ornithine phenylacetate oral (MNK-6106) / Mallinckrodt, Yaqrit - LARVOL DELTA

Randomized, open-label, phase 2a comparator study to assess the pharmacodynamics, safety and pharmacokinetics of oral administration of mnk6106 (l-ornithine phenylacetate) vs. rifaximin in subjects with hepatic cirrhosis and a previous history of hepatic encephalopathy (EASL 2025) - "Group B (L-OPA 4 g BID) showed the highest decrease in plasma AMM concentrations which was about 6 times greater than Rifaximin and this dose may be selected for future trials. All doses of L-OPA were safe and well tolerated."

Clinical • P2a data • PK/PD data • CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Liver Cirrhosis • Psychiatry

Synergy between ornithine phenylacetate and strategies targeting endotoxemia with either a toll-like receptor 4 antagonist (TAK-242) or Yaq-001 for the treatment of hyperammonemia in cirrhosis and ACLF (EASL 2025) - "Dual targeting of ammonia and endotoxins are synergistic in reducing ammonia levels, enhancing ureagenesis, ameliorating liver injury and preventing coma in ACLF animals. This combined approach should be explored in clinical trials for managing hyperammonemia and HE in ACLF."

CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Infectious Disease • Liver Failure • TLR4

Yaqrit prepares phase 3 for ammonia scavenger in hepatic encephalopathy (GlobeNewswire) - "Yaqrit...announced today that its recently acquired ammonia scavenger, L-ornithine phenylacetate (OPA), is progressing to phase 3 for treatment of acute hepatic encephalopathy, a life-threatening complication of decompensated cirrhosis....IV formulation to enter phase 3 in 2025; oral formulation to enter phase 2b trials for HE prevention and phase 2a for urea cycle disorders."

New P2b trial • New P3 trial • Hepatic Encephalopathy

Attenuating hyperammonemia preserves protein synthesis and muscle mass via restoration of perturbed metabolic pathways in bile duct-ligated rats. (PubMed, Metab Brain Dis) - "OP attenuated hyperammonemia, preserved muscle protein synthesis and prevented muscle mass loss in a preclinical model of CLD through restoration of perturbed signalling responses and altered TCA intermediary metabolites. Ammonia-lowering strategies have the potential for rapid clinical translation for simultaneous neuroprotection and sarcopenia prevention in patients with CLD."

Journal • Preclinical • CNS Disorders • Hepatic Encephalopathy • Hepatology • Sarcopenia

Abnormal brain oxygen homeostasis in an animal model of liver disease. (PubMed, JHEP Rep) - "Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration...Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Liver Failure

Emergency Use of OCR-002 in Acute Liver Failure (ALF) (clinicaltrials.gov) - P=N/A; N=N/A; No Longer Available; Sponsor: Ocera Therapeutics, Inc.; Phase classification: P2 ➔ P=N/A

Clinical • Phase classification • Hepatology • Liver Failure

Robert Rahimi and Jasmohan Bajaj on a Potential New Option for Hepatic Encephalopathy (MedPageToday) - "Hepatic encephalopathy is becoming more widely prevalent, owing to the multifaceted management of chronic liver disease patients, leading to an older patient population living with cirrhosis, so further therapies with different mechanisms of action are needed. Most of the currently approved therapies for hepatic encephalopathy in the United States have a gut-focused mechanism of action, so our STOP-HE team performed this study to determine if an ammonia scavenger that specifically targets ammonia in the systemic circulation and leads to subsequent urinary excretion could demonstrate a promising result."

Interview

Bile-duct ligation renders the brain susceptible to hypotension induced neuronal degeneration: implications of ammonia. (PubMed, J Neurochem) - "In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1g/kg) for 3 weeks before induction of hypotension...Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk."

Journal • CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Hypotension • Immunology • Mood Disorders • Psychiatry • Transplantation • CASP3

MNK6106 for Liver Disease (Hepatic Cirrhosis) That in the Past Has Affected the Brain (Hepatic Encephalopathy) (clinicaltrials.gov) - P2a; N=50; Completed; Sponsor: Mallinckrodt; Recruiting ➔ Completed

Clinical • Trial completion • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Liver Cirrhosis

MNK6106 for Liver Disease (Hepatic Cirrhosis) That in the Past Has Affected the Brain (Hepatic Encephalopathy) (clinicaltrials.gov) - P2a; N=48; Recruiting; Sponsor: Mallinckrodt; Trial completion date: Mar 2020 ➔ Aug 2020; Trial primary completion date: Mar 2020 ➔ Aug 2020

Clinical • Trial completion date • Trial primary completion date • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Liver Cirrhosis

MNK6106 for Liver Disease (Hepatic Cirrhosis) That in the Past Has Affected the Brain (Hepatic Encephalopathy) (clinicaltrials.gov) - P2a; N=48; Recruiting; Sponsor: Mallinckrodt; Trial completion date: Oct 2019 ➔ Mar 2020; Trial primary completion date: Oct 2019 ➔ Mar 2020

Clinical • Trial completion date • Trial primary completion date

MNK6106 for Liver Disease (Hepatic Cirrhosis) That in the Past Has Affected the Brain (Hepatic Encephalopathy) (clinicaltrials.gov) - P2a; N=48; Recruiting; Sponsor: Mallinckrodt; Trial completion date: Jul 2019 ➔ Oct 2019; Trial primary completion date: Jul 2019 ➔ Oct 2019

Clinical • Trial completion date • Trial primary completion date