Aladote® (PP-100)

Preventive treatment of acute liver failure caused by acetaminophen/paracetamol poisoning

Aladote® (active ingredient: calmangafodipir) is being developed to counter the onset of acute liver failure caused by paracetamol (acetaminophen) poisoning. Paracetamol is one of the most commonly used drugs in both deliberate and accidental overdoses.

High concentrations of paracetamol breaking down in the liver can lead to acute liver failure, and even death. The current treatment for paracetamol poisoning (N-acetylcysteine) is effective if the patient seeks medical care within 8 hours of ingestion. However, there is currently no well-functioning treatment for patients who arrive more than 8 hours after ingestion.

Preclinical studies have shown that Aladote® was effective in animal models for a much longer period than N-acetylcysteine (NAC). An Aladote® safety and tolerability study began in May 2017 at the Edinburgh Royal Infirmary. The trial is being led by Dr James Dear, Reader in Pharmacology at the University of Edinburgh. PledPharma is currently preparing the initiation of a clinical Phase II study.

One of the most common causes of drug poisoning

Intentional or accidental overdose of paracetamol is one of the most common methods of poisoning. Most people experience few or no symptoms during the first 24 hours after poisoning. However, if patients do not receive treatment within the first 24 hours after an overdose, it can lead to acute liver failure – which can result in the need for liver transplantation and, in severe cases, death.

In the US, paracetamol poisoning leads to 78,000 emergency room visits, 33,000 hospitalizations, and hundreds of deaths every year. The UK has the highest numbers of paracetamol poisonings in the world, where it is the leading cause of acute liver failure, and leads to more than 38,000 hospital admissions every year. In Sweden, the number of calls to the Poison Information Centre referring to paracetamol poisoning has increased threefold since 2000.

About acute liver failure

Acute liver failure severely damages liver function, and has a high mortality rate if it is left untreated. Although there are various causes of acute liver failure, the most common is paracetamol poisoning. Other causes include acute viral infections, poisoning with mushrooms or other drugs, and severe liver disease.

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The figure shows the protective effect of acetylcysteine over time, after administration of a hepatotoxic dose of acetaminophen. During the metabolic phase, acetaminophen is partly converted (metabolized) to NAPQI. Following binding to glutathione, NAPQI may be excreted through the kidneys. High doses of acetaminophen deplete liver glutathione layers and a consequential binding of NAPQI to liver cells. This causes severe oxidative stress. NAC exerts its effect during the degradation of acetaminophen (metabolic phase) by restoring the glutathione layers. However, during the latter part of the poisoning, when the glutathione layers are exhausted (oxidative phase) and NAPQI has been bound to the liver cells, NAC has no protective effect on the liver. As Aladote® enhances the body’s defense against oxidative stress; the drug candidate can thereby protect liver cells.

Treatment of acetaminophen poisoning and acute liver failure

Early symptoms of acute liver failure are usually mild or non-existent, meaning that many patients do not realise that anything is wrong, and do not seek medical advice until it is too late.

N-acetylcysteine is an antidote for paracetamol poisoning which acts by increasing the formation of glutathione in the liver, which binds with toxic metabolites. Administration of N-acetylcysteine within eight hours after ingestion results in an almost complete protection against liver damage. However, more than eight hours after ingestion there are currently no drugs available for treating paracetamol poisoning. Liver transplantation is the only remaining treatment option for acute liver failure.

Preclinical studies have suggested that Aladote® may be effective for patients who are treated after the eight-hour limit for N-acetylcysteine. This has the potential to reduce the need for liver transplantation in patients who present when N-acetylcysteine’s efficacy is impaired or exhausted.

Preclinical data indicates protective effect in late-presenting patients

Preclinical studies show that Aladote® enhances the body’s defence against oxidative stress, and so protects liver cells during paracetamol poisoning. Aladote® also appears to be more effective than N-acetylcysteine in lowering the level of ALT (enzyme), especially in the later stages of paracetamol poisoning. ALT levels of above 1000 units/litre is a biological marker of acute liver failure in humans. These results suggest that Aladote® may be effective for patients who present more than eight hours after their overdose, when N-acetylcysteine is minimally effective.

Clinical development program

A clinical study evaluating the safety and tolerability of Aladote® was initiated in May 2017. The 24-patient trial is being conducted at the Edinburgh Royal Infirmary, and is being led by Dr James Dear, Reader in Pharmacology at the University of Edinburgh.

Following the completion of the safety and tolerability study, PledPharma plans to conduct an initial Phase II dose-finding study of Aladote® in paracetamol poisoning patients. Up to three different doses will be evaluated and compared to placebo. In the planned study, each patient will be treated individually and repeated dosages will be administered until the liver enzymes (ALT and AST) have stopped rising or have stabilized. A larger, confirmatory study will be conducted before the drug can obtain marketing approval.

As N-acetylcysteine is widely acknowledged as inadequate for patients who don’t present until more than eight hours after their overdose, and provided that PledPharma’s drug candidate proves to have the efficacy demonstrated in animal models, an application to the FDA for “breakthrough” status might be feasible.

The market potential for Aladote®

N-acetylcysteine is the current treatment for paracetamol poisoning. When administered within eight hours after ingestion of paracetamol, N-acetylcysteine provides an almost complete protection against liver damage. The problem with N-acetylcysteine is that its efficacy gradually decreases, and after 15 hours the antidote effect is minimal. Preclinical results have shown that Aladote® is effective for much longer than N-acetylcysteine.

According to leading clinicians and researchers in paracetamol poisoning, as well as scientific literature, it is estimated that the proportion of patients arriving more than eight hours after ingestion is between 25 and 30 percent of all cases of paracetamol poisoning. In the US alone, this would mean that there are approximately between 20,000 and 24,000 patients annually who require a treatment that is effective beyond eight hours after ingestion.

To the knowledge of PledPharma, there are currently no drugs on the market or in clinical phase that addresses the need of these patients. Aladote® has the potential to become the leading treatment in this crucial area.

The cost of treatment of paracetamol poisoning patients is very high, as they require maximum intensive care, and in some cases liver transplantation. A treatment for the later stages of poisoning would have the potential to save lives, as well as reducing the costs and strain on healthcare systems.

IMS Health Capital calculates that a treatment for paracetamol poisoning within the extended treatment window could reach annual sales of 400-500 million USD in the United States alone.