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Dr LaHood is an ophthalmologist specialising in refractive cataract and laser surgery in Adelaide, Australia. His research and teaching focus on the management of astigmatism. He is a consultant to Alcon and Zeiss.

Giving due consideration to preoperative marking and the surgical technique in toric IOL implantation, as well as being diligent about reviewing postoperative results, can improve patient outcomes whilst minimising the chance of errors.

Toric IOLs for beginners: What to consider before and during surgery and in the postoperative period

This three-part feature discusses tips for success when getting started with toric IOLs. Part 2 tackles calculating toric IOL sphere and cylinder power; though it can seem daunting when treating astigmatism, the process can be simplified with a few key considerations.

Toric IOLs for beginners: Advice on selecting and calculating toric IOL sphere and cylinder power

This three-part feature discusses tips for success when getting started with toric IOLs. Part 1 looks at patient selection and optimising biometry; Part 2 examines IOL calculation; and Part 3 looks at the perioperative period and postoperative troubleshooting.

Toric IOLs for beginners: Tips for patient selection, preoperative assessment and biometry

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

As artificial intelligence (AI) begins to establish a larger presence in medical care, questions surrounding cost arise. A recent study,

 led by first author Mahoor Ahmed, MS, and colleagues found that “autonomous AI-based screening is a more effective screening strategy compared to the standard eye care provider (ECP)-performed eye examinations with greater cost-effectiveness for smaller health systems and cost-saving for larger ones.” She is from the Section on Biomedical Informatics and Data Science, Johns Hopkins University, Baltimore.

Autonomous AI already has been shown to be safe and effective for screening patients for paediatric diabetic retinal disease (DRD) and can potentially enhance health equity and clinician productivity.

However, the researchers pointed out that cost among other factors may deter patients from screening, especially in rural and low-resource settings.

 “With DRD screening rates as low as 20% nationwide,” they stated, “health systems and medical practices are considering alternative methods to increase screening access and adherence.

 Therefore, considering the financial expenditures associated with AI screening is an important step in determining if and how to implement these systems.

In this next-step study, Ahmed and colleagues examined the cost-effectiveness of an autonomous AI strategy versus a traditional ECP strategy during the initial year of implementation from a health system perspective in order to obtain some solid financial data. The incremental cost-effectiveness ratio was the main study outcome measure.

The bottom line, according to Ms Ahmed and colleagues, was that “The base-case analysis showed that the AI strategy resulted in an additional cost of $242 [€235] per patient screened to a cost saving of $140 [€127] per patient screened, depending on the health system size and patient volume, compared with the ECP strategy."

The investigators also reported that the base-case analysis showed that the anticipated AI strategy cost was between $19,368 and $133,900 (equivalent to €18,848 and €130,306, respectively), compared to that of the ECP strategy, which is between $8,927 and $357,072 (equivalent to €8,687 and €347,488, respectively). 

“Thus, excluding insurance reimbursements, the AI strategy results in additional costs of up to $10,441 [€10,160] and potential cost savings of up to $240,972 [€234,504] depending on the size of the health system. Regarding effectiveness, the AI strategy consistently results in more patients being screened, ranging between 43 and 1,724 additional patients screened annually, depending on patient volume.”

They continued, “Notably, the AI screening strategy breaks even and demonstrates cost savings when a paediatric endocrine site screens 241 or more patients annually. Autonomous AI-based screening consistently results in more patients screened with greater cost savings in most health system scenarios.”

Their hope is that this analysis can assist providers in weighing the value proposition of implementing AI screening and support informed adoption decisions.

Ahmed M, Dai T, Channa R, et al. Cost-effectiveness of AI for pediatric diabetic eye exams from a health system perspective. 

https://doi.org/10.1038/s41746-024-01382-4

Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic retinopathy preferred practice pattern®. 

Draznin B, Aroda VR, Bakris G, et al. 14. Children and adolescents: standards of medical care in diabetes—2022. 

Benoit SR, Swenor B, Geiss LS, Gregg EW, Saaddine JB. Eye care utilization among insured people with diabetes in the U.S., 2010–2014. 

Autonomous, AI-based screening consistently resulted in more patients screened with greater cost savings, investigators said

Artificial intelligence supports screening more paediatric patients at lower cost

RhyGaze, a biotechnology company based in Basel, Switzerland, and Philadelphia, Pennsylvania, announced it has secured Series A financing of $86 million. Financing was led by Google Ventures, Arch Venture Partners, F-Prime Capital and founding investors BioGeneration Ventures and Novartis Venture Fund.

The funding will aid the further development of RhyGaze’s lead clinical candidate, a novel gene therapy for optogenetic vision restoration in diseases causing blindness. It will also support activities like formal pharmacology and toxicology testing; a non-interventional, observational study to assess potential clinical endpoints in patient groups eligible for the therapy; and a first-in-human clinical trial to test the safety, tolerability and potential efficacy of the lead candidate.

RhyGaze was co-founded by Botond Roska, MD, PhD, who is also a founding director of the Institute of Molecular and Clinical Ophthalmology Basel (IOB).

“This programme exemplifies a key goal of IOB: combining our deep understanding of retinal biology and vision with breakthrough technologies to develop novel therapies for vision loss,” Dr Roska said.

Other researchers involved in development and testing of the therapy said they look forward to the next steps in the programme. Bence Gyorgy, a group leader at the IOB and RhyGaze scientific co-founder, said, “We are excited to see this programme moving forward because it uniquely presents the opportunity to restore high-resolution vision in blind patients.”

Katherine High, CEO of RhyGaze, sees collaboration with IOB as a valuable opportunity to reach the goals of the therapy. She said, “I look forward to partnering with colleagues at IOB to bring this novel gene therapy to patients, and I am excited about the team we are assembling to pursue this important goal. RhyGaze will determine over the next few years whether the compelling data generated at IOB can translate to clinical outcomes. If that is true, this innovation will have a worldwide impact in improved therapeutics for blindness.”

Institute of Molecular and Clinical Ophthalmology Basel Spinout RhyGaze Closes USD 86 Million Series A Round to Further Novel Gene Therapy for Vision Restoration. Businesswire. Accessed January 13, 2025. 

Institute of Molecular and Clinical Ophthalmology Basel Spinout RhyGaze Closes USD 86 Million Series A Round to Further Novel Gene Therapy for Vision Restoration | Business Wire

The company, which has European headquarters in Basel, Switzerland, plans to use the funds for a non-interventional, observational study and a first-in-human clinical trial

RhyGaze announces $86 million in Series A financing for optogenetic vision restoration therapy candidate

Overview of Novel Treatments for Retinal Vascular Diseases

Video content above is prompted by the following: 


Could you briefly provide an overview of the new treatments available for retinal vascular diseases?

A panelist discusses novel treatments for retinal vascular diseases, including faricimab, aflibercept, and port delivery system with ranibizumab.

Video Series

Advantages of the Molecular Structure of Aflibercept

Video content above is prompted by the following:

Aflibercept 2 mg is considered the standard of care for retinal vascular diseases. Can you briefly explain the structure of the aflibercept molecule and its significance?

Panelists discuss how aflibercept’s molecular structure contributes to its clinical efficacy as a standard treatment for retinal vascular diseases.

Corneal cross-linking (CXL) has transformed the disease course of patients with corneal ectasias since its introduction to clinical practice in 2002. But what CXL had not been designed to achieve was improvements in visual outcomes.

The original (and until recently, the undisputed gold standard) CXL protocol for ectasia has, for most of this time, been the Dresden protocol.

 It involves epithelium removal and 20 minutes of riboflavin application, followed by 30 minutes of UV light irradiation at 3 mW/cm² to deliver a total fluence of 5.4 J/cm². Dresden protocol cross-linking might flatten the cornea by a small amount—often in the range of 1.5 D—but this flattening is too small to make a meaningful difference to the vision of patients with corneal ectasias who undergo the procedure.

But CXL has moved on. We know that oxygen diffusion into the stroma is an essential – and rate-limiting – step in the UV-riboflavin photochemical reaction, and that accelerating the delivery of the 5.4 J/cm² fluence results in a reduction in the stiffening effect.

 The essential role of oxygen also explains why many of the older epithelium-on (epi-on) CXL protocols delivered a poorer corneal stiffening effect than epi-off protocols3: the epithelium consumes oxygen and absorbs UV energy.

 Today, modern, higher-fluence (up to 10 J/cm²) protocols are set to close this efficacy gap.

 Learnings made during these developments prompted a re-thinking of how corneal flattening might be achieved.

The evolution of customised cross-linking

The first generation of customised cross-linking employed the following approach: delivering gradients of UV energy fluences over an epi-off cornea with the highest fluence over the tomographically largest bulging of the posterior cornea. This tomography-guided pattern generates more cross-links over the tip of the keratoconus and thus a greater flattening.

 To achieve the effect, surgeons have to use a UV-A delivery device with an integrated eye tracker that can deliver the different UV fluences to different parts of the cornea, rather than using a regular cross-linking device that delivers a uniform fluence across the cornea.

 Even so, the flattening effects were only moderately predictable: approximately 2 D to 4 D in total,

 even when using adjuncts like supplemental oxygen to improve the cross-linking effect.

ELZA-PACE customised CXL: The next generation

The ELZA Institute has developed a second-generation customised cross-linking method, called 

ELZA phototherapeutic keratectomy (PTK)-assisted customised epi-on cross-linking (PACE)

. ELZA-PACE is a mixture of ELZA’s new epi-on CXL (which needs neither iontophoresis nor additional oxygen) and an epi-off area over the centre of the keratoconus. The epi-off area is created using an excimer laser PTK. 

The PTK is tailored to the center of the keratoconus cone, respecting the individual epithelial thickness profile of that area, thus entirely preserving the stromal tissue – and this brings with it a corresponding impact on oxygen and UV energy penetration into the stroma.

Following the epithelial map-driven PTK, a penetration-enhancer is applied, followed by the riboflavin we developed, which establishes a riboflavin concentration gradient that peaks at the cone. In addition, a greater amount of UV irradiation is applied over the cone area and less over the peripheral regions of the cornea during cross-linking (

Taken together, this generates three gradients: UV fluence, riboflavin and oxygen, as opposed to the one gradient (UV fluence) generated by the earlier, first-generation approach.

Initial findings show a flattening effect significantly stronger than that achieved by earlier generations of customised CXL. Most interestingly, we not only observed maximum keratometry (Kmax) reductions of 4 D to 5 D within the first post-procedure month, but we also saw a steepening of the opposing superior area of several diopters, due to a coupling effect. Taking these two effects together, we often see a marked improvement in the symmetry of the astigmatism.

These changes lead to improvements in the wavefront errors and thus an increase in corrected distance visual acuity with glasses. Over six months to a year, PACE often achieves 8 D to 12 D of total asymmetry reduction and, in some cases, a gain of corrected distance visual acuity with glasses of up to 6 lines. This regularisation of the corneal surface is achieved by remodeling only, all without removing stromal tissue.

Can PACE be performed with a manual abrasion?

We tried and we failed to see a similar effect when performing PACE with a manual abrasion. The reason is that the abrasion has to be tailored around the tip of the keratoconus using a specific topographic map. Doing this manually would mean transferring a specific abrasion offset in the range of 20 µm onto the cornea, and performing an abrasion that includes the area of interest within a few micrometerss.

Patients with corneal ectasias with Kmax values in the range of 50 D to 60 D are excellent candidates for ELZA-PACE. The marked flattening over the cone shifts the patient’s refraction towards hypermetropia. The patients should therefore be at least mildly myopic to begin with. Also, the classic bow-tie keratoconus pattern responds better to ELZA-PACE than other topographical forms.

ELZA-PACE can be used not only in progressive keratoconus but also in stable keratoconus: a typical example would be a 35-year-old patient with stable keratoconus who had been using contact lenses for almost 20 years and who started developing contact lens intolerance.

We avoid performing ELZA-PACE in K readings below 50 D, because we might theoretically encounter slow and long-term flattening. So having a starting point that is beyond 50 D will prevent the cornea from flattening intonon-physiological values.

ELZA-PACE can be combined with other treatments such as the use of intracorneal ring segments (such as the all-Femto-CAIRS [corneal allogenic intrastromal ring segments] procedure by Soosan Jacob, DNB, MS, FRCS, and Shady Awwad, MD, that uses allogenic corneal tissue) and corneal wavefront-guided photorefractive keratectomy.

Our method is based on our new epi-on CXL protocol. During epi-on CXL, we pre-treat the cornea with special drops that enhance the penetration of riboflavin. These penetration enhancers are the result of several years of research and are currently awaiting the CE mark. Once the CE mark is given, ELZA-PACE can be performed by any colleague equipped with an MS-39 device for the epithelial maps and generation of the ablation file (CSO Italy), a SCHWIND AMARIS excimer laser for the custom PTK driven by epithelial maps (SCHWIND-eye-tech-solutions GmbH) and the C-eye cross-linking technology for customised CXL (EMAGine Switzerland).

ELZA-PACE represents a significant advancement in keratoconus treatment without the need for corneal tissue removal. By leveraging the combined gradients of riboflavin, oxygen, and UV irradiation, ELZA-PACE achieves outcomes that surpass those of first-generation customised cross-linking. As ophthalmologists, we must consider ELZA-PACE as a first-line visual rehabilitation option for patients with keratoconus, ensuring they receive the most effective and advanced care available.

1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. 

Am J Ophthalmol. 2003;135(5):620-627. doi:10.1016/s0002-9394(02)02220-1

2. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F. The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol. 2013;2(7):6. doi:10.1167/tvst.2.7.6

3. Hammer A, Richoz O, Arba Mosquera S, Tabibian D, Hoogewoud F, Hafezi F. Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances.

4. Kling S, Richoz O, Hammer A, et al. Increased Biomechanical Efficacy of Corneal Cross-linking in Thin Corneas Due to Higher Oxygen Availability. 

5. Torres-Netto EA, Kling S, Hafezi N, Vinciguerra P, Randleman JB, Hafezi F. Oxygen diffusion may limit the biomechanical effectiveness of iontophoresis-assisted transepithelial corneal cross-linking.

2018;34(11):768-774. doi:10.3928/1081597X-20180830-01.

6. Freeman RD. Oxygen consumption by the component layers of the cornea. 

J Physiol. 1972;225(1):15-32. doi:10.1113/jphysiol.1972.sp009927

7. Harvitt DM, Bonanno JA. Oxygen consumption of the rabbit cornea. 

Invest Ophthalmol Vis Sci. 1998;39(2):444-448

8. Seiler TG, Komninou MA, Nambiar MH, Schuerch K, Frueh BE, Buchler P. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. 

. 2021;223:368-376. doi:10.1016/j.ajo.2020.11.001

9. Abrishamchi R, Abdshahzadeh H,
Hillen M, et al. High-fluence accelerated epithelium-off corneal cross-linking protocol provides Dresden protocol-like corneal strengthening. Transl Vis Sci Technol. 2021;10(5):10. doi:10.1167/tvst.10.5.10

10. Kanellopoulos AJ, Dupps WJ, Seven I, Asimellis G. Toric topographically customized transepithelial, pulsed, very high-fluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus. 

Case Rep Ophthalmol. 2014;5(2):172-180.doi:10.1159/000363371

11. Wu D, Lim DK, Lim BXH, et al. Corneal cross-linking: the evolution of treatment for corneal diseases. Front Pharmacol. 2021;12:686630. doi:10.3389/fphar.2021.686630

12. Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized corneal cross-linking: one-year results. Am J Ophthalmol. 2016;166:14-21. doi:10.1016/j.ajo.2016.02.029.

13. Nordstrom M, Schiller M, Fredriksson A, Behndig A. Refractive improvements and safety with topography-guided corneal crosslinking for keratoconus: 1-year results. 

Br J Ophthalmol. 2017;101(7):920-925. doi:10.1136/bjophthalmol-2016-309210

14. Cassagne M, Pierne K, Galiacy SD, Asfaux-Marfaing MP, Fournie P,
Malecaze F. Customized topography-guided corneal collagen cross-linking for keratoconus. J Refract Surg. 2017;33(5):290-297. doi:10.3928/1081597X-20170201-02

15. Mazzotta C, Sgheri A, Bagaglia SA, Rechichi M, Di Maggio A. Customized corneal crosslinking for treatment of progressive keratoconus: Clinical and OCT outcomes using a transepithelial approach with supplemental oxygen. 

2020;46(12):1582-1587. doi:10.1097/j.jcrs.0000000000000347.

Hafezi is a refractive and cataract surgeon based at the ELZA Institute in Zurich, Switzerland. Prof Hafezi is a council member of the European Society of Cataract & Refractive Surgeons and holds academic positions at the University of Geneva, the Keck School of Medicine of USC, the NYU Grossman School of Medicine, and Wenzhou Medical University. Financial disclosures: EMAGine AG (shareholder); PCT patent/application holder (corneal apparatus for CXL)

Stabilising keratoconus and improving vision using ELZA-PACE customised CXL

Dr Ben LaHood

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