Biosimilars have yet to make an impact in ophthalmology
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It has been nearly 3 years since the first ranibizumab biosimilar was approved for use in the U.S.
Byooviz (ranibizumab-nuna, Samsung Bioepis, Biogen) was approved in 2021 followed by Cimerli (ranibizumab-eqrn, Sandoz) in 2022. Since then, aflibercept biosimilars have been approved but have not been commercialized. In general, biosimilars remain a hot topic in ophthalmology, as well as across medicine.
Source: Devon Willock
“There are many hundreds of thousands, maybe millions, of patients on biologic drugs like aflibercept or systemic ones like Humira,” David A. Eichenbaum, MD, said. “Theoretically, the promise of biosimilars is that we can deliver the same efficacy as the originator product and save the patients, as well as the health system, money in the process. That’s why it’s an important topic. Resources are limited, and we want to do the best for our patients while reducing the cost to the system.”
Uptake on biosimilars has been slow, Eichenbaum said. Some of this can be attributed to the safety concerns seen with Razumab (Intas Pharmaceuticals), which was associated with inflammation in India, as well as efficacy concerns compared with originator products.
“Safety was talked about a lot around the launch of biosimilars in the U.S.,” Eichenbaum said. “The discussion was probably out of an abundance of caution.”
Selection
According to a study presented by Anton M. Kolomeyer, MD, PhD, at this year’s American Society of Retina Specialists annual meeting, biosimilars accounted for only 3.7% of total anti-VEGF injections in 2023, a little more than 51,000, primarily for the treatment of exudative age-related macular degeneration. Cimerli comprised 89% of these injections compared with 11% for Byooviz.
For approval, biosimilars must undergo an analytic similarity comparison to show their biosimilarity to the reference drug. They must also be tested in comparative clinical trials to ensure safety and efficacy.
The process, however, is much shorter than what an originator biologic must go through.
“Trials for biosimilars are smaller and more abbreviated,” Priya S. Vakharia, MD, said. “They often have fewer patients with an 8-week primary endpoint. So, real-world experience and post-marketing surveillance are key. It’s important to monitor these products to ensure that their efficacy and safety pan out to what we expect. To date, the biosimilars on the market seem quite safe compared with the reference product and equally as effective. There haven’t been issues to date in the United States with biosimilars for vitreoretinal diseases, but these are important things to keep in mind, especially as more biosimilars enter the space.”
In a review recently published in Cochrane Database of Systematic Reviews, researchers looked at nine randomized controlled trials comprising more than 3,800 patients to compare the safety and efficacy of biosimilars and reference drugs. Seven studies had Lucentis (ranibizumab, Genentech) as the reference drug, and two had Eylea (aflibercept, Regeneron).
The meta-analysis found that there was no significant difference in change in best corrected visual acuity or proportion of patients losing fewer than 15 letters at 24 to 48 weeks between biosimilars and reference drugs. Both groups also had a similar safety profile and similar proportions of patients with serious ocular adverse events, with 1.4% in the biosimilar group and 1.2% in the reference group, according to the study.
Clinicians who have experience with these biosimilars have seen similar safety and efficacy evidence, according to Carl C. Awh, MD.
At the 2023 ASRS annual meeting, Awh presented data from a retrospective study he and colleagues conducted on their initial clinical experience with both Byooviz and Cimerli.
The study comprised 5,085 eyes of 3,964 patients who had at least 28 days of follow-up after their first injection with either drug. The researchers assessed new findings of anterior chamber or vitreous cells, endophthalmitis, uveitis, vasculitis or other adverse events.
Across more than 5,000 Byooviz injections and more than 8,400 Cimerli injections, they found nine cases of minimal anterior chamber or vitreous cells without vision loss. There were no cases of retinal vasculitis or inflammation presumed secondary to a drug reaction.
Out of all injections, there were three cases of bacterial endophthalmitis, and none occurred over the course of the last 12,500 injections.
“Biosimilars seem to function just as the brand name Lucentis has for years,” Awh said. “I think the major barriers now are logistical ones, like having to obtain drugs from new sources, the associated buy and bill issues, and the need to store yet another drug in an already crowded refrigerator.”
Awh said utilization of ranibizumab biosimilars has been low in part because use of ranibizumab is tapering off in favor of drugs such as aflibercept.
“Even in the absence of biosimilars, ranibizumab is not the drug that many retina specialists use as a first-line or second-line therapy,” he said.
This was demonstrated in Kolomeyer’s study. Ranibizumab was third in terms of most utilized therapeutics inclusive of all indications. No. 1 was aflibercept 2 mg, followed by bevacizumab, with faricimab in fourth place.
Eichenbaum said his practice was slow to adopt biosimilars, starting to use them about a year ago mostly because of a reduction in manufacturer support for Lucentis, he said.
“We rely on manufacturer support for these costly drugs. There was a lot of support for biosimilar ranibizumab, especially at that time for Cimerli,” he said. “We had good results with Cimerli, and we continue to use it. It’s just a little bit of a different economic game. There are more rapid changes in average sales price with the biosimilars because of the economic model behind them, and that requires management and vigilance, but we’ve been happy with our Cimerli clinical experience.”
The benefit of using biosimilars, at least theoretically, is ongoing manufacturer support for older therapeutics, lower cost to the patients and health care system, and better economics for the practice, Eichenbaum said, but this has not yet been the case.
“The average sales price of originator Lucentis I think is still less than biosimilar ranibizumab, but that average sales price is eroding rapidly for biosimilars,” he said. “The cons for ranibizumab biosimilars, of course, are that there’s no prefilled syringe, and it’s still a different product than the Lucentis that we’ve known and loved for 18 years since approval in 2006. The cons for both originator and biosimilar ranibizumab are that there are better drugs out there than ranibizumab. Ranibizumab is an old product in 2024, and it probably makes up less than 10% of our practice’s current total injection volume with a decreasing proportion.”
Carl J. Danzig, MD, said his practice has not incorporated any biosimilars yet because of the decreased utilization of ranibizumab overall.
“Provided a patient is started on off-label bevacizumab, why would we switch someone to Lucentis when we can switch them to Eylea, Vabysmo (faricimab, Genentech) or Eylea high dose (aflibercept 8 mg, Regeneron)?” Danzig said. “I just don’t know what the benefit is to the patient. We have relatively more durable medicines, already available, that have broad coverage.”
Vakharia said that, so far, biosimilars have not necessarily done much to improve access.
“The access issue is that patients cannot get access to FDA-approved medicines as first-line therapy,” she said. “Insurance companies are still requiring us to start with repackaged bevacizumab. I think if an insurance company allowed us to use a biosimilar as a first-line therapy, that would improve access to care, but so far, none of them have followed suit with that.”
Aflibercept biosimilars
Ophthalmic biosimilars have now expanded beyond ranibizumab to aflibercept.
In May, the FDA approved Yesafili (aflibercept-jbvf, Biocon Biologics) and Opuviz (aflibercept-yszy, Samsung Bioepis). A little more than a month later, the FDA approved FYB203/Ahzantive (aflibercept-mrbb, Formycon, Klinge Biopharma).
These drugs are not yet commercially available in the U.S. but represent a potential shift in biosimilar interest.
“It will be interesting to see what happens when the aflibercept biosimilars become available,” Awh said. “Aflibercept is more widely used than ranibizumab and will probably continue to be a popular drug among retina specialists for some time. Therefore, aflibercept biosimilars will be a better test of physicians’ willingness to use biosimilars.”
Eichenbaum said it is unclear when these products will become available because they are tied up in patent litigation with Regeneron.
“I don’t know where things are going with that. These are private litigations,” he said. “But I get the sense that there will probably be a launch of an aflibercept biosimilar by the end of calendar year 2024, Q3 or Q4, just because of the level of interest that we are currently seeing in aflibercept biosimilars. I just look at the environment and feel that one of the many companies that has developed an aflibercept biosimilar may launch at risk.”
Eichenbaum said there are several aflibercept biosimilars in the pipeline, but it is unclear if they will all seek approval in the U.S.
“I get the sense that not all of them will have equal commercial success because there are only so many slots in the fridge,” he said. “How many aflibercepts do you need? It will be a combination of manufacturer support, economics and, most importantly, clinical performance. If one or two or more of the aflibercept biosimilars have any hint of a problem, that would eliminate that particular biosimilar from the market.”
Awh also believes that the market will be tight for all these drugs.
“With at least eight projected producers of biosimilar aflibercept, there will likely be significant price competition,” he said. “This is a very different scenario than when one company introduces a new drug and has the exclusive rights to that drug. Relatively soon, we may have multiple providers of biosimilars that are similarly safe and effective. That’s when we will see the impact of payer negotiations, pricing incentives and the power that distributors will exert to shape the market.”
Because the arrival of aflibercept biosimilars is not imminent, Vakharia said a lot remains to be seen in terms of their actual utilization.
“If aflibercept biosimilars launch in several years as some have speculated, the biggest question will be, how much aflibercept 2 mg are we going to be using at that time vs. aflibercept 8 mg?” she said. “I do think that retina specialists will adopt aflibercept 2 mg biosimilars more quickly than they adopted ranibizumab biosimilars, and it may improve access to certain patients. But if we still have step therapy mandate through repackaged bevacizumab, then many patients will still have access issues. Furthermore, all of this will change if there happens to be an FDA-approved bevacizumab at that time.”
Danzig said his main concern is if the addition of new drugs will just mean another step to get the best medication.
“If it becomes mandated by insurance companies, then it’s being used as a step,” he said. “We want to do better for patients, but now we have another step to get to the best medication. We know from clinical trial data that Eylea HD and Vabysmo have better durability compared to Eylea 2 mg in their respective phase 3 trials. Furthermore, no one is asking for more needles in his or her eye, and the current biosimilars on the market don’t solve the problem of desiring fewer injections. The present landscape doesn’t help the durability issue, and it doesn’t change the treatment burden.”
While there are a lot of considerations for their use and a lot to be learned about biosimilars in the future, Awh said he believes they will have a spot in the future of ophthalmology.
“My own impression with the ranibizumab biosimilars is that this is really something that’s allowing, over time, expanded access to superior drugs made in a way that we should be confident about once they’ve gone through the appropriate regulatory scrutiny,” he said. “We can use them in the same way that we use reference drugs from what we’ve seen so far.”
As the situation progresses and biosimilar options for more commonly used drugs become available, Eichenbaum holds concerns about interchangeability and choice for patients and physicians.
“The ultimate choice needs to remain with the physician and the patient,” he said. “These step edits and double step edits are a poison pill that complicate the field and reduce the ability to do your best by making independent choices for each individual patient. Even though I believe biosimilars do have promise, I don’t think that we should have a biosimilar mandate. The mandate is to take care of your patient and do the best for each patient in front of you.”
Click here to read the At Issue, “Do you expect to use more biosimilars in the future?”
- For more information:
- Carl C. Awh, MD, of Tennessee Retina, can be reached at carlawh@gmail.com.
- Carl J. Danzig, MD, of Rand Eye Institute in Florida, can be reached at carldanzigmd@gmail.com.
- David A. Eichenbaum, MD, of Retina Vitreous Associates of Florida, can be reached at deichenb@yahoo.com.
- Priya S. Vakharia, MD, of Retina Vitreous Associates of Florida, can be reached at priyasharma141@gmail.com.
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