Engineered macrophages for treating liver cirrhosis

An Open-label Phase 1/2 Multicentre Study to Evaluate the Safety, Tolerability and Efficacy of RTX001 Autologous Macrophages in Participants With Liver Cirrhosis Who Have Hepatic Decompensation (EMERALD)

This study is testing a new treatment using specially modified immune cells to see if it can help people with severe liver disease feel better and improve their liver function.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Resolution Therapeutics Limited (network)
• Drugs / interventions: prednisone
• Locations: 14 sites (Barcelona and 13 other locations)
• Trial ID: NCT06823713 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and efficacy of RTX001, an autologous engineered macrophage cell therapy, in patients with end-stage liver disease who have recently recovered from hepatic decompensation. Participants will undergo leukapheresis to collect their white blood cells, which will then be processed to create RTX001. The study is designed as a Phase 1/2 open-label trial, comparing the results to external control data from a related natural history study. The goal is to determine if this innovative therapy can improve liver function in affected individuals.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18-75 with a diagnosis of liver cirrhosis who have experienced a recent major hepatic decompensation event.

Not a fit: Patients with liver cirrhosis who have not experienced a recent decompensation event or those with other severe comorbidities may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could significantly improve liver function and quality of life for patients with end-stage liver disease.

How similar studies have performed: While this approach is novel, similar studies involving macrophage therapies have shown promise in other conditions, indicating potential for success.

Eligibility criteria

Individuals eligible to participate in this study must meet the following criteria:

Inclusion Criteria:

1. Male or female age ≥18-75 years.
2. Patient confirms willingness/ability to comply with all study procedures.
3. Diagnosis of liver cirrhosis based on at least one of:

   1. Clinical and radiological features that correlate with a diagnosis of cirrhosis.
   2. Transient elastography (Fibroscan) \>15 kPa.
   3. Previous liver biopsy confirming histological features of cirrhosis.
4. Aetiology of liver disease of steatotic liver disease including MASLD or Met-ALD or ALD

   a. Participants with alcohol-related liver disease (ALD or Met-ALD) only if they are confirmed to not be drinking alcohol above Met-ALD limits defined in this protocol. (N.B. No more than 34% of the total treated participants in this protocol will be ALD \[excludes Met-ALD\]).
5. Hospitalised as an inpatient for a recent major hepatic decompensation event including ascites, hepatic encephalopathy, variceal bleed, HRS-AKI or SBP, this being the only hospitalisation for an hepatic decompensation event hospitalisation within the last 6 months, and where recent is defined as within 6 weeks of hospital discharge.
6. Outpatient: Medically refractory ascites (ONLY), that recurs (i.e., second therapeutic LVP) within a 6-month period. Medically refractory ascites is defined by the repeated (≥2) need for LVP (i.e., therapeutic, not diagnostic) at least once per 8 weeks despite best medical attempts to control the ascites by sodium restriction and diuretic treatment, as confirmed by the Investigator. Onset is defined as the date of the second therapeutic LVP.
7. Confirmatory PEth alcohol test \<200 ng/ml
8. MELD score of 12-20 taken within two weeks of 'qualifying' decompensation event.
9. No known contradictions to filgrastim or leukapheresis procedure.
10. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
11. Willing and able to give signed informed consent, and if applicable assent.

Participants are excluded from the study if any of the following criteria apply:

Exclusion Criteria:

1. Liver cirrhosis due to:

   1. any viral hepatitidies, or
   2. autoimmune and cholestatic aetiologies including, but not limited to, primary biliary cholangitis and primary sclerosing cholangitis.
2. Acute liver disease in the absence of underlying liver cirrhosis, including, but not limited to, drug induced liver injury.
3. Any current organ failure requiring more than outpatient supportive care, and not associated with the participant's qualifying hepatic decompensation event.
4. Known splenomegaly ≥16 cm.
5. Thrombocytopenia \<50×109/L.
6. Presence or suspicion of any of the following co-morbidities:

   1. History of liver transplantation or other organ transplant.
   2. ACLF.
   3. Sepsis (with positive microbial cultures) or as defined by the Principal Investigator, unless stable and is at least 4 weeks after having completed a full course of IV antibiotics.
   4. Known human immunodeficiency virus.
   5. Known syphilis.
   6. Known human T-lymphotropic virus 1.
   7. Pulmonary embolism.
   8. Hepatocellular carcinoma, or any active malignant disease within the last five years, (excluding non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, benign polyps etc.).
   9. Co-hepatic morbidities e.g., portal vein thrombosis.
   10. Participants with hepatic hydrothorax are excluded unless it is a small hydrothorax, not clinically apparent, that is detected incidentally by radiologic evaluation that does not require clinical intervention.
   11. Chronic renal impairment (on dialysis) or unresolved AKI.
   12. Acute or chronic heart failure (New York Heart Association Grade III/IV).
   13. Porto-pulmonary hypertension.
   14. Severe chronic lung disease e.g., chronic obstructive pulmonary disease or interstitial lung disease where the forced expiratory volume in the first second (FEV1) is less than 50% and/or FEV1/forced vital capacity is less than 60%.
   15. Hepatopulmonary syndrome.
   16. Previous or current treatment with multiple infusions of albumin for therapeutic intent. \[Use of albumin infusion at the time of large volume paracentesis for circulatory support is allowed.\]
   17. Significant untreated/unstable psychiatric disease.
   18. Transjugular intrahepatic portosystemic shunt (TIPSS).
7. As judged by the Investigator, any evidence of intercurrent illness that is either life threatening or of clinical significance such that it might limit compliance with study procedures.
8. Current or planned use of immunomodulators or immunosuppressive medication; note: low doses of corticosteroids up to 10 mg/kg/day prednisone or equivalent are permitted, or inhaled steroids to manage asthma.
9. Received a gene or cell therapy at any time.
10. Current or planned use of a live attenuated vaccines four weeks or fewer prior to enrolment (and for 3 months after the last administered dose of RTX001).
11. Received any investigational product within the past 6 months, or five half-lives (whichever is longer) or participated in another investigational interventional study within 30 days prior to the screening visit.
12. Participants with a known hypersensitivity to dimethyl sulfoxide (DMSO).
13. Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
14. For female participants only - pregnant or breast-feeding or plans to become pregnant over the next year, or of childbearing potential and unwilling to comply with contraceptive requirements.
15. Alcohol misuse in the period between identification of the participant as potentially suitable for this study to Screening (Visit 1), defined as alcohol intake greater than three units/day for females and four units/day for males, or binge drinking (\>14 units/day) as determined by the Investigator. N.B. One unit is equivalent to 14 g of alcohol: a half-pint (\~240 mL) of beer, one glass (125 mL) of wine or one (25 mL) measure of spirits.
16. Intake of non-medically supervised drugs of abuse that are judged (by the Investigator) to be a high risk to the participants acute health or which makes the participant likely to be non-compliant with follow-up.

Where this trial is running

Barcelona and 13 other locations

• Hospital Universitari Vall d'Hebron — Barcelona, Spain (RECRUITING)
• Hospital Universitario Reina Sofía — Córdoba, Spain (RECRUITING)
• Hospital General Universitario Gregorio Marañon — Madrid, Spain (RECRUITING)
• Hospital Universitario Ramón y Cajal — Madrid, Spain (RECRUITING)
• Hospital Universitario La Paz — Madrid, Spain (RECRUITING)
• Hospital Universitario Virgen del Rocío — Seville, Spain (RECRUITING)
• Bristol Royal Infirmary — Bristol, United Kingdom (RECRUITING)
• Royal Infirmary of Edinburgh — Edinburgh, United Kingdom (RECRUITING)
• Glasgow Royal Infirmary — Glasgow, United Kingdom (RECRUITING)
• Royal Liverpool University Hospital — Liverpool, United Kingdom (RECRUITING)
• King's College Hospital — London, United Kingdom (RECRUITING)
• St George's Hospital — London, United Kingdom (RECRUITING)
• St Mary's Hospital — London, United Kingdom (RECRUITING)
• Nottingham University Hospital — Nottingham, United Kingdom (RECRUITING)

Study contacts

• Study coordinator: Resolution Therapeutics Clinical Enquiries

Conditions: End-stage Liver Disease, Cirrhosis, Liver, Cirrhosis, Decompensated, Liver Diseases, Fibrosis and Cirrhosis of Liver, Decompensated Liver Cirrhosis, Decompensated Cirrhosis, Steatotic Liver Disease