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Selecting the Right Patients for Anti-VEGF Biosimilar Therapy

Impact of Biosimilars on the Healthcare System

Key Clinical Findings on the Efficacy, Safety Profile and Immunogenicity of Biosimilar SB11

Review of the Phase III Clinical Trial for Biosimilar SB11

Biosimilar Approval Process by Regulatory Bodies

Overview of Biosimilars

Need for Awareness About Biosimilars

Over the last 15 years, biosimilars have become a major feature of the health care landscape. Physicians in many disciplines, particularly oncology and immunology, have embraced biosimilars. However, access to educational resources on these powerful biologics can be inconsistent, and in turn, some ophthalmologists who could benefit from the adoption of biosimilars are left in the dark.

The real-world application of biosimilars was the focus of discussion for Martin Zinkernagel, MD, PhD, chair of the Department of Ophthalmology at the University Hospital of Bern, Switzerland, and Paolo Lanzetta, MD, professor of ophthalmology and chairman of the Department of Medicine-Ophthalmology at the University of Udine in Italy. In their discussion, the experts addressed several common questions, framed around the phase 3 clinical trial for biosimilar SB11 (BYOOVIZ) from Biogen. SB11 is approved in Europe and the United Kingdom. Like the reference product ranibizumab (Lucentis), SB11 is approved for the treatment of retinal disease including neovascular age-related macular degeneration (nAMD).

Addressing physicians’ levels of familiarity with biosimilars, Dr Lanzetta attributed much of the variation to regulatory discrepancies. “The uptake of biosimilars varies throughout Europe by country and by product,” he said. “Obviously, variation in the uptake of biosimilars [is] influenced by government involvement, reimbursement issues and tender procurement policies.” Recent survey data have revealed gaps in awareness across Europe and in the United States on the efficacy and safety of biosimilars for retinal diseases, Dr Lanzetta said, especially in terms of “real-world data.”

In a clinical application, Dr Lanzetta said, biosimilars may exhibit minor differences from the reference products, but they aren’t considered to have significant impact on the efficacy or safety profile. Typically, the biosimilar and reference medicine must have the same posology and route of administration, with few exceptions, he added.

Dr Lanzetta also said that in the last 10 years, the European Medicines Agency (EMA) has approved the highest number of biosimilars worldwide.

 “And this means, to us physicians, having both the possibility to have experience on their use in terms of safety and evaluating the efficacy after that,” he explained.

One common misconception about biosimilars is that these therapeutics are interchangeable with the idea of generic medicines. But there is a key indicator that biosimilars are unique: the cost. “While generic medicines are marketed at a significantly lower price than name brand ones, why do we not see the same level of cost savings with biosimilars?” Dr Zinkernagel asked.

Dr Lanzetta explained that biosimilars are developed via a rigorous, complex and highly regulated manufacturing process. “Generics are simple chemical medicines or agents, which is not the case for biosimilars and biologics,” he said. “Unlike generics, biologics, and therefore biosimilars as well, are very complex; they’re very difficult to copy. And the development processes are patented and proprietary to the originators.” The proprietary nature of biologic development, he added, is why biosimilars may have differences from their originators.

Prof Zinkernagel and Dr Lanzetta used data from the SB11 phase 3 trial to expand upon the capabilities of biosimilars. Prof Zinkernagel detailed the study: over 700 patients were included in the randomised, double-masked, parallel-group multicentre trial. Over 52 weeks, investigators evaluated the efficacy and the safety profile of this biosimilar SB11 in comparison with monthly ranibizumab for the treatment of nAMD.

“Patients with neovascular AMD were included, [with a] visual acuity range between 20/40 and 20/200,” Prof Zinkernagel said. “[Patients] were randomised in a 1:1 ratio to either have the originator or the biosimilar every 4 weeks from baseline up to week 48.”

Primary end-points were change from baseline in best corrected visual acuity at week 8 and change from baseline in central subfield thickness at week 4. The pre-specified secondary efficacy end-points included longer-term assessments of change from baseline in visual acuity, and the proportion of participants who lost fewer than 15 letters or who gained 15 or more letters in visual acuity from baseline at weeks 24 and 52.

“Other secondary end-points included, of course, change from baseline in central subfield thickness and central retinal lesion thickness at week 24, as well as change from baseline in choroidal neovascularisation [CNV] size and proportion of participants with active CNV leakage seen via OCT [optical coherence tomography] at week 24,” Prof Zinkernagel continued. Describing the results, he said, “When you look at the visual acuity improvements, it’s really equivalent. You have equivalence between the originator and the biosimilar, and the same holds true for a decrease in central retinal thickness. So the curves are basically the same, and also the secondary end-points.”

Prof Zinkernagel also spoke about the immunogenicity outcomes of the SB11 trial, as immunogenicity reactions have been a common problem in past assessments of anti–vascular endothelial growth factor (VEGF) agents. Along with detrimental effects to visual acuity, immunogenicity reactions can also lead to vasculitis and vitritis.

“Now, in this trial, the overall cumulative incidence of anti-drug antibodies, antibodies reacting against this specific drug up to week 52, was very low,” Prof Zinkernagel said. “For the SB11 biosimilar, it was 4.2%, and for the originator it was 5.5%. So very, very similar.”

He also noted that most antibodies were non-neutralising, which generally indicates a weak antibody response. “Furthermore, no statistical or clinically relevant differences in the incidence of anti-drug antibodies and neutralising antibodies were observed between treatment groups at any of the time points,” Prof Zinkernagel explained.

Dr Lanzetta highlighted the unique potentialities for anti-VEGF therapies as an area where physicians can consider treating patients with a biosimilar. “You can either switch a patient from the originator, obviously, or you can also consider treating with a biosimilar treatment-naive patients who may benefit…from being treated with that reference agent or originator agent,” he said. When to deploy a biosimilar will depend on many factors, including the locality where a patient is being treated. “Europe has different countries, different health care systems,” Dr Lanzetta said. “You may consider treating with the biosimilar patients who may not be strictly adherent to the cost of therapy and the frequency of treatment because of some cost issues.”

Just as education on biosimilars is vital to practitioners, awareness and education resources for patients are vital, too. “We spend a lot of time with our patients in letting them know that biologics did undergo a very rigorous approval process through studies, efficacy and safety studies,” Dr Lanzetta emphasised. This education is vital to getting patients on board with biosimilars, and it sparks enthusiasm about the potential benefits. “Once they do understand that, I think they will be very prone to receive a biosimilar; [it’s] in their interest and in the interest of the community, the whole community of patients, and in the interest of the health care system,” Dr Lanzetta said.

1. Biosimilars in the EU: information guide for healthcare professionals. European Medicines Agency. Updated December 2, 2019. Accessed October 3, 2023. 

https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pd

Editor’s note: A prior version of this article contained a misspelling of the product name BYOOVIZ. It has been corrected. We regret the error.

How biosimilars expand treatment options for patients with retinal disease

John Kitchens, MD, is joined by Peter Kaiser, MD, to discuss higher molar dose and its translation into clinical practice. They also discussed the challenges they face in treating patients with higher molar doses, including insurance limitations, safety concerns and convincing insurance carriers to switch to a new dose. They shared clinical pearls for helping patients transition to a higher dose.

See the key takeaways below, and listen to the full podcast for all the clinical pearls.

Increasing aflibercept dose for longer drug duration in eyes.

A deep dive into how increasing aflibercept dose improves drug durability in the eye

Modeling suggests slower ocular clearance with higher dose of aflibercept

Drug half-life and dosing for anti-VEGF treatments in ophthalmology.

How the half-life of aflibercept is determined in the eye using PK sampling and modeling

Highlights of studies include dose regimen modifications and durability of drug in second year

Accelerating aflibercept dosing intervals for wet AMD patients.

Designing clinical studies translating the "treat and extend" approach to the real world

Potential benefits of longer-acting eye medication, including increased efficiency and reduced burden on healthcare providers

Potential biomarkers that indicate a need for frequent VEGF injections in wet AMD patients

Emphasising the importance of early treatment with the strongest medication for type three lesions to prevent permanent vision loss

Higher Molar Dose and Its Translation into Clinical Practice

John Kitchens, MD, is joined by David Brown, MD, to discuss the PULSAR study results and their relation to patients with neovascular age-related macular degeneration in clinical practice. They touch upon dosing strategies and also highlight two new drugs, faricimab and aflibercept 8 mg. They also discuss the potential benefits of increased molar dosing and the importance of maintaining dryness and durability in patient care.

Drug dosing and half-life in retina treatment.

Highlighting developments in ocular drug delivery, including new formulations of existing drugs and potential challenges in the clinic.

Discussing increased molar dosing of aflibercept.

Explaining the variability in patient clearance rates and their impact on treatment outcomes.

Aflibercept 8 mg, including study findings and clinical practice applications.

Clinical practice for aflibercept dosing, including loading doses and extension intervals.

Prioritising individualised approach based on patient's response and disease activity.

The safety and efficacy of a drug for treating retinal diseases.

Extending drug treatment from 8 weeks and onward with positive patient response.

Safety data and potential label change with regulatory agencies.

The importance of manufacturing processes and the challenges of creating fully human antibodies to VEGF.

John Kitchens, MD, is joined by David Brown, MD, to discuss the PULSAR study results and their relation to patients with neovascular age-related macular degeneration in clinical practice. 

PULSAR Results and Their Relation to nAMD Patients in Your Practice

Alan Franklin, MD, PhD, FASRS, discusses his presentation at ASRS, Intraoperative fluorescein angiography reduces the rate of postoperative vitreous hemorrhage

Intraoperative fluorescein angiography reduces the rate of postoperative vitreous hemorrhage

The Eye Care Network is on-site at this year's American Society of Retina Specialists (ASRS) meeting in Stockholm, Sweden. Alan Franklin, MD, PhD, FASRS, a retina specialist in Mobile, Alabama spoke about his presentation, "Intraoperative Fluorescein Angiography Reduces the Rate of Postoperative Vitreous Hemorrhage."

Editor's note: The below transcript has been lightly edited for clarity

: Hi I'm Alan Franklin, MD, PhD. FASRS, I practice at Diagnostic and Medical Clinic in Mobile, Alabama, [and I] had the opportunity to present intraoperative fluorescein angiography, how that's improving our outcomes in diabetic vitrectomy at this great venue in Stockholm, Sweden. intraoperative fluorescein angiography, was initially described by Steve Charles 20to 30 years ago, with the advent of digital visualization, it's gotten more traction as our visualization is better. The images and the video on the operating room are quite compelling, but the question begs is even though the video is great, and shows us reproducible biomarkers that we see in clinic, will it help her outcomes. 

So we did a study where we looked at our diabetic patients and looked at rate of vitreous hemorrhage after vitrectomy with or without fluorescein angiography guidance intraoperativly of laser and other surgical maneuvers. Indeed, we found that fluorescein angiography reduced our post-op vitreous hemorrhage rate greatly, especially over the first 1 to 2 months with corresponding better vision reported rate with fluorescein guidance during the surgery is on the order of 10%, which is much lower than the standard reported rates after vitrectomy surgery for diabetic retinopathy and we both Dr. Abruro, our colleague and Dominican Republic, and we showed a significant reduction and rates of vitreous hemorrhage after surgery compared to those who did not receive intraoperative fluorescein angiography before surgery, it was highly significant, especially at both the 1- and the 2-month time points And that we had about 90 patients that underwent fluorescein angiography, so it's still a relatively large study. It is limited by the retrospective nature. 

Hopefully it'll improve adoption. It's one thing to show pretty pictures and videos, but to show and prove surgical outcomes, hopefully will will get better adoption. We need to work on making this available for both digital visualization platforms and standard optical visualization with a surgical microscope as well.

Alan Franklin, MD, PhD, FASRS, a retina specialist in Mobile, Alabama spoke about his presentation, "Intraoperative Fluorescein Angiography Reduces the Rate of Postoperative Vitreous Hemorrhage."

ASRS 2024: Intraoperative fluorescein angiography reduces the rate of postoperative vitreous hemorrhage

Aurion Biotech, a clinical-stage biotechnology firm based jointly in the United States and Japan, announced two rulings by the US Food and Drug Administration (FDA). The FDA has granted AURN001, the company’s allogeneic cell therapy candidate for the treatment of corneal oedema secondary to corneal endothelial disease, with both Breakthrough Therapy Designation (BTD) and Regenerative Medicine Advanced Therapy (RMAT) Designation.

Sterling Chung, vice president of Regulatory Affairs and Quality at Aurion Biotech, said in a news release the company was pleased to receive the BTD and RMAT designations.

“These designations underscore the importance of developing a potential solution for millions of patients around the world who suffer from corneal endothelial diseases,” Chung said in the release. “We look forward to working closely with the FDA to expedite the development of our cell therapy.”

Greg Kunst, CEO of Aurion, pointed out the BTD and RMAT designations are important milestones for people living with corneal endothelial disease who need better, less burdensome and more accessible treatment options.

“I thank the Aurion team for their hard work and dedication, and I’m grateful for the essential contributions of clinical trial patients and their ophthalmologists—all of whom have helped to make today’s news a reality,” he said.

Aurion Biotech, in its news release, explained that corneal oedema secondary to endothelial dysfunction is a sight-threatening and debilitating condition, which affects millions of people throughout the world. When corneal endothelial cells die or degrade, they do not regenerate. If left untreated, corneal endothelial cell loss can cause corneal oedema and loss of vision.

A BTD from the FDA is designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

RMAT is part of the 21st Century Cures Act.

 The FDA noted, in a news release, that investigational drugs are eligible for RMAT designation if they meet the definition of regenerative medicine therapy; are intended to treat, modify, reverse or cure a serious condition; and preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such conditions.

Companies that earn BTD and RMAT designation can benefit from increased interactions with the FDA with the goal of expediting drug development. The dual designations granted to Aurion Biotech are based on the criteria, the unmet medical need among patients with corneal endothelial disease, and FDA’s review of clinical data from the AURN001 program, which includes multiple clinical trials with subjects having completed at least 12 months of follow-up.

This news comes on the heels of Aurion’s announcement that it has completed enrollment and dosing of its Phase 1/2 CLARA trial in the US and Canada.

The CLARA clinical trial is a prospective, multi-centre, randomised, double-masked, parallel-arm cell dose-ranging study in subjects with corneal oedema secondary to corneal endothelial dysfunction.

According to the company, the study will evaluate three different doses of 

 used in combination with Y-27632. The CLARA trial is designed to assess the safety, tolerability and efficacy of AURN001 for the treatment of corneal oedema secondary to corneal endothelial dysfunction. Ninety-seven subjects have been randomised at US and Canadian sites. The primary endpoint is the percentage of subjects who gain three lines of vision at 6 months.

In March 2023, the company received regulatory approval from Japan's Pharmaceuticals and Medical Devices Agency.

Aurion Biotech Receives Breakthrough Therapy Designation and Regenerative Medicine Advanced Therapy Designation for Its Drug Candidate AURN001. Businesswire.com. Published June 19, 2024. Accessed June 19, 2024. 

https://www.businesswire.com/news/home/20240619102413/en/Aurion-Biotech-Receives-Breakthrough-Therapy-Designation-and-Regenerative-Medicine-Advanced-Therapy-Designation-for-Its-Drug-Candidate-AURN001

Center for Biologics Evaluation and Research. Regenerative Medicine Advanced Therapy Designation. U.S. Food and Drug Administration. Published 2019. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation

Aurion Biotech Announces Completion of Enrollment In Phase 1 / 2 Clinical Trial. Aurion Biotech. Published April 30, 2024. Accessed June 19, 2024. https://aurionbiotech.com/aurion-biotech-announces-completion-of-enrollment-in-phase-1-2-clinical-trial

The US Food and Drug Administration issued designations for the allogeneic cell therapy candidate, a therapeutic for corneal oedema

Aurion Biotech candidate AURN001 receives US Breakthrough Therapy Designation and Regenerative Medicine Advanced Therapy Designation

Mentorship is a crucial component of a successful career in ophthalmology. Young ophthalmologists can improve their skills, and enhance their confidence, by finding support through a formal mentorship programme or establishing mentor-mentee relationships with their superiors, instructors or more established colleagues. Academic and research mentorship are commonly assumed to be the areas where mentorship can have the most impact.

However, data generated following a 5-year mentorship programme challenge those assumptions, according to researchers from the Casey Eye Institute, Oregon Health & Science University School of Medicine, Portland, Oregon.

 Outcomes from the study indicated that mentees most valued their mentors’ career advice, network building and wellness support. Mentorship also has a positive impact on gender equity in the field, expanding opportunities for promotion to women and aiding in career retention.

But where to begin? Three industry leaders spoke to 

 about their own experiences in early-career mentorship, including the specific ways that mentorship has aided in their careers. Though their specialities are different, all three women provided advice with striking similarities—and obvious impact.

For new ophthalmologists or established practitioners seeking out a change, we have compiled advice from 

, president of the European Society of Cataract and Refractive Surgeons (ESCRS) and head of ophthalmology at Hospital da Luz, Lisbon, Portugal; 

, a Clinical Senior Lecturer in Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, and honorary consultant ophthalmologist for glaucoma at St Pauls Eye Unit, Liverpool University Hospitals NHS Foundation Trust; and 

associate professor of phthalmology, Université Paris-Est Créteil, France, and the 2024 recipient of the French Retina Society’s Gabriel Coscas prize.

Often, students of ophthalmology don’t realise the full scope of the relationships they build during the first days of their careers. That impact is only obvious in hindsight. “Looking back, I can recognise the value of networking and building professional relationships very early in a career,” Dr Ribeiro said.

Dr Miere echoed that sentiment and reflected on a mentor relationship that has spanned the last decade. “I had the chance to find a very intellectually stimulating environment in...Le Centre Hospitalier Intercommunal de Créteil retina team, led by Professor Eric Souied who has been my mentor,” she recalled. Prof Souied and other instructors provided “the honest feedback I needed in order to contribute more significantly to the department, but also to grow as a clinician scientist, and as a person,” Dr Miere remembered. “When it comes to academia, unlocking individual potential is not only a question or a matter of personal will or hard work. But mentorship plays a really essential part.”

For Dr Ribeiro, connecting with mentors came as naturally as connecting with peers, since she began her career in hospital settings that put a strong emphasis on collaboration. Dr Ribeiro said that institutional focus on mentorship began during her initial rotation at Hospital Santo António dos Capuchos, in Lisbon, Portugal, and continued when she moved on to Hospital Fernando Fonseca in Amadora, Portugal. “I was lucky,” Dr Ribeiro said. “[There was] a very strong commitment to inclusivity and mentorship. The sense of belonging was really a nuclear, promoted value.”

In 2013, when Ms Vallabh was in her fourth year of ophthalmology training, she realised that she wanted to expand her horizons and pursue academic research. “It wasn’t something that I had come across until I started working in St Paul’s Eye Unit [at Royal Liverpool University Hospital],” she said. “I noticed that some of my peers were doing PhDs and MDs. That was what really inspired me at that point...seeing what colleagues were doing and thinking, ‘Well, is this something that interests me? Is it something that I could do?’” That’s when she found a mentor: Colin Willoughby, MD, BSc (Hons), FRCOphth, who was a professor and new to Liverpool at that point. “It was a great time, because he was just starting and looking for interested, enthusiastic individuals to do research,” Ms Vallabh said. “He was the person that I got in contact with, particularly because he had an interest in mitochondrial genetics in glaucoma.” That topic formed the basis of Ms Vallabh’s research degree.

While the clinical research component of a mentor relationship pays real dividends, it is far from the only benefit. Ms Vallabh recalled how her mentor, Prof Willoughby, helped her make a decision at a pivotal moment for her career and her family. “At that stage in time, I’d had one child, and I wanted to expand my family and have another child,” she said. “I was a bit concerned how this would impact...my ability to do research. At that early stage, I spoke to him and said, ‘You know, I’m just being honest here: I’m a mother, I would like to have another child, and would that impact my training?’”

Ms Vallabh had reservations, given the long history of
gender-based discrimination towards mothers in professional settings­—especially medical care. But Prof Willoughby reassured her that she didn’t have to choose between her academic passions and her family goals. “He supported my decisions. He knows it’s not just me as an academic clinician, but it’s me as an academic clinician–mother,” she said. “And when you speak about women in ophthalmology, I think that’s important to be open and honest about these things. The reality is that we do have a life outside of our career, and we can absolutely strike a balance.”

Dr Miere said that, as she’s progressed in her career, mentorship has taken on new importance. Now, she is learning how to mentor younger practitioners, too.

“I am currently an honorary research fellow at Moorfields with Professor Pearse Keane, and it is very interesting to see different styles of leadership and mentorship relations unfolding in a different workplace culture,” Dr Miere said. Seeing how other high-performing teams work has reignited her passion for her field, and she looks forward to applying all she has learned from her multiple professional role models. “The mentorship relationship is a source of learning for both the mentor and the mentee,” she emphasised. “Character skills in our mentorship relationship are as important, if not more important, than scientific ones.”

What does this advice look like in practice? How can the next generation of ophthalmologists find mentors who support them in a research setting, but also as professional peers? The first step, said Ms Vallabh, is being open to change, and finding different mentors for different goals or career stages.

“Life changes. I think we sometimes can start on one career path and realise that it’s not for us,” she said. “You can have multiple mentors along the way. [Work on] finding people who help to empower you.” Ms Vallabh said that a good mentor will celebrate your growth, even if it means you outgrow a role that keeps you in their orbit. That’s crucial for advancing in your career. “Keep your eye open for other interesting opportunities which you can take on. Then you can go on to flourish in those [areas] and develop them later,” she said.

Dr Miere’s advice mirrored that statement. The best way to find a mentor is often by finding a new challenge, she said. “Fight against the inertia of staying in a place where there’s no room for professional or personal growth,” she advised. “Even if that means getting out of your comfort zone: changing departments, changing cities, changing even countries.”

She also recommended building a sense of “grit” and determination to step up and ask for help, or connections, until that attitude becomes second nature. “You need a lot of courage and initiative,” she said. “Cultivate your network—again, this is really of paramount importance—and be very proactive in the journey to success.”

Finally, take advantage of the connections made possible by your educational institution or other affiliations, Dr Ribeiro said. Often, more established colleagues are happy to share their time, expertise and connections with more junior clinicians. Don’t be afraid to take part in the social aspects of social networking,
she advised.

“Join professional organisations—like ESCRS, for instance—and attend networking events,” Dr Ribiero recommended. Professional organisations often have the added benefit of being specialty-specific, so young ophthalmologists are more likely to find mentors who are familiar with the unique career challenges they may face.

1. Yang S, Glass ST, Clements JL, Reznick LG, Faridi A. Outcomes of a five-year formal ophthalmology residency mentorship program. 

2022;14(2):e178-e186. doi:10.1055/s-0042-1756133

2. Hoyer A, Randolph A, Syed MF, Elahhe Afkhamnejad, Mirza RG. Enhancing mentorship networks through the experiences of women professors of ophthalmology. 

2023;15(01):e1-e7. doi:10.1055/s-0042-1760206

Three leaders in glaucoma research, retina care and refractive surgery share their expertise

This program is initiated, funded, and developed by Biogen.

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