Specialists discuss role of biosimilars in future of retinal disease management
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Biosimilars are a promising option that might expand access to retinal therapies, reducing costs and improving real-world treatment outcomes as a result.
In July, the first FDA-approved biosimilar for an ophthalmic indication reached the market. Byooviz (ranibizumab-nuna, Biogen/Samsung Bioepis) is a biosimilar referencing Lucentis (ranibizumab, Genentech), indicated for the treatment of neovascular age-related macular degeneration, macular edema following retinal vein occlusion (RVO) and myopic choroidal neovascularization.
Source: Galit Yair-Pur
“It is a test balloon for us to understand how the regulatory pathway is, how the drug performs in clinical practice and whether there are any safety and efficacy concerns,” OSN Associate Medical Editor Rishi P. Singh, MD, said.
In August, the FDA approved Cimerli (ranibizumab-eqrn, Coherus BioSciences) as an interchangeable biosimilar to Lucentis, indicated for neovascular AMD, macular edema following RVO, diabetic macular edema, diabetic retinopathy and myopic choroidal neovascularization. It is expected to be commercially available in both 0.3 mg and 0.5 mg doses in October.
In other parts of the world, the introduction of biosimilars is also seen as an opportunity to go beyond the existing model of care and expand patient access.
“It can lead to increased adherence because the reference drugs can be a financial burden to many patients, and many discontinue treatment because they can’t afford it. Additionally, it expands our treatment choices because some patients may not respond well to bevacizumab and the cost of ranibizumab or aflibercept is too high,” Anat Loewenstein, MD, MHA, head of ophthalmology at Tel Aviv University, Israel, said.
No anti-VEGF biosimilars are currently available in her country, but they will be part of the changes she foresees in the management of patients during the next few years.
“What remains to be seen is whether real-world data will confirm the good safety profile we have seen in trials,” she said.
“After the red flag raised by brolucizumab (Novartis), ophthalmologists are particularly on the alert for immunogenic reactions. Immunogenicity, most frequently leading to the generation of anti-drug antibodies, should always be tested and monitored, but it is, however, inherent to biologic treatments. All biopharmaceuticals, including biosimilars, have the potential to elicit an immunogenic response,” Diego Fornasari, MD, PhD, professor of pharmacology at the University of Milan, Italy, said.
So far, no signs of immunogenicity have been observed in studies, but physicians should stay alert, and post-marketing data on a larger number of patients should provide more information, he said.
The approval process
Biosimilars are biologics that are not identical but highly similar in structure and function to an already approved biologic. With a strict stepwise, totality-of-evidence approach, they undergo head-to-head comparability assessment, followed by in vitro and in vivo studies, to prove that purity, physicochemical properties, therapeutic efficacy and safety match the attributes of the reference product.
“From a preclinical standpoint, the requirements for approval of a biosimilar are even higher and more stringent than they were for the originator biologic. The clinical trial program is proportionally reduced but on condition that comparability is rigorously demonstrated during the nonclinical stages,” Fornasari said.
Randomized controlled trials are then performed, with the classic visual acuity and OCT endpoints. Because high similarity has previously been proved, fewer patients and a shorter follow-up — usually 400 to 500 patients over 12 months in ophthalmology — are allowed by regulatory authorities.
“Immunogenicity is tested at this stage and during post-marketing surveillance. Reactions may not be so frequent during the limited time span of the trials, and this is why biosimilars are complemented by robust pharmacovigilance surveillance studies,” Fornasari said.
Testing outcomes, safety in the real world
“Given the smaller sample size and shorter duration of registration trials, phase 4 studies become key to identify potential efficacy or safety issues,” Singh said.
In his opinion, the studies themselves thus far have been undersized and less than adequate to demonstrate scientifically something new or interesting, neither in terms of safety nor in terms of efficacy and decreased treatment burden.
“We have just learned that biosimilars are equivalent, and phase 4 studies will be important to draw a true balance,” he said.
“Future real-world studies will determine the safety and efficacy of biosimilars, and they will become part of our clinical routine,” Loewenstein said.
She foresees changes in the conduct and overall concept of clinical trials, which will be mostly using artificial intelligence combined with real-world data.
“AI-identified predictive biomarkers could rapidly and efficiently identify patients who are more likely to respond to a therapy or more likely to develop adverse reactions, and it will assist us in our treatment decisions. Clinical trials could have a reduced number of participants because we would be able to reach specific populations according to AI-identified biomarkers,” Loewenstein said. “Trials like the CATT, comparing two drugs, may no longer be needed.”
On the other hand, fewer patients in a trial may lead to missed safety signals.
“I have mixed feelings about it. On one hand, maybe nowadays we need fewer patients than in the past; on the other hand, we need to be aware that we may miss some signal of side effects that needs larger numbers to be captured,” she said.
Extrapolation
Extrapolation is the process by which the indications approved for the reference biologic are also granted to the biosimilar. Byooviz was evaluated for biosimilarity in neovascular AMD, and by extrapolation, without specific trials, approval was given also for macular edema following RVO and myopic choroidal neovascularization.
Both the FDA and the European Medicines Agency state that if the totality of evidence and scientific justification support biosimilarity for one of the reference product’s indications, these data can justify approval for other indications held by the reference product.
Fornasari reassured ophthalmologists, who often express concern about this practice, that extrapolation has a scientific rationale.
“If the totality of evidence derived from preclinical and clinical data demonstrates that at every step the two molecules are similar and share the same mechanism of action, this further step is justified,” he said.
Extrapolation eliminates the need for duplicative clinical studies, thus reducing development costs and, eventually, the final cost of the drug.
The experience with Razumab in India
The patent for Lucentis expired in 2020 in the U.S. and is expiring this year in Europe, Japan and China. Eylea (aflibercept, Regeneron) may come off patent in 2023 in the U.S. and in 2025 in Europe and this year in Japan and China. Currently, there are 10 biosimilars to ranibizumab, with two approved in India, and Byooviz approved by the FDA and EMA. The others are in advanced stages of clinical trials. In addition, there are five biosimilars to aflibercept under investigation, and all have reached phase 3 studies.
Razumab (Intas Pharmaceuticals) was approved by the Drug Controller General of India (DCGI) in 2015, and since then, it has been in clinical use in hospitals and private practices.
“Considering that it is half the cost of Lucentis and one-third the cost of Eylea, it is preferred by patients who don’t have insurance and have to pay out of their own pocket,” Monika Kapur, MD, assistant professor of ophthalmology at Hamdard University in Delhi, India, said.
Indications for Razumab are AMD, diabetic macular edema, macular edema secondary to RVO and choroidal neovascular membrane in patients with pathologic myopia.
With the initial batches of Razumab, sterile endophthalmitis occurred in 10% of patients, raising concerns about safety, and manufacturing was stopped.
“The cause was identified to be higher endotoxin levels in the buffer used in the manufacturing process. A different buffer was utilized, and new batches were gradually released with careful monitoring. Since then, no severe reactions were observed, and the safety profile is now similar to ranibizumab and other anti-VEGFs,” Kapur said.
Subsequent real-world studies have demonstrated good outcomes and equal efficacy and safety to ranibizumab.
“Previously, when I was in my residency, we used Lucentis because Razumab was not yet approved. Then we started using Razumab and found it had a similar kind of profile with no serious adverse reactions. We reported minor side effects such as a transient IOP increase in some patients, but this was also the case with Lucentis,” Kapur said.
Beyond Avastin
Currently, Avastin (bevacizumab, Genentech) is the most commonly used anti-VEGF in India because it is one-fourth the cost of Razumab. Like everywhere else, it is not approved by the DCGI for ophthalmic use and is used off label.
“Additionally, the problem here is that if you open one vial, you should perform at least five to 10 injections to be cost-effective. Centers that have a high volume of patients prefer Avastin, and in small practices, we advise patients who cannot afford Razumab to go to a high-volume center where they can get Avastin,” Kapur said.
There were also a few reports of cluster endophthalmitis with Avastin use in India, which shed light on potential problems with microbial contamination when the individual syringes are prepared from the large vial.
“Compounding pharmacies are quite rare in India and even more in other developing countries, and this is one more reason why approved biosimilar drugs are needed and are a massive market opportunity,” Kapur said.
Other biosimilars may be introduced, such as biosimilars to Eylea, but the cost is expected to be higher because the price of the reference drug is higher.
“We prefer cheaper options because most of our patients have a low economic status, and there is a high rate of treatment dropout. Anti-VEGFs are a long-term treatment with frequent injections, and the effect shows after at least three injections. People easily drop out if they are discouraged by the cost,” Kapur said.
Educating clinicians to prevent the nocebo effect
Byooviz has just been introduced in the U.S. market, and it is too early to tell if and how fast it will gain traction in the retina community, according to Singh.
“Lucentis has a long track record of efficacy and safety in the U.S. Though not the market leader, it is a good second agent still utilized for a variety of indications. However, I suspect that many physicians won’t understand how biosimilars are studied and approved, so there will be likely some gaps of knowledge that hopefully can be addressed,” he said.
The experience gained in other therapeutic areas in which biosimilars have been available for years has shown that physicians need to develop a good understanding of the approval process and consequently gain confidence in biosimilars. Only then will they be able to communicate effectively with patients and avoid the nocebo effect.
“If the patient perceives that the treatment proposed is a cheaper copy of the branded drug, they are likely to fall into psychological distress, modulate the outcome of the therapy in a negative way and develop side effects. The nocebo effect is crucial, especially when the patient is prescribed a biosimilar after being treated with a branded drug. We all have a tendency to think that more expensive is better, not only in medicine,” Loewenstein said.
A gradual, inclusive approach
Another concern of ophthalmologists is that the adoption of biosimilars might be dictated by insurance companies and hospital policies rather than the clinician’s choice.
“I expect there will be negotiation on this matter, but in hospital settings, where they have to save money, biosimilars will be a good opportunity,” Singh said.
A gradual introduction into clinical practice should help clinicians to develop well-founded trust in biosimilars and prevent the nocebo effect in their patients, according to Fornasari.
“I think there should be a time during which biosimilars are used only in treatment-naive patients. This will reassure the patients who are already using a branded drug that they can continue to be treated in the same way and give clinicians the time and opportunity to assess the results of biosimilars from baseline. With more real-world, post-marketing data, we’ll be able to see if biosimilars are truly as good as we expect them to be, if there are really no differences from the reference drug in terms of safety and efficacy. Then the clinicians will be confident enough to propose a switch to patients who are already on treatment,” he said.
Conversely, if health or hospital authorities take the lead and mandate the adoption of biosimilars, without a period of transition and without involving clinicians in the choice, acceptance could be irreparably compromised.
“If regulatory authorities are wise, they will involve the clinicians in the post-approval regulatory processes. The top-down approach adopted in some countries for biosimilars in oncology, just for the sake of saving money, has failed. Non-inclusive approaches never win, and the first to be included must be the clinicians,” Fornasari said.
He also believes that the savings generated by the adoption of biosimilars should be reinvested in research and services to improve patient care.
“This is an important step in the overall process because saving for the sake of it is not ethical and not acceptable in medicine,” he said.
Competing with bevacizumab
While in developing countries biosimilars can be a potentially cost-effective alternative to bevacizumab, without the risk for contamination due to lack of compounding pharmacies, competing with it in the developed world may be more challenging because bevacizumab is cheap and available without substantial risk, Loewenstein said.
Singh too said that bevacizumab is a competitor and that biosimilars will never be equally cheap.
“Avastin will still be the off-label lead biologic being used for similar indications,” he said.
In Israel, to reduce the financial burden on health care, Avastin is mandatorily administered as a first-line treatment, and Loewenstein, like many of her colleagues, would gladly use a biosimilar instead.
“I would do it without thinking because I don’t like to inject a drug that says on the label ‘don’t put it into the eye.’ If I had a biosimilar that was approved, I would prefer to start with that,” she said.
However, price remains an important issue in this decision.
“If the cost will be more like bevacizumab, I’ll switch to a biosimilar, but if it is very close to ranibizumab, I would still continue with bevacizumab,” she said. “I know it will be cheaper than other drugs, but I don’t know if it will be as close to the unregistered drug as I would want it to be.”
When patents expire
The leading global pharmaceutical companies that have so far dominated the anti-VEGF therapeutic market have seen their sales grow constantly over the past 20 years. In the U.S., the annual average revenue from ranibizumab since launch has been $1.568 billion. U.S. sales in 2021 were $1,353 million, with a decline of 4% from the previous year “driven by continuing competition,” as stated in a company report. Novartis, which holds the rights for Lucentis outside the U.S., reported $2,160 million in sales in 2021. Regeneron and Bayer reported a total $9,384.7 million in Eylea sales globally in 2021.
Loss of market exclusivity will inevitably lead to significant loss of sales revenue. In oncology, sales of Avastin declined by 47% in the U.S. and 66% in Europe after the launch of biosimilars in 2019 and 2020, respectively. According to a 2021 Roche finance report, “The introduction of a generic, biosimilar or non-comparable biologic version of the same or a similar medicine usually results in a significant reduction in net sales for the relevant product, as other manufacturers typically offer their versions at lower prices.”
However, companies know the game and will respond with new research and new products.
“Patents and their expiry are, and always have been, an integral part of the group’s business model and future growth will remain driven by innovation,” the report said.
“Companies have reaped the benefits of their anti-VEGF drugs over the past few years to make up for their development cost and more. For example, Lucentis has been protected from a biosimilar for almost 22 years. Now they are moving on to newer products which biosimilars will not be present for, such as faricimab (Genentech) and high-dose aflibercept 8 mg,” Singh said.
“Companies are aware that they need to look for something else, like longer duration drugs, drugs with a good safety profile, drugs that in the future will reduce fibrosis and atrophy, innovative technologies,” Loewenstein said.
“Patents play an essential role in encouraging and safeguarding innovation. They help recoup the huge investments made for the research, development and marketing of a new drug and secure against infringement cases. Companies are given a fair amount of time to maintain the intellectual property or their products, and then, when the time expires, it is right that they should resume their mission, that is, to do innovation,” Fornasari said.
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- For more information:
- Diego Fornasari, MD, PhD, can be reached at Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Vanvitelli, 32, Milan, Italy; email: diego.fornasari@unimi.it.
- Monika Kapur, MD, can be reached at Department of Ophthalmology, HIMSR & HAHC Hospital, Hamdard University, Alaknanda, Delhi 110062, New Delhi, India; email: monikadkapur@gmail.com.
- Anat Loewenstein, MD, MHA, can be reached at Tel-Aviv Medical Center, Department of Ophthalmology, 6 Weitzmann St., Tel Aviv, Israel 64239; email: anatl@tlvmc.gov.il.
- Rishi P. Singh, MD, can be reached at Cleveland Clinic Florida, Martin Health, 200 SE Hospital Ave., Stuart, FL 34994; email: singhr@ccf.org.
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