Pump Prime Awards
Workshop: Clinical Trial Readiness for CNS Drug Delivery – 8-9 November 2021
On 8-9th November 2021, we held our third workshop, this time specifically focussing on clinical trial readiness for CNS drug delivery.
During this event, we launched a pump prime funding opportunity for projects that will move trial proposals into an advanced state of readiness.
We awarded three pump prime awards, two of which are detailed below. We are awaiting the signed agreement before we can share details of the third project.
Antonios Pouliopoulos, Kings College London
Focused ultrasound for targeted carboplatin delivery in Diffuse Intrinsic Pontine Glioma
Although submitted as part of CBTDDC's 'Clinical Trial Readiness' pump prime opportunity, this project is funded by Abbie’s Army, who partnered with us on this initiative.
Patients with diffuse intrinsic pontine glioma (DIPG) have limited treatment options and poor outcomes, leading to a median survival of 9 months. Most drugs fail partly due to the blood-brain barrier (BBB), which blocks them from entering the brain.Focused ultrasound (FUS) in combination with microbubbles allows targeted and non-invasive BBB opening, thereby increasing the dose delivered to the tumour.
FUS-mediated drug delivery has been tested for over two decades in animal models,and is rapidly translating into the clinic. We have developed a neuronavigation-guided FUS system, which is being used in a phase I trial in DIPG patients in the US (NCT04804709). The US trial aims to enhance delivery of oral panobinostat. Here, we will combine FUS with intravenous carboplatin.
We have previously tested the FUS system in non-human primates, and have established its radiological, histological and behavioural safety. Regulatory authorities are expected to request additional data with a DIPG model, so this project will use a DIPG mouse model. The aims are to: (1) establish radiographic and histological safety of the system using clinically relevant parameters, (2) demonstrate local control of the disease through MRI, and (3) measure the drug delivery increase and survival benefit compared with control mice. The preclinical evidence we gather from this project will support an MHRA application for our phase I clinical trial.
Since starting the pump prime project, Antonios has been awarded £850k from the Little Princess Trust to develop focused ultrasound and thermosensitive liposomes for paediatric brain tumour treatment.
Wenbo Zhan, University of Aberdeen, UK
Optimisation of infusion catheter posture for improving convection-enhanced drug delivery to brain cancer
Convection-enhanced delivery (CED) can effectively bypass the blood-brain barrier. However, its delivery outcomes remain disappointing, mainly due to heterogeneous drug distribution and insufficient drug accumulation. These limitations can largely be attributed to the highly anisotropic brain tissue that is induced by widely distributed axon bundles.
Axons fibres in brain white matter form several cable-like bundles. These bundles present different orientations that vary considerably depending on location in the brain. These bundles can consequently guide the flow of drugs in undesired directions, and thereby reduce drug distribution. Optimising the CED infusion direction and infusion site with respect to local tissue anisotropy is critical to achieving maximal drug coverage of the tumour. This project aims to tackle this challenge through multiphysics modelling.
In this project, multiphysics modelling will be used to study the tissue-drug interplays upon CED. The model will be developed to cover the key intracerebral drug transport process. A 3D realistic brain model will be reconstructed from patient-specific MR images. The tissue anisotropy will be extracted from diffusion-tensor images for the same patient.
Through this project, we aim to identify the optimal posture of infusion catheter, both in terms of infusion direction and infusion site. This will then enable researchers worldwide to optimise the effectiveness of CED and reduce the risk of failure of CED trials.
The mathematical model for simulating CED has been developed. Based on the theory of fluid mechanics, mass transport and bioreaction, this model can predict the interstitial fluid flow and drug transport upon CED infusion. A 3D realistic brain model has been reconstructed from patient-specific MR images, and the mathematical model we developed has been applied to predict the drug distribution in this brain tumour model. We are now focusing on examining the impacts of infusion direction with respect to the orientation of local axon bundles.
Publications and grants
Tian Yuan, Wenbo Zhan, Asad Jamal, Daniele Dini. On the Microstructurally-Drive Heterogeneous Response of Brain White Matter to Drug Infusion Pressure. Biomechanics and Modelling in Mechanobiology. 2022, 21: 1299-1316. (DOI: 10.1007/s10237-022-01592-3)
Image-based modelling and optimisation of convection-enhanced delivery for combination therapyagainst heterogeneous human brain tumour, The Royal Society, PI, £12,000, Grant No. IES\R1\221015,12/08/2022 - 11/08/2024