Resolution Therapeutics raises $85 million to advance its macrophage therapy

Photo credits: Steve Johnson
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A week after Vicebio’s $100 million series B round, another U.K.-based biotech makes the headlines. Today, Resolution Therapeutics, a clinical-stage biotech company, secured $85 million (£63.5 million) in series B financing to advance its lead product candidate, RTX001, into clinical trials.

The financing led by Syncona will enable the company to push forward its macrophage therapy for the treatment of end-stage liver disease. With no effective treatments beyond liver transplants for these patients, RTX001 presents a first-in-class potential solution.

RTX001 is an engineered, pro-regenerative macrophage therapy that leverages the body’s immune system to counteract the severe inflammation and fibrosis that characterize end-stage liver disease. As the company gears up for the phase 1/2 EMERALD clinical trial, set to begin patient recruitment by Q4 2024, let’s take a look at how the treatment fits into the current landscape of end-stage liver disease and macrophage therapies.

This financing round also supports further pipeline growth and manufacturing enhancements, positioning Resolution Therapeutics in a good spot of regenerative medicine for fibrotic diseases.

Resolution Therapeutics’ approach: Engineering pro-regenerative macrophages

Macrophage therapy is a promising approach in regenerative medicine due to the critical role macrophages play in tissue repair and inflammation resolution. In healthy individuals, macrophages remove damaged cells and initiate tissue repair, making them a key target for therapeutic interventions in diseases characterized by chronic inflammation and fibrosis, like end-stage liver disease​, Resolution Therapeutics’ primary area of focus.

Amir Hefni, chief executive officer (CEO) of Resolution Therapeutics explained where the idea for the macrophage therapy started.

“The idea came from studies carried out in Professor Forbes’ lab that highlighted how macrophages with a pro-regenerative phenotype were necessary for fibrosis remodeling and liver regeneration. Additional studies demonstrated how macrophages with this phenotype were able to inhibit scar formation in models of chronic liver injury. Together with Professor John Campbell, they recapitulated these findings using human monocyte-derived macrophages and translated this into a first-in-human study in cirrhosis.”

In the context of late-stage liver disease, the liver becomes scarred and functionally compromised due to prolonged inflammation and fibrosis. Liver cirrhosis, a condition often leading to end-stage disease, has limited treatment options, with liver transplantation being the only definitive solution. 

“Today, patients with end-stage liver disease have no pharmacological treatment options. The only therapy available is a liver transplant, and few patients make it onto the transplant list. Unfortunately, not every patient is able to receive a transplant, and some will continue to deteriorate, often fatally. The prevalence of cirrhosis continues to grow, yet the shortage of available organs and the complexity of the surgery means there is an urgent need to develop new therapies for this patient population,” said Hefni.

Resolution Therapeutics is addressing this with its lead candidate, RTX001, an autologous, engineered macrophage therapy. This therapy modifies macrophages to express therapeutic genes that amplify their anti-inflammatory and anti-fibrotic effects. 

Patients with end-stage liver disease have significant inflammation and fibrosis impacting organ function and resulting in multi-organ complications, and reduced life expectancy. According to Hefni, pro-regenerative macrophages are particularly well suited to tackle this because they have two main functions.

“First is an anti-inflammatory activity. Second is an anti-fibrotic activity where macrophages break down scars and prevent the formation of new scars. Together, these enable the liver to recover sufficient function for patients to avoid further complications of the disease.”

“With RTX001, we engineered the cells to enhance the anti-inflammatory and anti-fibrotic properties by delivering payloads to transiently increase expression of genes already present in macrophages. We have also improved our manufacturing process to be able to produce and freeze multiple doses from a single leukapheresis,” explained Hefni.

Macrophage therapy: end-stage liver disease and beyond 

Hefni pointed out that macrophages were versatile immune cells with potential applications across a broad spectrum of indications. Resolution is focused on developing pro-regenerative macrophages in diseases where the anti-inflammatory and anti-fibrotic properties of macrophages are key to delivering transformative outcomes but that does not mean their potential stops there.

“We’ve identified graft-vs-host-disease and lung fibrosis as two promising therapeutic areas beyond the liver, where the biological rationale is particularly strong, and the size and severity of the unmet need is high,” added Hefni.

Resolution Therapeutics is not the only company developing macrophage therapy but its focus on fibrotic conditions makes it unique. Indeed, it is in oncology where macrophage therapy has made the most noise so far. 

Carisma Therapeutics is a prime example as the company appears as a clear frontrunner in the field. Its proprietary CAR-M (chimeric antigen receptor macrophages) platform focuses on genetically engineering macrophages to target and destroy cancer cells. These engineered macrophages are designed to reprogram the tumor microenvironment, drawing in other immune cells to enhance the anti-tumor response. 

The company is developing several CAR-M therapy programs in collaboration with Moderna but the candidates are still in preclinical stages. However, Carisma does not focus solely on oncology targets and might rise as a competitor for Resolution as it recently presented preclinical proof of concept data of its macrophage therapy for liver fibrosis. The company’s therapy demonstrated a 116% reduction in fibrosis compared to controls in a liver fibrosis model, marking their entry into non-oncology indications​.

However, Hefni thinks Resolution and RTX001 have an edge over their potential competitors.

“What makes RTX001 unique is its pro-regenerative phenotype aimed at tackling inflammatory and fibrotic diseases. Additionally, RTX001 has been engineered to increase the activity of existing genes critical for resolving inflammation and breaking down fibrosis. As a therapy, RTX001 has the potential to be outpatient-compatible, with a short infusion time and no requirement for patient pre-conditioning or bridging therapy. This means we expect RTX001 to benefit from a broad uptake beyond tertiary into secondary centers.”

The field of macrophage therapy isn’t that crowded and as it advances its candidates through the pipeline, Resolution could establish itself as a leader in the area.

What’s next for Resolution Therapeutics and macrophage therapy?

Hefni declared this series B round represented a major milestone for the company, allowing it to deliver the EMERALD phase 1/2  study, improve the manufacturing process, and expand its pipeline. 

“In the MATCH study conducted by the University of Edinburgh, where a single dose of non-engineered macrophages was given to patients with compensated cirrhosis, we saw macrophages were very well tolerated. Additionally, we saw significant improvement in survival and transplant-free survival, as was presented by Professor Forbes at EASL earlier this year in Milan. We hope EMERALD will show similar safety and efficacy in patients who have recovered from a recent hepatic decompensation.”

Getting RTX001 to market will come with its challenges and that is the reason why Resolution is trying to anticipate manufacturing in parallel with the EMERALD study. “Our short-term strategy has been to remove manufacturing capacity as a bottleneck to enable a timely execution of EMERALD. We also recognize the usual challenges faced by autologous cell therapies. This is why part of the proceeds from series B will be invested in process and analytical development to reduce both the cost of manufacturing and the vein-to-vein time of RTX001,” said Hefni.

Regarding the bigger picture for macrophage therapy, Hefni sees macrophages earning recognition as a new modality in cell therapy with great potential given their versatility of function and it will gain traction over the year to come. 

“We expect interest in macrophages to continue growing as their application across therapeutic indications is demonstrated clinically by companies like Resolution Therapeutics. In parallel, macrophage therapies will benefit from the ongoing investment in cell therapy more broadly, from logistics and infrastructure to manufacturing technologies and capacity,” said Resolution Therapeutics’ CEO.