In July 2016, the FDA approved the first absorbable stent for coronary artery disease: the Absorb GT1 Bioresorbable Vascular Scaffold (BVS) system. The Absorb GT1 is a non-metallic stent that releases the drug everolimus to limit the growth of scar tissue, ¬and – as its name suggested – is gradually absorbed by the body after implantation. Here, Richard Rapoza Divisional Vice President of R&D for Abbott Vascular, discusses the road to approval...
How did you come to work on Absorb?
After an undergraduate degree in chemical engineering, I started to consider further study in biology or medicine. So I went back to grad school and signed up for a PhD program in biomaterials, and studied the interactions of polymers with blood. After I graduated, I got a job creating coatings for medical devices that would prevent blood clots from forming on their surfaces. Since then, I’ve had the opportunity to work on various cardiovascular implants, with the latest being Absorb.
How long have you been a part of the project?
It started in 2003, and I joined the team in 2006 when we had the six-month first-in-human results. We had a small set of patients, mainly in New Zealand and Europe, and at six months the imaging results looked very good; the company was ready to commit to a higher-level effort. They assigned me to make that happen and, over time, the group developed from the original 30 people to almost 350.
What attracted you to the device?
Actually, when I learned about it, my first thought was “it will take a miracle to get this working!” I could see a technical path to implementing it, but I knew there would be many variables to adjust, and I couldn’t see any easy answers as to where those different variables might land.
We took it one step at a time, at first making best guesses as to what needed to be controlled and how that could be achieved. We soon learned that there were several key parameters, and recognized that, if we kept those under control, everything else would fall into place.
Can you tell us more about the development process?
First, we asked ourselves about the properties of metallic stents that make them effective. Long term, you’re really only wanting the stent to remain stable while not causing any adverse reactions. The short term is all about performing its crucial functions: it has to push the plaque out of the way, and to deliver enough drug to control the tissue reaction. Then, as with any permanent foreign body, the best you can hope for is that the body will adjust to it.
Next, the question became: how long does our stent need to look, feel and act like a metallic drug-eluting stent, before the body can take over? Our literature reviews suggested that we needed to keep the diameter of the blood vessel constant for the first six months, and the vessel could then take over. It was key that the polymer structure would need to stay intact, even in the presence of degradation, for at least six months.
What are the long-term drawbacks to metallic stents?
As we discovered in our research, blood vessels only need support for a certain amount of time, and the presence of the implant past that window is actually detrimental to the healing of the artery. A permanent metallic cage prevents the vessel from dilating when you engage in physical activity – the diameter you’re left with will always stay the same. You could make the argument that the target demographic (mainly elderly people) don’t necessarily engage in a lot of difficult physical activity, but the reality is that the age of the population in need of this intervention is going down. So it’s important to get the implant out of the way as soon as possible to restore activity in the vessel.
A more practical consideration is that many patients with metallic stents experience restenosis and may need repeat procedures, which are not easy to perform when there is already a metal cage in the vessel. You can run out of room because you can’t keep dilating the blood vessels with more implants – after two or three stents you run out of options. But with an absorbable stent, the patient can be treated four or five years later as if their lesion is brand new.
What were the biggest challenges?
Perhaps surprisingly, the biggest issue wasn’t technical. Instead, it was the mindset we faced. Once you get used to a technology that works (in this case, ten years of using metal stents) it affects everything. The methodology, all of the specifications, what’s considered good or bad – it’s all defined around a permanent structure. A good example is that most trials have looked at the diameter of the metal at implantation, then gone back to remeasure at six months. You then subtract new diameter from the original diameter and, if you assume the metal is not corroding or disintegrating, the difference between the two is the amount of tissue that has grown inside. But with a polymer implant, when you go in six months later, lo and behold, the body may actually have made the stent bigger ¬– so subtracting diameters means nothing. Interpretation of our data has to be different, and this can perplex physicians, who ask us how it can grow – it’s not a permanent diameter and it’s not metallic, we reply. The wrong mindset can throw even the best idea into a spin. We had to change everything – the interpretation of our clinical trial and engineering data, and also how we think and speak about the stent to people – so that our efforts wouldn’t be hampered by stagnant thinking.
Is there potential for the technology to be applied to other areas?
Absolutely. We were approached about using the material in infants with fluid accumulation in the ear canal. In theory, a smaller version of the product could be implanted through the throat into the back of the ear canal to drain the fluid that’s causing the pressure imbalance, and possibly also deliver an anti-inflammatory drug to the canal to ease the swelling. We haven’t had the bandwidth to pursue the idea yet, but I do think it could be a brilliant approach.
Looking purely at drug delivery, because the stent is temporary, there are many possibilities. We have looked at an application for glaucoma – putting a temporary implant behind the eye that could deliver the drug where it is needed, but then eventually disappearing. We’d have to reconfigure the geometry of the implant, but it’s another really appealing idea.
You’ve now been working on Absorb for over ten years – how have you found the process?
When you look back it seems like an awfully long time, but when you’re in the middle of it, it seems like that’s the way it should be! We had a lot of steps to work through – the first six month’s results improved our understanding of what was happening inside the artery. It took us about a year to make the technical corrections required – changes to the chemistry and geometry of the stent, for example. After that, we were ready for a larger clinical study. It was great to see from the six-month results for the second set of patients that our corrections had been effective. At that point, we were ready to invest in a larger effort – getting pivotal trials underway, scaling up manufacturing – everything required to make the device commercial. And we weren’t aiming for one or two countries, we wanted to gain approval in the EU, in the US, and in China and Japan.
So you can imagine: one year of technical adjustments, six months of follow up on those patients plus a year to enroll them, and you’re already at two and a half years. Add on FDA negotiations, setting up a US trial, more follow up...
How did it feel to get it out into the clinic?
It was wonderful to see patients being treated. You really lose track of what you’re doing when only analyzing data table after data table, while figuring out what experiments to do next.. It’s completely different when you actually shake hands with patients – it’s a different world. My first opportunity to meet a patient was in Italy. He had participated in a trial, and came back to do an interview with the press. The physician who implanted the device was attending, and they very graciously invited me to come along. He was a young guy of only 42, but his father and uncle had both died of heart attacks. He had a relatively simple lesion with some symptoms, but had not yet suffered a heart attack. For him, it was the perfect solution– it fixed his problem but didn’t come with the longer-term risks and potential complications of a permanent implant.
What’s your biggest lesson learned?
If I think back ten years, I kept envisioning the point where we would get approval in a major country. When we finally got EU approval, it was so satisfying to see all the discussions and details pay off. In the US, you have to have a panel meeting with experts who judge your data and reach a conclusion about recommending approval, and I imagined myself in that meeting many, many times. So one big lesson learned is that you have to visualize where you’re going. But perseverance is the most important thing – with the right mindset, I believe you can achieve almost anything.
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