Fellow for the European Board of Opthalmology
European Board of Opthalmology
Dr. Athanasios Bezatis is an ophthalmology consultant who currently works at the world-renowned Moorfields Eye Hospital in London, UK. Athanasios has over 6 years of medical consulting experience, treating a range of eye conditions in the fields of Locum Adnexal and Oculoplastics. Moreover, he has also served as a Fellow for the European Board of Ophthalmology since 2014.
Section 1: Current Treatment Landscapes
1.1. What are the biological mechanisms that lead to AMD?
What happens in AMD is that the oxygen and nutrition supply to the retina and the deeper layer, the choroid, is impaired with increasing age. This ultimately leads to the death of cells in the retina, including photoreceptors and the outer layers of the retina.
Consequently, due to the lack of oxygen, there is the growth of new vessels that we call neovascular membranes and this forms wet macular degeneration. These new vessels tend to bleed and cause distortion in the anatomy and then these results turn into a scar which causes permanent damage to the central vision and impairs the quality of life. The most common age for patients who become affected with AMD is from 65 years onwards.
1.2. How would you describe the current treatment landscape for AMD?
Well it’s been pretty much unchanged over the last six to eight years. The dry form of AMD doesn’t have any treatment at all, and the wet form is treated with monthly injections. There are variable products out there on the market, the most popular are Lucentis and Eylea, although we will also often use Avastin. There are also some upcoming drugs, such as brolucizumab that have been approved by the FDA in the US. Again, this drug is an injection that has shown to have some promising results and has been developed by Novartis.
Historically, photodynamic therapy was used in the past but it’s now a very old-fashioned way of treating AMD because it causes scaring and is not really safe. It can cause further damage to the patient and so it’s out of the question for the modern world. I don’t expect there to be any new developments within photodynamic therapy and we have moved away from that phase of treatment towards anti-VEGF injections which are now the standard.
1.3. How do treatments vary between dry and wet AMD?
The dry form is a slowly progressing condition that results in scar formation, which we call an atrophy. Here, the layers of the retina that carry photoreceptors become very thin and lose their function.
There have been multiple trials and many drugs have been tried as a treatment for dry AMD including systemic drugs, injections and tablets. Unfortunately, there hasn’t been any effective way of slowing it down or reversing it at all and therefore there isn’t any effective form of treatment out there for dry AMD currently.
Some clinicians say that there have been some studies that show some slowing down of progression using certain vitamin complexes; but other than that, there is no drug or injection available that has been shown to stop the course of the disease. In terms of patient split between dry and wet AMD I would say that roughly 80% of patients have dry AMD whilst 20% have wet AMD.
Dry AMD develops much more slowly than wet AMD and it doesn’t lead to sudden vision loss that’s irreversible. It’s basically a less malignant or more benign form, whereas wet AMD results in sudden vision loss, which is irreversible, so the impact is much worse.
1.4. Which pharmaceutical companies are invested in providing treatments for AMD? Why?
In this area I would say that Novartis is the leading pharmaceutical company for providing these treatments. Most recently as I mentioned they had their drug injection Brolucizumab approved by the FDA and historically they have Lucentis which is a market leading drug for wet AMD. Genentech is another pharmaceutical company, based in Los Angeles, that produces treatments for wet AMD, but I would say that Novartis is the most active in this field.
The drug Eylea from Bayer or Regeneron is a standard treatment, which is nowadays deemed the gold standard. Lucentis used to be the gold standard, but currently, Eylea is the leader. However, there can be some variation here depending on your preference as a physician. Personally, I believe Eylea is better because it has a bit of a longer duration and it delivers better outcomes regarding vision and anatomical results. However, it’s as equally used as Lucentis I would say.
The new drug by Novartis, Brolucizumab, does offer some advantages over the other current treatments. One advantage that studies have shown is that people that have not responded well to standard treatments do in fact respond well to brolucizumab. It belongs in a category of drugs, but it also has an initial recommended dosing schedule.
The first few doses are given monthly, as the other treatments available, but then brolucizumab is believed to last longer and can be safely given to a patient every two to three months. In this case, there is a lower frequency of injection required for the patient, which is an advantage as it reduces costs and visits to the clinic.
The current range of injectable treatments for wet AMD are anti-VEGF therapies. Here, the lack of oxygen in the retina causes the production of VEGF and the VEGF complex is the growth factor that grows the new retina. It’s therefore a vicious cycle because the longer the condition exists, the more VEGF is produced in the retina. Moreover, these lead secondarily to the formation and growth of new vitreous cells; these new cells can then cause damage to the retina.
In summary, it’s a very malicious cycle and therefore by delivering the anti-VEGF drugs via injections, we aim to suppress the levels of VEGF within the eye, vitreous and retina. This commonly results in a complete resorption of the fluid. Sometimes it also reverses the vessels, and let’s say, deactivates them.
1.5 What are the pain points and issues with current AMD therapies?
Well, first of all the current therapies need to be injected on a monthly basis which increases the volume of patients we need to see. This causes problems as the waiting lists are longer and patients often don’t tend to receive the treatment on time because of the overwhelming number of patients. Therefore, here in the UK, there is a lot of pressure on the National Health Service (NHS).
Secondly, the costs are very high because the injections are still very expensive, and you need to employ lots of staff to be able to cover all these massive clinics and large numbers of patients. Moreover, the cost of traveling for the patients is also a financial problem.
Section 2: Future Treatment Landscape and Challenges
2.1. What is the potential of stem cell-based therapies for AMD? How far away are we from this being a realistic standardised treatment?
The studies for stem cell-based therapies for AMD have been taking place at one of the involved centers where I work. The clinical study for stem cell-based therapy has had some promising results although it must be said that it’s still in a completely experimental stage. Therefore, it’s still not available for most AMD cases, but they are getting some promising results especially in the advanced and very late advanced stages where the center of vision is typically completely lost.
This is not a sort of treatment that has been applied to early cases but it’s merely a reserved treatment for the latter stages of AMD. I definitely see great potential in stem cell-based therapies but obviously this requires a very specialized center and it will not be available to all patients so we’ll have to see how successfully it can be deployed.
The biological mechanism of stem cell-based therapy is completely different to the current anti-VEGF treatments. Stem cell therapy injects cells which proliferate and create a new retina therefore it’s cannot be applied to patients with active wet AMD. It’s a treatment that can be given to patients with the dry form and where there has been scar formation or where it was previously wet, and it has advanced, resulting in a scar. In essence, it’s injecting cells that proliferate and create healthy cells that give vision back and that’s the idea behind this difference. These are induced pluripotent stem cells that are used for the treatment. These are somatic cells that are taken from the patient and formulated into induced pluripotent stem cells which can be implanted under the retina.
In terms of timelines for this treatment to become standardized and widely available in the NHS, we are around ten years away from this. The reasons for this are that the clinical development process is still at an early stage and it’s also a very expensive technique to carry out. Moreover, it’s also a difficult treatment to administer as only a few eye centers will be able to offer it.
Besides stem cell-based therapy I have not really noticed any other novel treatments that are being pushed in this field. The only other treatment is the brolucizumab injection that we could give every 2-3 months which is clearly a benefit compared to the previous injectable treatments that we performed.
2.2. Will combination therapies will become the new standard of care for AMD?
To be honest, with AMD, we usually only administer one type of therapy, but I cannot exclude the possibility of using a combined therapy approach. If there was going to be a combined therapy approach in the future, I would suggest that it could be stem cell-based therapy combined definitely with an immunosuppressant agent to prevent any reaction from the body. However, it’s worth noting that this combination is standardized for stem cell therapy. Moreover, on top of that, some combinational therapies with the support of vitamins or maybe combined with anti-VEGF injections could also be an approach.
2.3. What are the main barriers preventing greater penetration of novel AMD therapies?
With regards to the brolucizumab therapy, it has not yet been approved in Europe. Due to the impact of COVID, everything with regards to approval of new drugs has been delayed. Initially, I was expecting brolucizumab to be approved by the end of 2020; however, the reality is that it will most probably be able to enter the EU5 market some time in 2021.
Besides the impact of COVID on the approval process I don’t really foresee any other issues in the approval of brolucizumab. I’m not 100% certain about the cost of the therapy compared to the other anti-VEGF injection treatments but I imagine it would be in a similar price bracket.
I think within the EU5 nations, brolucizumab will become a standardized available treatment once it is approved and is especially important as European nations deal with larger ageing populations. This will obviously increase the number of patients who have some form of AMD.
2.4. What difficulties exist in facilitating the market access of novel AMD therapies?
For stem-cell based therapies, it’s obviously a massive expense to the health service. Therefore, if there are methods to lower the cost of this treatment by maybe creating a method that would allow the injection to be easier, or require less equipment, it would be very financially beneficial.
Furthermore, in the production of these induced pluripotent stem cells, you would maybe need to simplify the technique of production to reduce costs. This would make it easier to provide the treatment at a lower cost for the NHS. For these types of treatment there may be the requirement for a different type of reimbursement contract which is more value based if you are looking to introduce such an expensive stem cell-based therapy. Obviously its important to remember that this stem cell-based therapy will mainly be for dry AMD patients which constitute the majority of the AMD patient population.
Dry AMD takes the form of a geographic atrophy which affects the area around the center of the eye. Initially, it spares the center but towards the end it includes the center where you will have complete scarring and a very thin retina that doesn’t function anymore.
I think with regards to stem cell-based therapy you would require it for later end-stage macular degeneration. We need better clinical results to create statistically significant results and be sure that this therapy is safe and effective. Obviously once this has been sorted out, we’ll have more data and we could definitely start treating the earlier forms of AMD. That for me personally is the most important goal.