Navigating Patent Cliffs in Neovascular Retinal Diseases: Innovation Beyond Expiry
From Blockbusters to Biosimilars and Beyond — Strategies and Partnerships Shaping the Future of Retinal Therapies
Blockbuster Drugs for The Treatment of Neovascular Retinal Diseases
Neovascular retinal diseases affect over 200 million individuals globally (1). Common neovascular retinal diseases include wet age-related macular degeneration (AMD), proliferative diabetic retinopathy and retinal vein occlusions. If left untreated, patients often experience retinal swelling and bleeding, which can eventually cause blindness.
Since the development of anti-vascular endothelial growth factor drugs (anti-VEGF) in the early 2000s (2), they have been the mainstay of treatment for neovascular retinal diseases. Most patients require at least one injection delivered intravitreally every 1 to 3 months. Given the recurrent administration, some of the anti-VEGF drugs such as ranibizumab (Lucentis, Roche and Novartis) and aflibercept (Eylea, Regeneron and Bayer) have attained blockbuster status, grossing annual sales of over USD $1 billion. Over the past decade, the clinical and commercial performance of these anti-VEGF drugs have sanctioned their positions as key revenue drivers in the pipelines of large pharmaceutical companies.
The Ongoing Patent Cliffs
Portfolios of patents protect these valuable revenue streams. Patents grant legal rights that allow owners to prevent others from making or selling an invention for a set period. In the United States, the U.S. Patent and Trademark Office grant patents with 20 years of exclusivity for producing and selling the invention. This time-limited market monopoly helps companies recover the substantial costs and time invested in research and development. By providing this economic incentive, patents encourage continued drug development, driving the creation of better performing therapeutics and addressing unmet clinical needs.
However, patent protections do not last indefinitely. Once they expire, generic and biosimilar manufacturers can offer lower-cost alternatives. Conversely, from the perspective of the pharmaceutical company, the introduction of such competition in the market leads to significant revenue declines. This phenomenon, known as patent cliff, represents a major financial challenge for pharmaceutical companies.
In the neovascular retinal diseases therapeutic space, key patent portfolios of Lucentis and Eylea are approaching expiration or have already expired. It is estimated that the patent cliffs will cost a contraction of over 4 and 10 billion dollars, respectively for Lucentis and Eylea (3, 4). Alongside these patent expirations, emerging biosimilars are devouring significant shares of the market.
The Emergence of Biosimilars
Biosimilar is a biologic medical product that is highly similar to a United States Food and Drug Administration (US-FDA) approved referenced biologic product. Since the original biologic product is already approved, biosimilars typically have shorter development timelines. Through the approval of biosimilars, governments globally aim to reduce healthcare costs and expand patient access to life-saving treatments.
The US-FDA approval of biosimilars is governed by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) (5). This act provides a shortened licensing pathway for biological products that are shown to be biosimilar or interchangeable with an FDA-licensed reference product. Companies can apply for a biosimilar license through the 351(k) of the Public Health Service Act (PHS Act) with less extensive pre-clinical and clinical data than the traditional application for innovator biologics (6). In particular, the 351(k) application requires biosimilarity to be determined using data from analytical studies, animal toxicity studies and limited clinical safety studies.
To leverage on this abbreviated regulatory pathway, unlike traditional novel drug development, companies often embark on the development of biosimilars with expansive collection of publicly available data on a patent-expiring drug of commercial interest. This includes pre-clinical, clinical trial and real-world post-market data. Thorough analysis of these datasets helps determine the original biologic’s structure, function, mechanism of action and clinical performance. These insights guide the production and characterisation of biosimilar proteins. Extensive structural and functional comparisons with the reference biologic are essential to assess properties like drug structure, activity and stability. Once sufficient similarity is established, the biosimilar progresses to pre-clinical testing through cellular and animal studies, which are typically less extensive than for novel therapeutics. Clinical trials then evaluate the biosimilar’s immunogenicity and pharmacokinetics or pharmacodynamics to ensure safety. Head-to-head trials with the reference biologic may be skipped if there is no strong scientific rationale for additional risk reduction.
This streamlined development process for biosimilars reduces 50% of patients required in studies and cuts costs by nearly 75% compared to developing a novel biologic (7). For biosimilar companies, this presents a valuable business opportunity – the chance to enter a large market with recurring revenue at a significantly lower development cost.
In retinal disease treatment, the US-FDA has approved biosimilars for Eylea (aflibercept) and Lucentis (ranibizumab), with many more in development worldwide (Table 1). The arrival of these biosimilars is beginning to challenge market dominance and pricing power of the original drugs. For example, in 2022 Biogen launched ranibizumab-nuna (Byooviz) at US$1,130 per single use vial, 40% lower than Lucentis’ original list price (8).
Key Strategies for Navigating the Patent Cliffs
In the pharmaceutical industry, a product’s value is closely tied to the strength of its intellectual property (IP) portfolio. Building a strong IP portfolio from the earliest stages of drug development is essential for protecting market share and sustaining long-term revenue. Beyond the active compound itself, companies can secure IP rights for various other aspects of the drug product to safeguard their position in the market.
As biosimilars enter the market, signalling the final phase of a biologic’s life cycle, companies often adopt strategic approaches to minimize or delay the loss of market share. Below are key patent strategies that help extend product longevity:
Patent Strategies
1. Formulation and Composition Patents
These patents protect the unique combination of active ingredients and excipients that influence drug stability, efficacy and safety (9). Developing improved formulations, such as high-dose anti-VEGF drugs that reduce treatment frequency, can extend product life cycles and maintain market exclusivity for longer periods.
2. Process Patents
Process patents secure proprietary manufacturing methods, ensuring consistent drug quality and production efficiency. Patenting processes such as cell culture systems and specialized purification techniques for anti-VEGF compounds impacts on the competitors’ freedom-to-operate by limiting their ability to manufacture the drug using similar methods.
3. Indication and Method of Use Patents
These patents provide exclusivity for specific treatment indications. Companies can extend market exclusivity by demonstrating the therapeutic benefits in new disease areas. For example, aflibercept received FDA approval in 2023 for treating retinopathy of prematurity (ROP), a paediatric disease characterised by abnormal retinal vascular growth and visual loss from retinal detachment (10).
4. Combination Therapy Patents
Combination therapy patents protect the use of two or more therapeutic agents together to treat a disease (11), focusing on the synergistic effects achieved through their combined use (12). For instance, combining existing anti-VEGF agents with inhibitors targeting alternative VEGF isoforms – like the approach pursued by Ophthea Therapeutics – may extend the relevance of current therapies and delay the shift to biosimilars (13).
By building a well-rounded IP portfolio with these patent strategies, companies can strengthen their market position and protect existing revenue streams. However, the practice of building dense patent landscapes, sometimes referred to as “patent thickets”, is under increasing scrutiny from policymakers (14). Proposed reforms aim to tighten patentability criteria, allowing patents only for substantial modifications and meaningful innovations to balance market access with innovation incentives.
Product Development Strategies
As the definition of innovation significance evolves, the societal expectation for continuous research and product development remains clear. To meet this demand, high-quality product innovation must be executed in efficient cycles to deliver advanced and more effective therapeutics. In AMD, where anti-VEGF therapies dominate the treatment landscape, companies have successfully built on existing data from previous drug approvals to achieve faster market entry. Below are some effective strategies that have contributed to these advancements:
1. New Indications and Label Expansions
In the United States, extending a drug’s label to cover new indications often involves submitting a supplemental New Drug Application (sNDA) or Biologics License Application (sBLA) (15). When scientifically appropriate, this process can be more straightforward, relying primarily on post-marketing surveillance data of the approved drug and only requiring new Phase II/III trial data to evaluate efficacy and safety for the new indication. For example, in 2023, the FDA approved the use of aflibercept in ROP based on a sBLA supported by data from two Phase III trials, BUTTERFLEYE (NCT04101721) (16) and FIREFLEYE (NCT04004208) (17).
2. Drug-Device Combinations
Combining drugs with medical devices can greatly enhance patient outcomes. Susvimo®, approved in 2021 for wet-AMD, is a refillable ocular implant that continuously delivers ranibizumab for up to six months. Despite the regulatory complexities associated with drug-device combination products, this development focused on adapting the formulation of ranibizumab to suit the implant, with existing data on the drug’s safety and efficacy supporting the approval process.
3. New Formulations
Similar to label extensions, developing new formulations can sometimes involve only a sNDA or sBLA when appropriate. Aflibercept 8mg, a high dose formulation of the original drug, was developed to extend dosing intervals for patients. In 2022, the FDA approved its use based on a sBLA that included the data from two Phase III trials, PULSAR (NCT04423718) (18) and PHOTON (NCT04429503) (19).
By identifying key additional datasets and streamlining clinical studies, companies can extend product life cycles, maintain revenue streams, and continue improving AMD treatment outcomes.
Leveraging on Private–Public Partnerships to Accelerate Innovations
Over the past decade, many public universities have shifted towards more industry-oriented research, focusing on practical, use-driven discoveries rather than purely exploratory science. This shift makes collaborations with companies smoother, as research outputs are now more advanced in terms of their technology readiness levels. Private-public partnerships can further accelerate innovation, especially when companies bring regulatory expertise and a track record of successful product development.
1. Access to disease models and biological insights
Exploring new therapeutic indications presents valuable opportunities, but the research required to demonstrate efficacy in uncharted disease areas can be extensive - particularly for the companies lacking prior experience in that space. Collaborating with public research institutes, where deep biological knowledge and preclinical models such as in-vitro cell lines, organoids or animal models are already established, can be advantageous. These partnerships are typically developed through fundamental research that may not offer immediate commercial returns.
For example, in a partnership between AstraZeneca (AZ) and the Liverpool School of Tropical Medicine to develop new macrofilaricidal drugs, the academic team created a whole-cell assay using an insect cell line infected with Wolbachia (20). This assay was later adapted for high-throughput screening (HTS) scale with AZ’s support. By combining academic disease expertise with industry-level drug screening capabilities, the collaboration screened 1.3 million compounds and identified 20,000 potential candidates from AZ’s compound collection.
2. Expanded Financial Resources For R&D Efforts
As public institutions increasingly engage in industry collaboration, dedicated fund programs have emerged to support these partnerships to help companies offset research costs.
One example is the U.S. National Science Foundation's GOALI program, which funds academia-industry projects addressing critical industry needs. In 2024, GOALI supported a joint initiative between the University of Texas at San Antonio and Bristol Myers Squibb to develop more efficient, eco-friendly pharmaceutical manufacturing processes – showcasing how public funding can drive meaningful industry advancements (21).
3. Talent development and Knowledge Exchange
Public-private partnerships also serve as valuable channels for talent development and knowledge sharing. Life science companies often face challenges in recruiting skilled technical talent, especially as research technologies evolve rapidly. These collaborations expose students and researchers to industry practices, equipping them with practical skills and creating a pipeline of industry-ready talent. Additionally, when companies license technologies from public institutions for further development, access to a well-trained workforce familiar with the technology can be essential for maintaining the product development momentum. This seamless transfer of expertise helps companies accelerate product timelines while fostering career growth for researchers.
Conclusion
The impending patent cliffs in the neovascular retinal disease space present both challenges and opportunities for pharmaceutical companies. As biosimilars reduce revenues from blockbuster anti-VEGF therapies, companies must adopt strategic approaches to stay competitive. Diversifying patents, advancing product innovation, and accelerating development through public-private collaborations can help extend product lifecycles and drive growth. These partnerships offer access to disease expertise, funding to ease R&D costs, and a pipeline of skilled talent. Ultimately, companies that embrace a well-rounded strategy will be best equipped to navigate market shifts and succeed in an ever-changing treatment landscape.
References
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