Results on the preclinical efficacy of uric acid in ischaemic stroke published

The study was carried outwithin the framework of the Stroke Preclinical Assessment Network (SPAN) in the USA, a network of experimental laboratories focusing on cerebral ischaemia, coordinated by the Keck School of Medicine of the University of Southern California (USC). Dr. Ángel Chamorro, head of the Cerebrovascular Pathology Unit at the Hospital Clínic Barcelona-IDIBAPS, scientific advisor at FreeOx Biotech and Assistant Professor at the University of Iowa, is one of the study’s signatories.

Stroke is a disease with a very high social impact and occurs when a blood clot cuts off the blood supply to part of the brain. It is estimated that one in four people over 25 will have a cerebrovascular accident in their lifetime, and each year over 12.2 million people have an ischaemic stroke worldwide.

During the first few hours after a stroke, it is crucial to act quickly, since on average two million brain cells die every minute. Current treatments aim to restore the blood flow, eliminating the clot through the administration of anticoagulants to dissolve it, by removing it surgically, or through a combination of both methods.

“Although these treatments help patients to recover, in the field of stroke we are looking for a therapy that can protect the brain from damage, a treatment with cerebroprotective activity”, says Ángel Chamorro.

Preclinical studies in animals had identified numerous promising therapies with neuroprotective effect, but the results had not been replicated in subsequent clinical trials.

Redesigning the preclinical approach

The aim of the SPAN study was to identify the most promising molecules for their subsequent assessment in pivotal phase III clinical trials funded by The National Institute of Neurological Disease and Stroke (NINDS) of the U.S. National Institutes of Health (NIH), which created the network.

In the current study, six candidate therapies were selected based on previous research showing evidence that they might be effective in treating stroke. Animals were randomly assigned to treatment and researchers from six different laboratories tested one of the therapies or a placebo. The efficacy of each treatment was assessed by giving the animals a series of behavioural tests.

After collecting these data, the researchers used a new statistical method to evaluate the therapies at four points in the testing process. They also measured MRI brain scans of the lesion volumes. Based on the test results, the treatments that failed to show sufficient efficacy were abandoned.

In addition to incorporating scientific rigour into the preclinical testing, the researchers used animal models that resembled typical stroke patients.

"We are faced with a critical need to redesign the entire preclinical approach", explained Dr. Francesca Bosetti, programme director at NINDS. “SPAN successfully applied well-known clinical research practices to a preclinical trial: randomization, predetermined sample sizes, treatment masking, blind analysis and efforts to make results reproducible in other laboratories”.

After two years of preclinical experiments, the SPAN study identified Uric Acid as the only effective treatment out of all the therapies evaluated in the different phases of the project.

Uric Acid is a neuroprotectant and cerebral reperfusion enhancer identified by Dr. Ángel Chamorro at the Hospital Clínic Barcelona-IDIBAPS and transferred to FreeOx Biotech for its development as a drug, Ox-01. This drug has been granted a patent in the USA for its use in combination with mechanical thrombectomy in ischaemic stroke. It had already demonstrated clinical relevant benefit in a pre-specified subgroup of stroke patients in the phase IIb clinical trial URICOICTUS led by Dr. Chamorro, who states that, “The SPAN study was carried out in animal models of ischaemic stroke, in experimental conditions with the maximum methodological rigour, which positions Uric Acid and FreeOx in an advantageous position for the clinical validation of Ox-01 in an upcoming pivotal clinical trial in stroke patients treated with mechanical thrombectomy”.

FreeOx Biotech is a spin-out of the Hospital Clínic de Barcelona-IDIBAPS, which develops innovative drugs that act by reducing oxidative stress processes in the body, especially those related to the neurological and cardiovascular systems. The company was founded in 2017 by Ángel Chamorro, Carlos Lurigados, Ángel Honrado, Tudor G. Jovin and Joan Bigorra, and has been granted a patent in the USA for the use of Uric Acid in Stroke in combination with Mechanical Thrombectomy

Image: Dr. Ángel Chamorro, study co-author (Photo: Francisco Avia).

Study reference: Lyden, P.D., et al. A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke. Science Translational Medicine. September 20, 2023. DOI: 10.1126/scitranslmed.adg8656