New drug trial could prevent deadly side-effect of cancer immunotherapy
A clinical-stage biopharmaceutical company based in London is about to test an oral drug at six NHS hospitals that, if successful, could stop patients on cancer immunotherapy developing a life-threatening overreaction of the immune system. The drug, POLB 001, is being developed by Poolbeg Pharma as a preventative therapy for cytokine release syndrome (CRS), a condition that can lead to organ damage and death.
Preventing the immune storm
CRS — often described as a cytokine storm — occurs when cancer immunotherapies such as CAR T-cell and bispecific antibody treatments activate T-cells to fight tumours, but the response becomes uncontrolled. Those T-cells release an excessive flood of signalling proteins called cytokines, triggering widespread inflammation that can damage organs including the heart, lungs, kidneys, liver and brain. In severe cases the inflammation can cause multi-organ failure and prove fatal.
Symptoms typically begin with fever and a raised heart rate, then may escalate to chills, dangerously low blood pressure, muscle and joint pain, fatigue, difficulty breathing, nausea, vomiting and diarrhoea. There is currently no approved therapy to prevent CRS, and its unpredictability means patients must be treated in specialist cancer centres where intensive care is immediately available. Jeremy Skillington, Poolbeg’s chief executive, said: “If somebody’s living in rural UK, they’re going to have to come up to London or go to a big city … because CRS is potentially fatal. There’s no diagnostic – you can’t predict who will develop it.”
About 70% of people receiving cancer immunotherapies from companies including Johnson & Johnson, Gilead, Novartis and AstraZeneca develop CRS. For CAR T-cell therapy, incidence can be as high as 70–90%. A related neurological side effect, known as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), can also occur — particularly with the same therapies — and may cause confusion, delirium, tremors, slurred speech, seizures or coma. ICANS often appears in patients who have already experienced CRS.
POLB 001 is an orally delivered p38 MAP Kinase inhibitor that works by blocking a specific cell signalling pathway involved in the excessive cytokine release. The drug was originally developed for chronic inflammation and was acquired by Poolbeg from Spain’s Palau Pharma. By keeping the immune response under control from the start, the company hopes to prevent CRS entirely. “You won’t develop CRS,” Skillington said.
The trial
The intermediate clinical trial, named TOPICAL, will enrol approximately 30 patients with relapsed or refractory multiple myeloma who are being treated with Johnson & Johnson’s bispecific antibody therapy teclistamab (sold as Tecvayli). Teclistamab works by binding to BCMA on myeloma cells and CD3 on T-cells, activating the immune system to destroy cancer cells, but it carries a high risk of CRS and neurotoxicity.
Patients will start taking POLB 001 at home before they begin cancer treatment, a design that allows a rapid read-out because CRS typically develops within days or weeks of starting bispecific antibody therapy. The trial is being led by the University of Manchester and the Christie NHS Foundation Trust. Dr Emma Searle (MBChB MA MRCP FRCPath PhD) is the chief investigator. Six NHS hospitals across the UK are participating: the Christie in Manchester, the Royal Marsden in London, University College London Hospitals, University Hospitals Birmingham, NHS Lothian in Edinburgh, and Royal Stoke University Hospital.
The UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted Clinical Trial Authorisation for the study. Poolbeg expects to have interim data by the end of the summer. The TOPICAL trial is part of a broader research programme called RISE (Reducing Immune Stress from Excess cytokine release in advanced therapies), which is supported by a £3.4 million grant from the Medical Research Council. Poolbeg is the lead business partner in the programme, alongside Johnson & Johnson and others. Johnson & Johnson is supplying teclistamab at no cost to the trial.
Cost savings for the NHS
If POLB 001 proves effective, it could transform how cancer immunotherapies are delivered. Currently, patients receiving these treatments must be supervised in centralised specialist cancer centres for two to three weeks because of the risk of CRS. That requirement ties up expensive hospital beds and limits the number of patients who can be treated. Skillington said the NHS was “bursting at the seams” under cost and demand pressures. “If you can reduce that burden, that’s the ultimate goal.”
By preventing CRS, the drug could allow care to take place in community hospitals, cutting the cost per patient and freeing up capacity in major cancer centres. Poolbeg estimates that about half a million people diagnosed with the blood cancers multiple myeloma and diffuse large B-cell lymphoma will receive immunotherapy by 2031 in the United States and the five largest European countries. Currently, a course of cancer immunotherapy can cost $300,000 to $400,000. Poolbeg has suggested a potential price of $20,000 (£15,000) per POLB 001 treatment, which would make a market worth up to $10 billion. Independent US payer research has indicated multi-billion-dollar peak sales potential in the United States alone.
Poolbeg Pharma was spun out of the clinical research organisation hVIVO in July 2021 and listed on the London Stock Exchange’s Aim market, raising £25 million to develop medicines. The company is named after the Poolbeg peninsula in Dublin by its co-founder, Irish entrepreneur Cathal Friel. hVIVO, also based in Canary Wharf, traces its roots back to Retroscreen Virology, which was spun out of Queen Mary University of London in 1989 by Professor John Oxford. Separately, Poolbeg is developing an oral encapsulated GLP-1 weight loss pill with the Irish microencapsulation company AnaBio Technologies. That drug will be tested in 20 healthy volunteers with a body mass index of more than 30 in an early-stage trial later this year, led by Dr Carel Le Roux, professor of metabolic medicine at Ulster University.
