Pharmacokinetics of DUR-928 in alcoholic hepatitis patients - a phase 2a study

Shah, Jaymin; Blevins, Christina; Scott, Debbie; Lin, WeiQi

doi:10.1016/s0168-8278(20)30869-2

Cited by 2 publications

(2 citation statements)

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“…25HC3S has also been evaluated in vitro (cells) and other in vivo animal models, including NAFLD, NASH, hepatectomy, and acute multiple organ injury [ 25 , 29 ]. As an investigative drug, DUR-928 (25HC3S) has been in clinical trials in patients with NASH and acute alcohol-associated hepatitis [ 58 , 59 , 60 , 61 ]. Results from this study suggest that 25HC3S in PG and its appropriate combination have the potential in preventing or treating certain acute organ injuries.…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

Wang

Pandak

Lesnefsky

et al. 2021

Cells

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Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of 5mCpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury.

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Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

Wang

Pandak

Lesnefsky

et al. 2021

Cells

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“…130,131 The intravenous administration of one of these oxysterol sulfates, DUR-928, has been evaluated in a pivotal, phase IIA, open-label study enrolling 19 patients with moderate-severe acute alcoholic hepatitis. Based on promising safety and efficacy signals, 132,133 phase IIB studies have now been planned (ClinicalTrials.gov identifiers: NCT03917407 and NCT04563026).…”

Section: Key Pointmentioning

confidence: 99%

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

Caraceni

Abraldes

Ginès

et al. 2021

Journal of Hepatology

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Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.

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Pharmacokinetics of DUR-928 in alcoholic hepatitis patients - a phase 2a study

Cited by 2 publications

References 0 publications

25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

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