Biosimilars to expand AMD treatment options
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As novel treatment options, including biosimilars, for age-related macular degeneration emerge, it has become a “fascinating time to practice,” according to Aleksandra Rachitskaya, MD.
“We have new biologics coming out, novel approaches to treating patients that require intravitreal injection and this kind of booming pipeline of biosimilars,” Rachitskaya, assistant professor of ophthalmology at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a retina physician at the Cleveland Clinic Cole Eye Institute, said. “It’s going to be interesting to see how all of this affects our practice patterns as well as the treatment landscape.”
In an interview with Healio, Rachitskaya discussed the potential benefits and drawbacks of biosimilars for AMD, the data supporting their development and how the availability of these treatments will eventually affect clinical practice.
Healio: How do biosimilars differ from generics?
Rachitskaya: This is a common and important question. To understand the difference between biosimilars and generics, we need to step back and actually talk about biologics.
In ophthalmology, there are many biologics, including mainstay retina therapies such as Lucentis (ranibizumab, Genentech), Eylea (aflibercept, Regeneron) and Beovu (brolucizumab, Novartis). When we think about the way that biologics are made, they are, by definition, therapeutic agents that contain proteins that are derived from living organisms. They are produced through biotechnology in a living system, be it a microorganism, a plant cell or an animal cell. Consequently, they need cell lines and growth media, and there are translational modifications and a purification process. That is how we get our biologics. Therefore, by definition, you actually cannot have a generic to a biologic because generic drugs are basically carbon copies of branded drugs. Generic medications are exactly the same in that they have the same active ingredients and the same chemical formulations as the branded drugs upon which they are based. Generics are also derived from much simpler pharmacologic chemical reactions, whereas biosimilars require much more complex systems to reverse engineer the branded drugs and are therefore not perfectly identical to the original biologic. However, they are structurally similar with no clinically meaningful difference in safety or efficacy when compared with the original biologics.
Healio: What would be the benefits of biosimilars for treatment of AMD?
Rachitskaya: If you look at the treatment landscape not only for AMD but for diabetic macular edema, diabetic retinopathy or retinal vein occlusion with macular edema, there is an exponential need for injections. Our population is aging, and the number of patients with these conditions, especially AMD, is going to increase. In fact, I have seen some statistics that show that by 2050, which is not that far away, the number of patients with AMD is expected to exceed 5 million. Of course, the majority of patients have dry AMD, not neovascular AMD, and do not require injections, but in general, as the number of patients with AMD grows, so will the percentage of those who do require injections.
The drugs that we currently have are excellent, and we have wonderful outcomes in terms of vision and the ability to control the disease. However, these drugs are expensive. The price for branded drugs is somewhere between $1,800 to $2,000 per treatment, and if you look at data from Medicare, for example, we spend billions on intravitreal injections. Biosimilars would be similar to the original biologic in terms of safety and efficacy but would present a cheaper alternative. This makes them an attractive option.
Healio: Are there any concerns about the use of biosimilars?
Rachitskaya: Biosimilars are still a bit of a black box. There is no biosimilar that is currently being used in the United States. We have some real-world experience with biosimilars from India where they have been in use for several years now, which has to do with its landscape in terms of managing diseases that require intravitreal injection. However, it is hard to translate the experience in India to what we would expect in the United States because the regulatory requirements, for example, are different between the two countries. The studies that were conducted to approve Razumab (Intas Pharmaceuticals Ltd., India), which is one of the most widely used biosimilars in India, were different in terms of design than what we use for U.S. approval.
Additionally, although we have seen the adoption of biosimilars in India, there are still some basic concerns. For instance, there have been clusters of endophthalmitis as well as some recalls along the way. However, again, it is hard to make a direct comparison between the United States and India because there are different practice patterns and different regulatory requirements for approval.
Therefore, we have to go on the current studies that are being done to evaluate potential biosimilars, and the biggest questions that we are going to see when it comes to adoption of these biosimilars are related to efficacy and safety. So far, the studies suggest that these biosimilars appear to work as well as our branded drugs.
Finally, in terms of safety, we are lucky to practice in an environment where I know that if I treat a patient with the currently available options, the treatment is most likely going to control their disease, if not improve their vision, and is overall safe. Whenever you introduce something new, the safety is an important aspect, and currently we only have data from the clinical trials. They show, so far, an overall good safety profile. But we will also have real-world data once these drugs are available in clinics.
Healio: What does the research say regarding safety and efficacy of these biosimilars?
Rachitskaya: Let’s step back for a second to our discussion about generics, biologics and biosimilars so we can look at the bigger picture.
Development of a biologic will probably take 10 to 15 years and, on average, the cost to bring this new drug to the market will be expensive — anywhere from $1.2 billion to $2.5 billion. Development of a generic will take about 3 to 5 years, with the cost being $1 million to $5 million. However, because of the way a biosimilar is developed and the regulatory environment, it takes, on average, 8 to 10 years to develop, and the cost is $100 million to $200 million. That is still a lot of money, but it is significantly cheaper than development of the original biologic. Essentially, it still takes time and money to develop a biosimilar.
When the drugs that we currently use in practice were first introduced, researchers had to complete phase 1, 2 and 3 trials to receive FDA approval. With biosimilars, this process is different in that phase 1 and 2 trials are not necessary and only a phase 3 trial is required. In the United States, this means the standard prospective, multicenter, masked, randomized phase 3 study in which the biosimilar is compared with the original biologic. Interestingly, these trials can sometimes be shorter than the standard 2-year studies that we do for the original biologics, and if the biosimilar is shown to be safe and efficacious, then you do not need to do separate trials for different diseases, such as one in AMD, one in RVO and one in DME. Usually, if you can show that the biosimilar is safe and effective for one disease, then those findings are extrapolated to other diseases.
I say all this because I want to make sure that there is an understanding about what data we are discussing in that they are a different kind of data than we get when a brand-name biologic is approved. There have been great studies that have recently been published on biosimilars. For instance, we have data on Byooviz (ranibizumab-nuna, Samsung Bioepis, Biogen), the first FDA-approved biosimilar in ophthalmology, showing that it is similar in efficacy to the biologic ranibizumab and that adverse events were comparable between the two treatment groups.
There are also some phase 3 studies of other biosimilars that, so far, have not highlighted any concerns. Most of the biosimilars that are in this stage of development are demonstrating equivalent efficacy and similar safety profiles when compared with the original biologics. However, we only have a few phase 3 trials that have been completed and a small number of biosimilars that are at the point where we can discuss their results.
Healio: What impact do you think the approval of Byooviz will have on clinical practice?
Rachitskaya: In the phase 3 randomized controlled trial of Byooviz in patients with wet AMD, results basically showed that it was equivalent to ranibizumab when it came to best corrected visual acuity and central retinal thickness and had low immunogenicity and an overall similar safety profile.
However, even though Byooviz has been approved by the FDA, it is not actually available to U.S. physicians and probably will not be until next summer, according to some of the press releases that I have seen. The ultimate question, though, is what is going to be the price point? As we discussed, it will definitely be cheaper than a brand-name biologic, but it still took time and money to develop. We are not in a situation where we have no other options, so the question will be, where is it going to fall in relationship to the other drugs that are currently available? It will be interesting to see what real-world data show in terms of its safety and efficacy once it is available in clinics.
Also, this brings up the question of whether our use of Avastin (bevacizumab, Genentech) will change. Data from the United States show that many people use Avastin, and it is affordable, so how is a biosimilar going to compare in price and efficacy to Avastin?
Finally, we also do not know how insurance will handle these biosimilars because insurance companies sometimes have mandates in terms of how we treat patients, so it will be fascinating to see what the adoption of Byooviz will be.
Right now, there are a lot of unknowns, and we will see more as these biosimilars actually become available for use in clinics.
Healio: In what type of clinical scenario might a biosimilar be more appropriate than the currently available treatment options?
Rachitskaya: If we as a retina community feel that these biosimilars are as safe and efficacious as other drugs that we currently have, a lot will come down to price as well as ease of use. Those are the big factors. Is the retina community going to feel that we are getting similar outcomes with biosimilars, and are they as safe as branded drugs? If so, what is the price point? I can envision that for some patients these cheaper alternatives could be beneficial.
Healio: Are there other biosimilars in development?
Rachitskaya: There are two big camps in terms of biosimilars right now: biosimilars to ranibizumab and biosimilars to aflibercept.
One ranibizumab biosimilar on the horizon is FYB201 (Formycon, Bioeq). Results from the phase 3 COLUMBUS-AMD trial showed that there were no significant differences in visual acuity outcomes or adverse events between FYB201 and ranibizumab.
In addition, there are several other ongoing studies of both ranibizumab and aflibercept biosimilars that look promising.
Healio: Do you have a take-home message for our readers?
Rachitskaya: It is nice that we are going to have more treatment options for our patients, including biosimilars. Overall, it is an exciting time, and I am looking forward to seeing more data on biosimilars and how FDA-approved biosimilars are going to be incorporated into clinical practice.
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Healio Interview
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