Peter Kaiser, MD

When it comes to biosimilars, it’s important for an ophthalmologist to look very closely at the clinical studies to understand the approval process and to understand what a biosimilar is. Now, it goes without saying that the first biosimilar to be FDA approved came in at a list price considerably lower than reference ranibizumab, so this is a good thing for the health care system, and it remains to be seen what the pricing [will be] of the additional biosimilars that are currently in front of the FDA. In terms of concerns with using the biosimilar, the FDA does a good job testing the analytics of these medications and the clinical studies show us that the safety and efficacy, at least in a 1-year time point, is very similar. From my standpoint, I do not have any hesitation using a biosimilar. I will, of course, watch the patients closely and these companies are having postmarketing pharmacovigilance to look for anything that may not have come out in the clinical studies, but right now, I don’t have any overt concerns.

When we look at biosimilars, this is a new treatment that we need to put into our refrigerators. We have to decide which patients we may use a biosimilar on, which patients we may use a reference product on, and which patients we have to use a totally different anti-VEGF medication. These are all things that we are going to work out over time. Thankfully, we know the pricing of the first ranibizumab biosimilar to be FDA approved and it’s considerably lower than the reference product. But it’s important for anyone considering the use of biosimilars to look at the reimbursement, understand what this means for their particular situation and their particular practice, and understand some of the patients’ assistance programs, etc, that are being put into place by companies selling biosimilars. But you may need to make sure that your patients, their payer mix, and their insurance coverage is all answered before you use this, but suffice it to say, that just like reference ranibizumab, all of those programs that you were used to having are being put into place by the companies marketing and selling the biosimilars of ranibizumab.

When you talk to patients about the use of biosimilars, patients at this point in life have become used to the idea of biosimilars. The reason I say that is because they are so used to generics and although biosimilars are not a generic (I don’t want my audience to get confused by that), the fact of the matter is, that even when I go to a pharmacy, I am always asking for the generic version of the medication because I know that the FDA has shown the similarity and has FDA approved it, so I’d rather pay less. Patients are similarly going to accept biosimilars since they understand how expensive it is and they are always asking if there is any way to reduce pricing and this is really one way. It is up to us as ophthalmologists to explain to the patients about the approval process and to explain the safety and efficacy that was shown in clinical studies, but at the end of the day, patients will accept biosimilars. In fact, of all the cogs in the health care system, both the insurance companies and the patients are the ones who are most apt to accept it. It is up to the physicians to be the conduit of information for their patients.

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Dr Peter Kaiser shares helpful hints for patient communication and for including biosimilars in clinical practice.

Helpful Hints for Use of Biosimilars in Ophthalmology Practices

When we discuss challenges to the use of biosimilars in ophthalmology, the biggest challenge is trust, so we have been using ranibizumab for many years and the reference ranibizumab and biosimilars are new. We need to trust the FDA and that their analytical studies are appropriate, and the safety is good, but overall, we need to trust that the outcomes will be the same and the clinical studies help us with that trust, but you only develop trust when you actually use something yourself. Over time, as we use this, we will develop the trust we need to use biosimilars.

Antidrug antibodies are something that we’re starting to learn a lot more about. Prior to brolucizumab and the intraocular inflammation that we saw with brolucizumab postlaunch, we didn’t pay attention to antidrug antibodies. Now, it seems that in the patients who are developing intraocular inflammation, a lot of them developed antidrug antibodies, which would explain the intraocular inflammation that they were seeing. What’s interesting is, that for all of our anti-VEGF agents in the clinical studies, antidrug antibodies were seen, both at baseline—so even before patients receive the drug, they could have antidrug antibodies—or even later in the clinical study, they may develop antidrug antibodies. It is important to watch for at baseline how many patients have it, as well as how many patients develop it over time. In all 3 of the clinical studies for biosimilars to date, the phase III studies that have been published, there was no increase in terms of ADA, or antidrug antibodies, in the biosimilar arms versus the ranibizumab reference arms. Even though in ophthalmology we do need to look at antidrug antibodies, at least with ranibizumab and biosimilars, the antidrug antibody production doesn’t seem to be leading to any differences in intraocular inflammation rates.

An ophthalmologist discusses challenges and concerns that physicians might face when using biosimilars for retinal diseases.

Challenges in Use of Biosimilars in Ophthalmology Practices

When we look at biosimilars in ophthalmology, we have an FDA-approved biosimilar. It was formally called SB11, but now it's called ranibizumab-nuna. We also have 2 biosimilars to ranibizumab that are currently in front of the FDA. One is CHS-201/ FYB201, which is in front of the FDA, and a second called Lucane, and there's not yet a 4-digit name for either of these 2 because you only receive that designation after you get FDA approval. In addition, there are 2 or 3 other companies looking at ranibizumab biosimilars that are currently in clinical trial phases. It's an exciting time in ophthalmology because we have 1 approved and, hopefully, 2 more biosimilars to ranibizumab coming very shortly.

When we look at the clinical studies for CHS-201/FYB-201, the clinical study was performed in patients with neovascular age-related macular degeneration [AMD]. The primary outcome was at 4 weeks and 8 weeks in the United States. The 8-week visual acuity had to be noninferior to reference ranibizumab. In both treatment groups, the treatment was exactly the same in that the patients were randomized 1 to 1 to receive either reference ranibizumab or CHS-201 on a monthly basis with the primary outcome at week 8. The primary outcome was met in that the results of patients receiving CHS-201 were noninferior to those of patients receiving the reference ranibizumab with a difference between the groups of less than 1 ETDRS letter, so very, very similar. In addition, when you look at the safety of the drug at 1 year, the amount of neutralizing antibodies, the amount of adverse events, and the number of patients who had intraocular inflammation, was also noninferior between the 2 groups. When I look at a clinical study for biosimilars, I look very closely at the safety, so the adverse events as well as the treatment emergent adverse events. In both of those categories between the 2 treatments, there was essentially no difference. I was very excited about both the safety and the efficacy of CHS-201 vs reference ranibizumab in its phase 3 clinical study in wet AMD.

When we look at the recently FDA-approved ranibizumab biosimilar ranibizumab-nuna, which was formerly known as SB11, they also performed a clinical study in patients with wet age-related macular degeneration, randomizing patients to ranibizumab-nuna vs reference ranibizumab in a 1 to 1 treatment paradigm with the primary outcomes being central subfield thickness being noninferior at week 4 and each DRS [digital retinal imaging] visual acuity being noninferior at week 8. Similar to FYB201/CHS-201, ranibizumab-nuna was not inferior to reference ranibizumab in either OCT [optical coherence tomography] outcomes at week 4 and the ETDRS visual acuity outcomes at week 8. As one would hope, the visual acuity outcomes were maintained through 1 year of the studies for 52 weeks, and the adverse event profiles were also similar between the 2 drugs. When I look at the results of the COLUMBUS-AMD study [NCT02611778], which was the biosimilar FYB201 vs SB11, the already approved biosimilar ranibizumab-nuna, the outcomes were the same. As you would hope, in that the patients did well from an efficacy standpoint, being not inferior, and safety was excellent between the 2 drugs. I wouldn’t think or pretend to think that there is any difference in outcomes at this point. Obviously, with additional pharmacovigilance, we’ll see if there is any difference long-term.

Dr Peter Kaiser provides an overview of biosimilars that are either approved or are being developed for treatment of retinal diseases.

CHS-201 and Other Ranibizumab Biosimilars in Ophthalmology

When we look at biosimilars for ophthalmology, the first to be approved are ranibizumab biosimilars. The reason for this is because ranibizumab's patent has expired already. Because of that, other companies are able to enter this space. In the future, we may see aflibercept biosimilars because the aflibercept patent is also expiring in the next few years. For the ranibizumab biosimilars, though, it's not like you can just decide to do a clinical study and the analytical studies right away. It's been many years that companies have been working on these drugs to allow them to receive FDA [United States Food and Drug Administration] approval in the case of ranibizumab-nuna, but several other companies have already completed phase 3 clinical testing and all of the analytical studies and have already submitted them to the FDA for approval. I'm hoping to see several biosimilars for ranibizumab hitting the market shortly.

When we look at the approval pathway for biosimilars, it does differ from the reference product, and specifically, in the analytical studies, the FDA is looking at how similar the reference product is to the biosimilar—[such as] what are the pharmacokinetics and pharmacodynamics of the biosimilar—and they need to be obviously similar to the reference product, but not identical—and I want to underline that—these are not identical medications. From the clinical studies, there are several things that we look for as ophthalmologists. We're used to seeing clinical studies last 1 or 2 years, so it’s very surprising to see the primary outcomes of some of these biosimilar agents at 4 weeks and 8 weeks. For many people, it was very confusing as to why such early time points were the primary outcomes. The answer is very simple: the FDA and EMA [European Medicines Agency] require these early time points. You need to prove from an efficacy standpoint that the biosimilar is noninferior to the reference product. The noise around visual acuity measurements at 4 weeks or 8 weeks is considerably greater than it is at 52 weeks, for example. Even if you were to test the reference product against itself, the hardest time points to meet the biosimilarity noninferiority would be at 4 and 8 weeks. In addition, when you look at the OCT [optical coherence tomography] central retinal thickness at 4 weeks and 8 weeks, there's considerable variability and noise around those time points. Trying to prove noninferiority of OCT outcomes at 4 weeks is considerably harder than showing noninferiority at about 52 weeks. The fact that the biosimilar clinical studies primary outcomes are at 4 and 8 weeks is a regulatory requirement that the companies would've been happy to go at 52 weeks, but the safety is shown because the studies go for 52 weeks to show similar safety between the biosimilar and reference product. When I look at the clinical studies from a safety standpoint, 1 of the areas that I look at in particular is immunogenicity because we want to make sure that we're not seeing, for instance, higher levels of intraocular inflammation and that we're not seeing higher amounts of neutralizing antibodies—all things that we are concerned about as ophthalmologists. The clinical studies look very closely at immunogenicity to make sure that there's no difference between the reference and the biosimilar.

Dr Kaiser shares critical differences in primary outcome readout in clinical studies for biosimilars vs reference products for retinal diseases.

Peter Kaiser, MD

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