Resolution Therapeutics: pioneering macrophage therapies for liver diseases
2024 has become a pivotal year in the history of liver diseases with the long-awaited first FDA approval for a drug to treat metabolic dysfunction-associated steatohepatitis (MASH) – the fatty liver disease that big pharma had targeted for decades.
First described in 1980, MASH is the advanced stage of metabolic-dysfunction-associated steatotic liver disease (MASLD) where the body begins storing excess fat in the liver.
While this fat storage does not always cause problems, it can inflame and damage the liver, causing scarring, cirrhosis and liver failure in patients who are not using large amounts of alcohol.
It was Madrigal Pharmaceuticals that was first to gain an historic “yes” from the FDA for its Rezdiffra (resmetirom) in March 2024, although there are many potential competitors chasing it down.
But Rezdiffra could be the tip of the iceberg for MASH and related liver diseases, with many other potential therapies making their way through the pharma pipeline.
UK based Resolution Therapeutics (Resolution) is hoping that the approval of Rezdiffra will pave the way for other treatments for liver diseases.
Following approval by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) in June, Resolution, based in Edinburgh and London, is gearing up for the Phase I/II EMERALD study for its lead candidate RTX001 in decompensated liver cirrhosis.
This followed breakthrough data published at the European Association for the Study of the Liver (EASL) Congress in Milan at the beginning of June.
Macrophage technology
Following the announcement, Optimum caught up with Lara Campana, Resolution’s VP of Research Operations, for a podcast briefing on the company’s technology, which aims to unlock the regenerative potential of immune cells known as macrophages.
RTX001 is an engineered autologous (taken from the patient) macrophage cell therapy, designed to tackle fibrosis (scarring) and inflammation in patients with end-stage liver disease.
It is engineered using a unique combination of therapeutic genes known to be expressed in macrophages to enhance the inherent regenerative properties of the modality for superior efficacy and durability.
As well as EMERALD, Resolution is running the ongoing OPAL study a multi-centre natural history study in patients with liver cirrhosis who have been hospitalised for the first time with hepatic decompensation.
The objective of the OPAL study is to generate novel data on disease trajectory to optimise the control arm for the planned EMERALD study. EMERALD is an open-label first-in-human study of RTX001 measuring clinical events as the primary efficacy endpoint and could begin as early as the third quarter of 2024.
Campana told the podcast that Resolution intends RTX001 to be the leader in a pipeline of products based on macrophage cell therapy, focusing on inflammatory organ damage.
“Inflammatory organ damage is one of the major killers and unmet medical needs of the 21st century and Resolution proposes to utilise macrophages with a very specific phenotype, that we call pro-regenerative, to combat the inflammation and fibrosis that often comes in these types of diseases.”
The first target organ is the liver, in particular end-stage liver disease, Campana explained, the only chronic disease that is on the rise in the UK and other developed countries with major unmet need and no current available therapy.
Campana had studied the role of macrophage phagocytosis in acute and chronic liver injury at the University of Edinburgh.
This was sparked by a long-term research interest in the role of inflammation in tissue repair after gaining a PhD in Cellular and Molecular Immunology as part of a programme run by the San Raffaele University in collaboration with the UK’s Open University.
Campana co-founded Resolution with Prof. Stuart Forbes, Professor of Transplantation and Regenerative Medicine at the University of Edinburgh, and Dr Philip Starkey Lewis, who was also part of Prof. Forbes’ research group.
Campana had been working in the field since 2006 and has been inspired by a “fascinating” medical problem of the underlying mechanism causing sclerosis.
Until recently there had been comparatively little research into the phenomenon and Campana has been driven on by the lack of available treatments for patients with end stage liver disease.
For patients with decompensated liver disease, the very end stage of the disease, survival expectancy is similar to certain cancer patients, between nine months and two years.
Patients are often of working age so there is also a huge impact on their families and friends, Campana noted.
“There is a human aspect to liver disease that I think it’s very important to be mindful of. That really inspires me and inspires everyone at Resolution,” she said.
Liver transplant is the only option available – but organs are not always available, it’s a complex procedure, not all patients are well enough to withstand it, and aftercare is complicated too.
Macrophage therapy
Resolution says that RTX001 could help very sick patients with its double action, acting on the scarring and inflammation associated with the condition.
“Our pro-regenerative macrophages are able to directly secrete enzymes that ‘chew’ on the scars, so eat the scar away, and they are also able to stop the cells that produce the scars from producing more scar [tissue].”
They also eat all the dead and dying cells and bacteria so that they create a clean environment for liver regeneration.
Crucially, they recall other macrophages from the patient. “So, if you give one therapeutic macrophage, after a while you will have many therapeutic macrophages in the liver. That amplifies the anti-inflammatory and anti-fibrotic effect.”
Campana also gave an overview of the recent Phase 2 MATCH study, which provided proof of concept for RTX001 involving 50 patients in Scotland with cirrhosis caused by a variety of different factors, such as alcohol, fatty liver disease, and viral hepatitis.
This provided a strong efficacy signal, with a significant reduction in death and severe liver events in the treated group compared with a control group, 2.5 years after injection with the therapy.
This builds on the findings of a Phase 1 trial that provided supportive safety and dosage data, and the company will look to replicate findings in the Phase I/II EMERALD study, also involving RTX001.
The primary analysis will focus on safety and major clinical events including death. The study will also evaluate biomarkers such as the Model for End-Stage Liver Disease (MELD) score which is used to assess disease severity and prioritise patients for a transplant.
Preparations under way
EMERALD will focus on sicker patients and Resolution expects to see the benefit earlier, as patients in the control group will likely develop events earlier.
Resolution is busy building manufacturing capabilities and preparing logistical arrangements so that the trial can go ahead.
“We have to take the cells of the patients, take them into our GMP facility, manufacture them and then send them back at the treatment centre to be administered to the patient.”
The first site is expected to begin recruiting in September and is hoping to treat the first patients with cells at the beginning of November. When the trial is in full swing, there will be around 10 sites in the UK and five in Spain, where talks are ongoing with regulators for clinical approval.
Campana is excited about the potential of the therapy, for patients and the healthcare systems around the world, where costs could be saved by prevention of expensive transplant procedures.
She’s also hopeful the technology could be used earlier in liver disease to prevent it from becoming decompensated.
“If one can dream what can happen in the next 10 years, it would be good to see how Resolution and others could evolve this technology,” she concluded.
