In this article, we delve into the world of biosimilars, which are chemically comparable agents that seek to change the outlook of intravitreal treatment in retina practices. Biosimilars have been the focus of many pharmaceutical companies, as the Food and Drug Administration (FDA) has incentivized their production. As new drugs arise through this modified FDA approval process, the hope is that they will improve patient access, reduce costs, and increase overall medication availability. This article also highlights the significance of the modified approval process and explains where current retinal physicians stand in utilizing these agents.
Key points
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Several biologic treatment modalities are currently the mainstay in the treatment of diabetic macular edema and neovascular macular degeneration.
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Biosimilar agents that are genetically complex, yet seek to be equivalently effective to biologics, are in active development to address availability and cost.
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As biosimilars receive foundational approval and become commercially available, physicians must be informed about the efficacy and safety profiles of such agents.
Background
Biopharmaceuticals are medications derived from, manufactured in, or synthesized from biological agents. These can include vaccines, blood product, gene therapies, and specific proteins, such as vascular endothelial growth factor (VEGF) inhibitors. Biologic therapies have been revolutionary in the treatment of many systemic and ophthalmic diseases, particularly neovascular macular degeneration (nAMD) and diabetic macular edema (DME). These conditions continue to increase in prevalence as more of the population is diagnosed with diabetes mellitus and advances toward the tide of the “silver tsunami.” Biologics such as ranibizumab (RZB; Lucentis), aflibercept (Eylea), and faricimab-svoa (Vabysmo) are all approved by the US Food and Drug Administration (FDA) to treat nAMD and DME by targeting and inhibiting VEGF). Bevacizumab (Avastin) serves as another anti-VEGF agent that has been used off-label by ophthalmologists worldwide in the treatment of these diseases. Since their inception, these biologics have served to improve visual outcomes and prevent the progression of severe ophthalmic diseases.
Biologics have been proven to be efficacious, yet despite accounting for only 2% of prescriptions, they constitute 37% of net spending on medications [ ]. The increased costs associated with biologics may limit both their accessibility and treatment duration for patients. Here enter the biosimilars. Biosimilars are defined as drugs that are like and mimic the effects of their reference drug but do not have identical ingredients [ ]. This includes the unique inactive components of the drug, termed excipients. Biosimilars provide an interesting prospective avenue for pharmaceutical companies, who have entered and expanded this market rapidly after the first generation of biologics began to lose their patents in 2015.
In 2009, Congress passed the Biologics Price Competition and Innovation Act (BPCIA). This legislation created an expedited approval pathway for biologic products that were deemed by the FDA to be similar or interchangeable with already-approved FDA products ( Fig. 1 ) [ ]. The goals of this law were to improve patient access, increase treatment options, and potentially reduce treatment costs [ ]. The way that this law sought to expedite approval has been focused on a point called “bioequivalence.” Per the FDA, a bioequivalent drug must have evidence that “no clinically meaningful differences occur in safety, purity, and potency between the biosimilar and reference product.” [ ] The way that this is demonstrated is through pharmacokinetic and pharmacodynamic studies, as well as a study of clinical immunogenicity. Studies must also demonstrate the safety of the new excipients for the approved indications of the reference drug. A comparative clinical trial into the systemic safety and efficacy of the biosimilar must also be conducted.
However, a few key differences occur between these new drugs and their reference compound. Firstly, biosimilars rely on more analytical data comparison and similarities in biochemical properties [ ]. Biosimilars only require 1 clinical efficacy comparative trial as opposed to reference products, which typically are subject to 2 trials. Additionally, the efficacy of biologics is determined based on predetermined margins that were set by the reference product [ ]. The goal is for these biosimilars to be as pharmacokinetically and mechanically comparable to the reference product, and based on these trials and equivalency, they may be approved for any or all indications of the reference product. The biosimilars are not exactly parallel to generic drugs, as their creation still relies on complex protein structures and similar active structures to the reference drug. They also are not inherently interchangeable drugs, meaning that they cannot be simply substituted for a reference drug by a pharmacist without prior physician approval unless the FDA specifically approves this designation through additional studies.
Once no clinically meaningful differences are found through this process, the biosimilar is generally approved by the FDA for as many indications of the reference drug as possible, even if the biosimilar was not directly involved in the clinical trials specifically for each indication. This concept is known as “indication extrapolation.” [ ] This extrapolation functions as following approval, it is assumed that the chemical properties of the drug will mirror the reference product, and thus can be utilized to treat similar entities as the reference drug. Through this approval process, the FDA feels ensured that biosimilars will provide the same benefits clinically as their reference products, which has opened an entirely new avenue for ophthalmologists and pharmaceutical companies alike [ , ]. As products such as RZB-nuna (Byooviz; SB-11) and RZB-eqrn (Cimerli; FYB-201) have received FDA approval, with many more on the horizon, it is clear that the biosimilar landscape has become more prominent and ophthalmologists should be aware of the clinical, fiscal, and social impact of these medications.
Significance
According to the Centers for Disease Control and Prevention (CDC), approximately 19.8 million Americans over the age of 40 are living with AMD. Of these patients, about 1% have an advanced stage of AMD that is vision-threatening [ ]. Specifically regarding wet AMD, certain pharmaceutical companies expect the mark to reach 22 million people by 2050. Additionally, the CDC has crude estimates of diabetes in the American population numbering around 38.4 million people in 2022, with almost one-fourth of these individuals being undiagnosed cases. As the population developing diabetes becomes younger, more cases of diabetic retinopathy become apparent and will persist into these patients’ older age. Almost 4.2 million will have diabetic retinopathy as a complication. Clinically significant macular edema is expected to increase to 28.6 million people by 2045 [ ]. Currently, for both DME and nAMD, VEGF inhibitors are a first-line treatment by the American Academy of Ophthalmology (AAO) with the goal of improving edema and reducing proliferative retinopathy. As of this publication, there are only 4 approved agents for both conditions: Avastin (bevacizumab) used off-label, Lucentis (RZB), Eylea (aflibercept), and Vabysmo (faricimab-avoa). Two biosimilars are approved in the United States by the FDA: Byooviz (RZB-nuna) and Cimerli (RZB-eqrn). Two agents are approved for use outside of the United States, which are razumab and LUBT010; both are biosimilars to Lucentis. Biosimilars have received significant funding and attention due to the potential promise of increasing drug availability, improving patient access, and providing cost savings in the long term, all of which will be discussed in this section.
As seen earlier, there are only 4 approved biologics currently being utilized to treat DME and nAMD with Avastin being used as an off-label medication. The AAO recognizes that the limitation in the number of medications may hinder access to treatment, as well as limit patient options when it comes to medical therapy. This limitation on treatment options is further compounded by the fact that not all anti-VEGF agents have the same effectiveness in each patient. No specific guidelines exist as to recommend which agent to use when, and most of the management is determined by a gestalt that a physician may have developed. Non-responders to 1 agent, or the few patients that may have had a loss of reactivity to 1 medication, pose a significant issue as there already are limited options. Studies have reported that anywhere between 10% to 50% of patients have inadequate or suboptimal response to RZB or bevacizumab administration [ ]. It is yet to be determined why certain patients may develop tachyphylaxis or have no response at all to available treatment options; thus, most ophthalmologists need to monitor patients closely.
Research has been conducted in analyzing the success rate of transition from 1 agent to another in those who were initially treated with Lucentis or Avastin but had an attenuated response, and in 1 study, 81% of cases were able to have improved outcomes when switched [ ]. When Eylea was initially approved in 2011, it was treated initially as an alternative and reimbursements were only available when using the drug in cases of residual fluid while on Lucentis or Avastin. However, as time has progressed, Eylea has readily emerged as 1 of the more consistently utilized medications for patients, particularly in those who have refractory symptoms. Now with the advent of Vabysmo, another agent has emerged to treat those with refractory symptoms. Currently, 3 biosimilars to RZB are awaiting approval in the United States, and another for aflibercept. Biosimilars pose a similar benefit, providing ophthalmologists with an increased number of agents that may be more readily available, more easily accessible, and may serve as alternative treatment options for patients who are refractory to initial medication selections.
Patient accessibility is another element that warrants discussion when considering the benefits of biosimilars. In certain parts of the world, lack of insurance accessibility, costs of medications, and agreements between suppliers and low-resource countries all serve as limitations in access to certain anti-VEGF agents. Patients who lack insurance in low-income countries, such as India, Brazil, and other South American or African nations, struggle to meet the costs of pharmaceutically licensed patented biologics. In 2006, generics were 6 times less expensive than brand-name medications. That difference may be as high as 38-fold higher for biologics today [ ]. According to the Medicare part B payments data from 2008 to 2021, RZB and aflibercept account for over 10% of the total payments, with an average cost of $1673.59 and $1385.95 per 0.5 mg service [ ]. It is thought that the introduction of biosimilars may help to reduce the costs of these essential treatments and help make these medications more accessible to patients. It may also aid in reducing the baseline cost of medications, to allow those in low-resource countries to afford life-changing treatment.
Additionally, biosimilars have the potential to improve patient accessibility by reducing treatment intervals and recurrence rates. The main studies on RZB were done with treatment regimens of monthly injections. In practice, the reality is that patients will often have widespread and variable treatment regimens that are adjusted based on imaging and patient-physician shared management. Many patients with these diseases have multiple comorbidities, suffer from poor vision, and may be unable to afford transport or have the appropriate time to come for monthly injections. However, newer medications may help to reduce this burden. For instance, 1 important aspect of the trials for Vabysmo was the observation that not only was it able to treat refractory patients, but also increased the extent of the recurrence interval to greater than 12 weeks. Fewer injections reduce the frequency of visits, improve the treatment burden, reduce costs for patients, make patients more amenable to receiving injections, and, through this, improve patient access to care.
As mentioned previously, cost is a major barrier to patient accessibility that is expected to be improved with the advent of biosimilars. In addition to reducing individual costs for patients receiving treatment, biosimilars have been projected to reduce overall spending on pharmacologic agents in the United States. From 2015 to 2016, spending on prescription medications increased by 4.8% to $323 billions [ ]. A large proportion of this total cost was attributed to biologics due to their high production costs. A sensitivity analysis published by Rand Health Quarterly in 2018 found that implementation of the BPCIA will be expected to yield approximately $54 billion in savings over a 10-year period, with a range of $24 billion to $150 billion. The biosimilar pathway is projected to achieve these savings by promoting competition among manufacturers to help reduce prices. Specifically, the manufacturer offering the best prices to providers (ie, hospitals, private practices) and the largest rebates to insurance companies will be expected to increase their market share and total revenue. The estimated projected savings from the biosimilar pathway are expected to benefit insurance companies, providers, and patients to differing extents. Insurers will benefit from reduced payment rates, with savings potentially leading to reduced insurance premiums for patients. Additionally, for federal insurance programs such as Medicare, decreased spending may translate into increased savings for taxpayers. As for providers, the BPCIA will lead to reduced purchasing costs and variable reimbursement benefits.
Although the Rand Health Quarterly cost savings estimate was determined for a 10-year period that has not been completed to date, data do exist showing the impact of the BPCIA in the field of ophthalmology in its early stages. The literature has shown that as of 2022 if all patients receiving RZB or aflibercept were switched to 1 of the RZB biosimilars (RZB-nuna or RZB-eqrn), savings would amount to $132 million for Medicare and $33.6 million for patients receiving treatment [ ]. Although seemingly promising early results, a few issues have arisen in the process of adopting the BPCIA. For example, there are currently 2 FDA-approved bevacizumab biosimilars—bevacizumab-bcvr and bevacizumab-awwb. After these medications were approved, insurance companies included them as part of step therapy for ophthalmic indications despite the presence of compounds in these biosimilars with the potential for ocular toxicity. The AAO contacted the FDA regarding their concerns with the result being that the ophthalmic indications for these biosimilars were revoked, but their potential use as part of step therapy was maintained. The use of biosimilars as part of step therapy can have potentially drastic effects on the efficacy of the BPCIA, as patients and providers will be limited by insurance company–determined algorithms for treatment options, ultimately making biosimilars less accessible.
Additionally, a bevacizumab biosimilar called bevacizumab-vikg has completed clinical trials and is pending approval for ophthalmic use by the FDA. However, since the reference medication has no approved ophthalmic indications by the FDA, this biosimilar is being analyzed as a novel medication. If this medication is ultimately approved for ophthalmic indications, accessibility to compounded bevacizumab will likely be significantly reduced, as the FDA prohibits the compounding of medications for the same FDA-approved indication [ ]. Currently, compounded bevacizumab constitutes approximately 40% of all intravitreal injections. If bevacizumab-vikg attains approval thereby preventing the use of compounded bevacizumab, issues may arise regarding limitations in supply for patients. Furthermore, there is concern as to how the likely increased cost of bevacizumab-vikg may reduce accessibility to patients and lead to a reduction in overall savings on prescription medications on a large scale. Based on current statistical models, the potential increase in cost associated with this new biosimilar will likely exceed any savings accrued from the use of RZB and aflibercept biosimilars. Specifically, if this new biosimilar were to be priced at $500 per injection, Medicare expenses would increase by 15.2% and patient spending would increase from $117 million to $768 million. Switching patients to a RZB or aflibercept biosimilar would only compensate for 28.8% of this increased cost [ ].
Additionally, as mentioned previously, the implementation of the BPCIA is expected to lead to variable reimbursement outcomes for providers. The BPCIA requires that reimbursement to physicians from Medicare for a given biosimilar include both an average sales price for all biosimilars sharing a similar reference biologic medication and a fixed percentage of the more expensive reference biologic agent. Concern exists as to how this reimbursement model can potentially lead to financial loss for providers, as some biosimilars may have lower reimbursement rates than their purchasing price. Thus, although early statistical analyses have shown promising results regarding the success of the BPCIA, many regulatory barriers that remain need to be addressed in order for the BPCIA to achieve full fruition.
Relevance and future avenues
Currently, there are 5 RZB and 8 aflibercept biosimilars undergoing trials and entering the pipeline for approval in the United States and worldwide. Several others are in development. The market is expected to be booming and everyone wants in. However, in a recent survey of retinal specialist in the United States and Europe, 56.3% indicated they felt they needed more information prior to incorporating biosimilars into their practices [ ]. Part of what ties into this concern is the fact that several of these biosimilars have presented with side effects that some posit may have been underreported.
For instance, Razumab, a biosimilar of RZB which was approved in India, was initially recalled due to several patients developing sterile endophthalmitis. It was thought that the adverse effects were due to bacterial endotoxins which developed during manufacturing of the product, but systemic inflammation also was thought to have played a role in the development of antidrug antibodies [ ]. This adverse effect instigated a drastic change in how trials are performed for biosimilars and their reference medications, with more emphasis now being placed on the proportion of patients who develop antidrug antibodies. It also changed the recommendations for endotoxin in any intraocular pharmaceutical.
Another drug, Beovu (brolicizumab), was initially found in the HAWK (Efficacy and Safety of RTH258 Versus Aflibercept – Study 1) and HARRIER (Efficacy and Safety of RTH258 Versus Aflibercept – Study 2) trials to have noninferiority to aflibercept, and with extended intervals between injections, was posited to improve cost-effectiveness as a new biologic on the market. However, during phase III trials, Novartis, the pharmaceutical company producing this biologic, found that the rates of intraocular inflammation following brolicizumab every 4 weeks was at a disproportionately high rate compared to aflibercept, at about 9.3%. This was not seen in the initial trials, and thus all trials looking at more proximate dosing regimens of brolicizumab were discontinued [ ]. This case lends curiosity toward the approval process of biosimilars, as they are only required to conduct 1 phase 3 trial, and it may lead retina specialists to be skeptical of using biosimilars as only after several studies did the safety data truly reveal adverse effects [ ]. Though not treating DME or nAMD, another medication, Syfovre (pegcetacoplan), highlights the importance of real-world safety data as well, as no cases of vasculitis were initially found in the clinical trials; however, in the real world, rates of retinal vasculitis, though rare, started being reported in the treatment populations.
For retinal specialists, the quicker approval process for biosimilars combined with the real-world presentations of adverse events in these medications will surely be a limiting factor in their readiness to utilize biosimilars. The questions that arise focus around whether the approval process is stringent enough, or if there should be more in-depth clinical trials conducted prior to approval. Shorter trial times for biosimilars mean that new options can hit the market with quicker turnaround times. Ophthalmologists theoretically will benefit from the advent of biosimilars as these products will demonstrate bioequivalence and be on the market within 2 to 3 years through approval as opposed to greater than 10 years with traditional development. However, 1 important aspect that physicians must remember with bioequivalence is that this does not mean the medication is an identical copy of the reference biologic. The underlying assumption is that as the biosimilar has shown the same pharmacokinetic properties as the reference drug, it will have the same safety and effectiveness. Theoretically, this will be true, but physicians should still be vigilant as the FDA does not require exact similar data, and the clinical trials are not as scrupulous as mentioned earlier in this article.
Another factor that may increase hesitancy toward the use of biosimilars relates to the principle of “indication extrapolation,” previously mentioned in this article. Specifically, there may be concern as to whether the approved indications of a particular biosimilar are sufficiently tested and represented through the clinical trials conducted. The pivotal trial conducted for Cimerli (RZB-eqrn) was conducted in patients with nAMD; however, it now is able to be utilized for all indications of RZB, including DME, diabetic retinopathy, retinal vein occlusion, and myopic choroidal neovascularization. Cimerli was also approved as an interchangeable biosimilar, meaning that an ophthalmologist is not required to intervene if the pharmacy wants to interchange RZB for Cimerli [ ]. It remains to be seen if these attributes of biosimilars will pose any adverse events to patient safety.
Lastly, it is important to note that although the World Health Organization established a set of regulatory guidelines for the biosimilar pathway, much confusion and variability exist regarding the approval process amongst a multitude of countries. For example, in an exploratory study performed by Rahalkar and colleagues [ ], challenges experienced by pharmaceutical companies during the development and marketing of biosimilars in numerous countries (Mexico, Russia, China, Brazil, Turkey, and so forth) were explored. One of the major limitations reported by most represented countries in this study was poor communication between regulatory agencies and pharmaceutical industries. This was attributed to a lack of expert personnel within the biologics departments at regulatory agencies. This limitation was further exacerbated by the reported lack of transparency in current established guidelines, making the implementation of the biosimilar pathway particularly challenging for countries seeking to join this emerging market. Additionally, many of the countries represented in this study experienced significant limitations with access to reference products secondary to limited sourcing countries, variability in access across different drug-substance lots, and the high costs associated with reference products [ ]. Also, as part of the approval process for biosimilars, bridging studies must be performed comparing local reference products to foreign reference products. These bridging studies are not only costly, with a reported cost of approximately several hundred thousand to 1 to 2 million US dollars per study, but also are a source of variability in the approval process as requirements vary among agencies. A proposed solution for the limitations imposed by bridging studies involves creating 1 standardized global reference product thereby eliminating all bridging trials. This solution would likely make the biosimilar pathway more accessible on a global scale, particularly in low-resource countries in which the elimination of unnecessary and redundant costs is the key [ ]. However, it remains to be seen whether the implementation of such a regulation will occur in the future.
Discussion/Summary
Biosimilars pose an exciting and influential new avenue in the treatment of DME and nAMD. Through the modified FDA approval process, their production seeks to provide multiple new options for intravitreal treatment at an expedited rate. With these additional treatment agents, the theoretic costs for pharmaceutical companies, insurance agencies, and of course patients are expected to be ultimately reduced. The availability of these agents also is posited to provide increased patient accessibility for treatment of diseases that will become increasingly more prevalent in the global population in the near future. Though cost savings may theoretically be substantial, several roadblocks may prevent these benefits from being realized. Limitations in the expedited approval process and the discovery of adverse side effects through real-world utilization will certainly limit biosimilars’ usage by practicing retina physicians. Additionally, certain federal regulations and policies may pose limitations on the full, projected economic gain from biosimilars. Further research and studies must be conducted to ensure that these biosimilars are produced as safely and with the highest efficacy as possible. However, despite current barriers, with continued progress and care, biosimilars may serve to provide improved ophthalmic care to patients and prevent the progression of debilitating diseases for millions.
Clinics care points
Pearl:
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Biosimilars are molecularly similar compounds that are being approved and examined as viable treatment options for diabetic macular edema (DME) and neovascular AMD (nAMD).
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Expedited approval through a modified FDA process will increase access and options for intravitreal treatment.
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Cost savings and accessibility are potential vision saving benefits associated with the production of these biosimilars.
Pitfall:
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Expedited processes may miss potential adverse effects that may reveal themselves only further down the real-world utilization of biosimilars.
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Federal regulations may pose limitations to the potential economic and social gains that are to be ascertained through the usage of biosimilars.
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