Mouse and human translational drug development of calmangafodipir as a new treatment for paracetamol overdose

J. W. Dear¹, E. Morrison¹, B. Gallagher², K. Oatey³, C. Weir³, R. O'Brien², J. Grahamslaw², M. Odam², T. Caparrotta¹, M. Eddleston¹, D. B. Henriksen⁴, J. Näsström⁴, J. Karlsson⁵. ¹University of Edinburgh, Edinburgh, United Kingdom, ²EMERGE, Edinburgh, United Kingdom, ³Edinburgh Clinical Trials Unit, Edinburgh, United Kingdom, ⁴PledPharma AB, Stockholm, Sweden, ⁵Linköping University, Stockholm, Sweden.

Introduction: Paracetamol (acetaminophen) is the leading cause of acute liver failure in the West. The current treatment is acetylcysteine (NAC), which increases the detoxification of the paracetamol metabolite NAPQI. However, NAC has little beneficial effect once NAPQI has initiated oxidative stress. Calmangafodipir (Ca₄Mn(DPDP)₅) is a unique chemical species that has anti-oxidant superoxide dismutase activity. This translational project has 2 complementary workstreams.

Study 1: investigated whether calmangafodipir prevented paracetamol-induced liver injury in mice at a late time when NAC was ineffective.

Study 2: is an on-going phase 1 trial that investigates the safety and tolerability of calmangafodipir in patients with paracetamol overdose being treated with NAC.

Methods:

Study 1: Male B6C3F1 mice, 5-6 weeks old, were used. Acute liver injury was induced by paracetamol (300mg/kg ip) then either NAC (300mg/kg) or calmangafodipir (10mg/kg) or both was administered intravenously. Then blood and tissue were collected for analysis.

Study 2: PP100-01 (Calmangafodipir) for Overdose of Paracetamol (POP). An open-label, randomised, rising dose, phase 1 safety and tolerability study in patients treated with NAC for paracetamol overdose. In total 24 patients will be assigned into one of 3 dosing cohorts of 8 patients (N=6 for calmangafodipir and NAC; N=2 for NAC alone). The study will primarily evaluate adverse events with calmangafodipir in combination with NAC as compared to NAC alone (ClinicalTrials.gov:NCT03177395).

Results:

Study 1: Paracetamol induced an elevation in serum alanine transaminase activity (ALT - median (IQR): 15,332U/L (5,216-18,712), N=13) that was attenuated when NAC was administered 1h after paracetamol (ALT 225U/L (162-671), N=5, P=0.004 by Mann-Whitney Test). However, there was no significant effect when NAC treatment was delayed to 2.5h. By contrast, calmangafodipir prevented acute liver injury even when administered 6h after paracetamol (ALT 113U/L (60-177) N=5, P=0.001 by Mann-Whitney Test). This effect on ALT was mirrored by prevention of liver injury on histological analysis.

Study 2: This phase 1 study was successfully opened and recruited the first patient on 8^th June 2017. On 15^th August 2017 the first dosing cohort was completed (N=6 calmangafodipir 2μmol/kg and NAC; N=2 NAC alone).

Discussion:

The data from the mouse model suggest that calmangafodipir could be an effective treatment for paracetamol overdose in patients who present late to hospital when NAC has lost efficacy. For the first time we have administered calmangafodipir to patients being treated with NAC for paracetamol overdose in order to translate our pre-clinical results into a treatment for an unmet clinical need.