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DISA Vascular has shown that with even a tenth of the drug
load compared to certain high dose Paclitaxel Eluting Stents,
the tissue response can be highly toxic if the drug is
released too quickly. While this toxic effect at the standard
endpoint of 28-days in the pig model looks angiographically
good - with a widely patent lumen - the histology shows that
this patency has been achieved through considerable necrosis
of the media, leading to a loss of tone, subsequent lumen
dilatation, stent malapposition and then an accumulation of
immature, amorphous, thrombus-like tissue between the stent
and the media. We found that at 3 months this unstable
environment resolves via a profound late-catch-up phenomenon,
leading to excessive neointimal hyperplasia. Typical examples
of these results are shown below:
DISA Vascular have subsequently developed a coating
formulation with a proven safe erodible polymer that provides
controlled and gradual release of a low total dose of
Paclitaxel (10µg on an 11mm stent) without an initial burst.
Sustained neointimal inhibition in the porcine model has been
demonstrated with this formulation even at the 3 month mark.
However the stent does allow for a small margin of late loss,
which we believe is necessary for endothelialisation and
safety. A small amount of stent coverage does not compromise
efficacy.
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28 Days |
3 Months |
Histology results
from Stellium porcine study
– slow release, total elution, stable, progressive healing |
A
series of 28-day and 90-day porcine coronary implant studies
was conducted by the American Cardiovascular Research
Institute (Atlanta, USA). A total of 15 pigs were used in
these studies and 45 implants were analysed. These included a
subset of drug-free implants, higher and lower dosing
variations and variations in dose-rate to investigate the
window of safety of the platform/drug delivery device.
There
were no premature deaths in these studies and all animals were
sacrificed at the protocol prescribed end-point. At time of
explant all stented arteries were widely patent. Histological
examination by an independent expert vascular histopathologist
confirmed consistent safety of the drug formulation across a
narrow range of total dose and elution rates in the porcine
coronary model through grading of various healing markers such as
inflammation, fibrin, necrosis and endothelial coverage. Results
also demonstrated significant neointimal suppression compared to
historical bare metal controls, suggesting a level of efficacy.
Based on these favourable results, DISA Vascular is currently
finalizing its
First in Man Clinical Trial
to determine the clinical safety of the Stellium DES. |
