ICF: Defining the role of PDE5 on cerebrovascular function in small vessel disease

Cerebral small vessel disease (cSVD) is the commonest vascular cause of neurodegeneration and causes at least 40% of all-cause dementia. cSVD affects >50% of people over 65. It is defined by progressive injury to cerebral small arteries, manifest by key imaging features on MRI. The underlying pathology remains unclear despite our demonstration of strong associations with endothelial dysfunction, impaired white matter perfusion and impaired control of cerebral blood flow. There is currently no specific treatment for SVD. PDE5 inhibitor drugs target the endothelium-dependent, nitric oxide-driven vasodilatory pathway, with the potential to reverse cerebrovascular dysfunction in cSVD. Recent Mendelian Randomisation analyses identified PDE5 underactivity as potentially causally associated with both imaging markers of cSVD and risk of dementia. We have recently shown that PDE5-inhibition improves cerebral blood flow and cerebrovascular reactivity, reversing SVD-associated dysfunction, but important knowledge gaps remain. These include the mechanism and locus of action for PDE5 effects on cerebrovascular dysfunction, and specifically, the balance of PDE5 effects on systemic perfusion, cerebrovascular function and cerebral tissue-level effects on neurodegeneration. The small molecule Mirodenafil® is a higher-specificity, higher-potency, CNS-penetrant PDE5 inhibitor (PDE5i) compared to alternative PDE5is, with excellent tolerability. Mirodenafil reduced biomarkers of Alzheimer’s Disease (AD) in phase-2 studies, and is being tested for efficacy in the POLARIS-AD phase-3 trial. However, the effects of mirodenafil in vascular causes of neurodegeneration, particularly in SVD, are unknown. Mirodenafil thus provides a readily-available intervention to test the site and role of PDE5-mediated vascular versus tissue-level dysfunction, with a clear pathway to translation for patient benefit via clinical trials. Hypotheses: PDE5-mediated dysfunction is present in both vascular and tissue-specific mechanisms in cSVD. PDE5-inhibition with the highly-selective, brain-penetrant PDE5i mirodenafil will reverse this dysfunction at multiple sites. PDE5-inhibition with mirodenafil has a predominant effect on cerebrovascular vasodilatory function across different doses. We propose an experimental, randomised, blinded, crossover, placebo-controlled, dose-ranging study, to test the effects of PDE5 inhibition at each site in the cerebral perfusion pathway, on mechanisms of cerebrovascular regulation compared to tissue-specific mechanisms. We will quantify the dose-dependent effects of mirodenafil on physiological measurements for which we have established expertise, but which are not used in clinical practice. Older people with chronic SVD defined on MRI (N=82), will receive placebo, 10mg, 30mg and 60mg of mirodenafil in randomised order, for 4 weeks on each dose. After detailed clinical and cognitive phenotyping, at each visit they will undergo: physiological testing with transcranial ultrasound for cerebral blood flow, cerebrovascular reactivity, and systemic cardiovascular function; plasma biomarkers for tissue-specific mechanisms; cognitive testing (DSST). On placebo and 60mg, they will have a physiological-MRI including reactivity, neurovascular coupling and blood brain barrier breakdown. The primary outcome is grey matter cerebrovascular reactivity on MRI for placebo versus 60mg mirodenafil. Secondary outcomes will determine the dose-response relationship of mirodenafil with: cerebral perfusion; cerebral blood flow velocity ; blood-brain barrier permeability; plasma biomarkers of amyloid, endothelial activation (VCAM/ICAM), blood brain barrier function (S100b) and neuronal injury (NFL) Impact. This experiment will provide detailed mechanistic information on a potentially causative pathway in cSVD. Specifically, it will delineate the role of nitric oxide-PDE5 vascular and tissue-specificpathways relevant to neurodegeneration, and identify opportunities to modify them. The existing strong relationship with our industry partner AriBio will enable future translation and development of novel therapeutics in SVD-related dementia, a major untreated patient group.