Calmangafodipir may reduce liver injury after paracetamol overdose: final results from the POP trial

ILC 2019: Phase 1 study demonstrates that superoxide dismutase mimetic, calmangafodipir, is well tolerated and may reduce liver injury after paracetamol overdose

12 April 2019, Vienna, Austria

EASL (EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER)

Final results from a Phase 1 study suggest that the novel superoxide dismutase mimetic, calmangafodipir, is well tolerated and may reduce liver injury after paracetamol overdose. The study, which was presented today at The International Liver Congress™ 2019 in Vienna, Austria, found that administration of calmangafodipir in combination with N-acetylcysteine (NAC) within 24 hours of overdose was associated with lower levels of biomarkers of hepatoxicity compared with N-acetylcysteine alone.

Paracetamol overdose is the most common cause of acute liver failure in the Western world, accounting for almost 50% of all cases in the USA1 and around 60% in the UK.2 NAC is the mainstay of treatment for paracetamol overdose, effectively preventing hepatotoxicity when used within 8 hours of paracetamol ingestion.3 However, the treatment has major shortcomings, with a complex and arduous 21-hour intravenous (IV) treatment regimen and a high risk of potentially severe adverse events, including anaphylactoid reactions.3

Calmangafodipir (PP100-01) is a superoxidase dismutase mimetic that has been shown to prevent paracetamol toxicity in mice.4,5 The agent has recently been explored in a Phase 1 tolerability and safety study,3 the results of which were presented today in Austria.

This randomized, open-label study involved 24 individuals who were recruited from the Emergency Department of a large teaching hospital in the UK within 24 hours of a single or staggered paracetamol overdose. All were considered candidates for NAC treatment at study enrolment. Participants were randomly assigned to one of three dosing cohorts, with each cohort randomized to receive NAC + calmangafodipir (n=6), or NAC alone (n=2). Calmangafodipir was administered IV between the first two NAC bags at doses of 2, 5, or 10 μmol/kg. The primary endpoint of the study was the safety and tolerability of the combination treatment. Secondary endpoints included alanine aminotransferase (ALT) activity and the biomarkers of hepatotoxicity, full-length keratin-18 (FLK18) and microRNA-122 (miR-122), measured at baseline, 10 hours and 20 hours after starting NAC treatment.

According to the investigators, the median time from overdose to starting NAC was 10.3, 6.5, 7.3 and 6.7 hours for the NAC alone, NAC + calmangafodipir 2, 5 and 10 μmol/kg groups, respectively. All participants experienced at least one adverse event (AE); however, no AEs or serious AEs were attributed to calmangafodipir. No increases in ALT were observed in any of the treatment groups during the study. Individuals who received the combination treatment had smaller increases in FLK18 than individuals who received NAC alone. Between baseline and 20 hours, median FLK18 levels increased 1.41-fold in the calmangafodipir 2 μmol/kg + NAC group, 1.02-fold in the calmangafodipir 5 μmol/kg + NAC group, and 1.17-fold in the calmangafodipir 10 μmol/kg + NAC group, compared with a 1.71-fold increase in the NAC monotherapy group. The median (range) FLK18 levels at 20 hours were 306 U/L (118–2606 U/L) with NAC monotherapy, 212 U/L (98–572 U/L) with calmangafodipir 2 μmol/kg + NAC, 163 U/L (100–287 U/L) with calmangafodipir 5 μmol/kg + NAC, and 155 U/L (103–508 U/L) with calmangafodipir 10 μmol/kg + NAC. A similar pattern of increases was observed with miR-122.

‘Calmangafodipir was well tolerated when coadministered with NAC in this study,’ said Dr James Dear from the University of Edinburgh in the UK, who presented the latest study results. ‘Although the results are preliminary and need confirmation in a larger study, the evidence suggests the treatment may reduce liver injury after paracetamol overdose.’

Prof Philip Newsome (Vice-Secretary, EASL) said, “These data demonstrate the potential value of novel agents in addition to N-AcetylCysteine in the management of paracetamol overdose. We look forward to testing in larger studies and in particular the value of calmangafodipir in patients presenting late after a paracetamol overdose.”

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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2019 will take place from 10­–14 April 2019 at the Reed Messe Wien Congress and Exhibition Center, Vienna, Austria.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

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Onsite location reference

Session title: ‘Acute and acute-on-chronic liver failure – Translational aspects’

Time, date and location of session: 16:30–16:45, 12 April 2019, Lehar 4

Presenter: James Dear, UK

Abstracts: PP100-01 (calmangafodipir) for overdose of paracetamol (The POP trial): Principal results (PS-099)

Author disclosures

James Dear is a member of the Expert Advisory Group for the Innovative Medicines Initiative-funded EU TransBioLine Consortium. This study was funded by PledPharma AB

References

  1. Bernal W, et al. Acute liver failure: A curable disease by 2024? J Hepatol. 2015;62(1 Suppl):S112–20.
  2. Bernal W, WendonAcute liver failure. N Engl J Med. 2013;369(26):2525–34.
  3. POP Trial Investigators, Dear J. Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N-acetylcysteine for paracetamol overdose-the PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial. 2019;20(1):27.
  4. Karlsson JO, et al. Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties. Drug Discov Today. 2015;20(4):411–21.
  5. Bedda S, et al. Mangafodipir prevents liver injury induced by acetaminophen in the mouse. J Hepatol. 2003;39(5):765–72.

 

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