavengers, or placebo plus IDM during a 24-week double blind treatment period. After completion of the 24-week double-blind treatment period, each participant will enter the long term, open-label extension, the first 8 weeks of which are blinded. During the longterm extension, all participants will receive the study drug (pegzilarginase) plus IDM.

  Lay Summary of Results:

  The study was conducted from May 2019 to February 2023 in the United Kingdom, Austria, France, Germany, Italy, Canada, and the United States.
  A total of 32 participants with ARG1-D were included in the study. 21 of these participants received pegzilarginase from the beginning, while 11 initially received a placebo for 24 weeks. After 24 weeks (double-blind treatment [DB] period, where doctor and participant did not know which substance the participant was taking), the participants had the option to receive pegzilarginase for up to 3 years in addition to their IDM. 31 participants entered in and completed this longterm extension (LTE). During the LTE, participants received pegzilarginase by IV (into-the-vene) infusion during the first 8 weeks, and as SC (under-the-skin) injection afterwards.
  Participants started with a pegzilarginase dose of 0.10 mg per kg body weight. Doctors could adjust the dose depending on how the participant responded. Participants who received pegzilarginase during the DB period, continued in the LTE with the dose that worked best for them. For SC administration, the starting dose was the same as the last IV dose.
  More than half of the participants (19 of 32) were male. Participants’ ages ranged from 2 to 29 years. 5 participants (16%) had more pronounced difficulties with gross motor skills. 21 participants (66%) had mild to severe spasticity.
  After 24 weeks of treatment with pegzilarginase, the amount of arginine in the blood dropped significantly - by 77% compared to those who received a placebo - and reached normal levels in more than 91% of participants. None of the placebo treated participants reached normal arginine levels in blood. During the LTE period, the observed reduction in blood arginine levels to normal values persisted in participants who continued to receive pegzilarginase, and arginine levels decreased to normal levels in those who switched to pegzilarginase from placebo.
  Mobility also improved. After 24 weeks of treatment with pegzilarginase, participants were able to walk an average of 5.5 meters more than those who received a placebo in 2 minutes. Functional mobility (walking, running, and jumping) increased by an average of 4 points after 24 weeks of pegzilarginase treatment, while the mean score of measurement remained unchanged in participants who received placebo. Improvements in mobility also continued or were achieved in the LTE. In addition, more than half the participants (16 of 19 with leg spasticity at Baseline) showed a decrease in leg spasticity during the LTE period.
  During the DB period, 6 participants (19%) had 1 or more health problems that the doctors thought were caused by the study drug (side effects). All but 1 of these participants received pegzilarginase. Only 1 side effect (vomiting with 2 events) occurred more than once. Most of them were mild or moderate in intensity. In 3 participants, pegzilarginase treatment was temporarily interrupted due to at least 1 side effect. 1 of these participants reported several side effects (high liver enzyme level and reduced blood clotting). For 1 participant receiving pegzilarginase, a side effect (brain disorder due to high ammonia levels) was serious, meaning that they had to be admitted to the hospital or stay there longer than expected.
  During the LTE, 12 participants (39%) had 1 or more side effects. Common side effects (that were experienced in more than 2 participants) were tiredness (3 participants, 10%), high liver enzyme levels (5 participants, 16%), and high ammonia levels (in 3 participants, 10%). Most side effects were mild or moderate in intensity. Pegzilarginase treatment was temporarily interrupted due to at least 1 side effect in 2 participants. 1 participant had to go to or stay at hospital longer because of a severe side effect (high ammonia level).
  No side effects led to leaving the study, stopping the treatment, or death. Most side effects were temporary, manageable, and most went away on their own or with routine medical care. No trends in changes over time were observed in blood parameters, vital signs, heart activity, or liver function tests. Overall, long-term use of pegzilarginase up to 3 and a half years was well tolerated.
  The results show that the treatment with pegzilarginase is general safe and works well over time in patients with ARG1-D.
  Where further information is available
  To learn more about this study, you can find more detailed information on this website (EU database of clinical studies): https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.clinicaltrialsregister.eu%252Fctr-search%252Fsearch%253Fquery%253D2018-004837-34.%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F2%2FNU9_AbID8g&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900243664%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=ibAp9CjjyXmUPo1A2IBYcj9rGUdkA788Pk%2B60JF%2B2%2Bw%3D&reserved=0
  You can also find more details about this study at (US database of clinical studies): https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT03921541.%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F3%2F28ph1-WUxM&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900266957%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=sqncU%2Fp9rO1P9C7JV%2B045FQW2dP13kBEfw9CyepcrOE%3D&reserved=0
  The study results were also published in a journal: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fpubmed.ncbi.nlm.nih.gov%252F38292042%252F%252C%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F4%2FaYhCsp4qrm&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900292673%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=Vdg05bsN2TDtQAZr%2B7CEiep9b5SlZ%2B5EZya0UorpdMc%3D&reserved=0 https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fpubmed.ncbi.nlm.nih.gov%252F40714964%252F.%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F5%2FPYWsayvLPb&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900318616%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=5QHbIEReuRsGky7pLz0JyMOg6OPR2Jq15jzm53LhqL8%3D&reserved=0

  Has the registry been updated to include summary results?: Yes
  If yes - please enter the URL to summary results: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT03921541%253Fterm%253DNCT03921541%2526rank%253D1%2526tab%253Dhistory%2526a%253D33%2523study-results-card%253B%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F6%2FGU2I1lqacF%23study-results-card&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900346207%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=yGhgDv%2FT6dnvJJKQrDanSxK9tM6B6nucG7jraDt7F9Y%3D&reserved=0; https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.clinicaltrialsregister.eu%252Fctr-search%252Ftrial%252F2018-004837-34%252Fresults%2FNBTI%2FwVPBAQ%2FAQ%2Fda88aeea-8ced-4ee5-af50-7f0592702ceb%2F7%2F2a9crD-6-w&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7C4454aec11b7c444d5f8208de21ca853f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638985350900373116%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=3%2FpNYqTxkBr5F5r%2FJWXOdmQNbdPc7I0baYHmHEGxnl4%3D&reserved=0
  If no – why not?:
  Did you follow your dissemination plan submitted in the IRAS application form (Q A51)?: Yes
  If yes, describe or provide URLs to disseminated materials: The dissemination plan has been followed as submitted in the IRAS application form.
  If pending, date when dissemination is expected:
  If no, explain why you didn't follow it:
  Have participants been informed of the results of the study?: No
  If yes, describe and/or provide URLs to materials shared and how they were shared:
  If pending, date when feedback is expected:
  If no, explain why they haven't: No official patient communication was developed. The trial investigators have been informed about the results of the trial, and able to share the results with their individual patients. Should they be contacted by a patient, they will be happy to share the study results, or they will direct the patient to the results online (clinicaltrials.gov or the HRA lay summary).
  Have you enabled sharing of study data with others?: Yes
  If yes, describe or provide URLs to how it has been shared: The study results have been shared with the trial investigators, and relevant ECs and CAs. The results have been published at scientific conference, in peer-review journals and reported on the clinicaltrials.gov and EudraCT website.
  If no, explain why sharing hasn't been enabled:
  Have you enabled sharing of tissue samples and associated data with others?: No
  If yes, describe or provide a URL:
  If no, explain why: No tissue samples have been taken.
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• REC name

  London - Surrey Borders Research Ethics Committee

• REC reference

  19/LO/0717

• Date of REC Opinion

  10 Jun 2019

• REC opinion

  Further Information Favourable Opinion