Anti-VEGF treatment regimen for AMD still unclear in real-life scenario

Predictive biomarkers of patients’ individual responses to treatment have not yet been identified.

Frank G. Holz

PARIS – Retina specialists are still unsure when it is best to re-inject patients with age-related macular degeneration after the 3-month induction-loading phase for intravitreal ranibizumab, according to a speaker here.

“There is no re-injection scheme that works for everybody, and predictive biomarkers of the patients’ response to the treatment are not easy to identify,” Frank G. Holz, MD, said at the Euretina meeting.

Large prospective trials have converged on two conclusions regarding intravitreal Lucentis (ranibizumab, Genentech/Novartis). First, all patients improve during the loading phase, with monthly injections in the first 3 months. Second, the best possible outcome is obtained with monthly injections in the maintenance phase as well. Other regimens have shown no better results, according to experts.

“Patients may lose when less frequent treatment is administered. However, does this mean that every patient has to be injected every 4 weeks?” Dr. Holz asked.

If this is true for the average patient, clinical practice shows that some cases improve with only a few injections. And in the SUSTAIN trial, 20% of patients did not require additional injections after the 3-month loading dose.

“Injecting these patients every 4 weeks may be considered a waste of resources and would expose them to unnecessary risks,” Dr. Holz said.

As-needed regimen issues

On the other hand, as-needed dosing presents several problems and could lead to undertreatment. The European Medicines Agency (EMA) recommends only re-injecting when five letters are lost, but the SUSTAIN study shows that a loss of five letters on average cannot be recovered by re-injection. In consideration of this, health authorities in Germany have issued revised criteria, freeing ophthalmologists there from adhering to the EMA recommendations, Dr. Holz said.

In an as-needed regimen, optical coherence tomography is theoretically the best instrument to evaluate central retinal thickness, Dr. Holz said.

“It is difficult to align consecutive measurements, and misalignment between two consecutive measurements might lead to false positives,” he said. “Reproducibility is poor with time-domain OCT technology up to more than 100 µm, and this is what has been used as a re-treatment criterion in the past. Spectral-domain OCT is much more precise.”

Other parameters can be evaluated by OCT. Accumulation of fluid in and around the fovea is an indication for re-treatment, in order to avoid the “accordion effect” of the fovea getting thicker and thinner, leading to irreversible damage. In the future, imaging technologies might also be able to help predict recurrence before any leakage occurs, but “there is enormous mileage before we develop such a molecular imaging that will detect in vivo these changes in the eye and make us treat before the irreversible damage occurs,” Dr. Holz said.

Predictive biomarkers of response to anti-VEGFs have not been clearly identified. Many factors have been considered, such as age, visual acuity, lesion type and size.

“They do have some small impact, but none of them is really helpful in terms of having a predictive marker that would tell us how many injections the patient needs and whether the patient who is sitting in front of us in our practice is one of the lucky 20% who will not need more injections,” Dr. Holz said.

Additional issues

Other questions remain: What are the stimuli for VEGF expression? What are the specific environmental factors that may impact the response to the treatment? What is the individual disease progression? What is the distribution and elimination half-life of the drug in the vitreous? And what are the modifying genetic factors?

“Without an answer to all these questions, a nomogram to assist in individual decision making regarding treatment cannot be formulated,” Dr. Holz said.

In addition, in real-life scenarios, patient adherence issues must be considered. Expecting AMD patients to be compliant with regular monthly monitoring visits is unrealistic, according to Dr. Holz.

“To show just a small piece of the mosaic, in Germany we monitored the outcomes of over 3,000 patients from a number of different sites,” he said. “It’s not a prospective study scenario, but in the real world, it turned out that the uploading phase worked very well and almost all patients had the three injections. But in the maintenance phase, due to a variety of factors, the average number of injections per year was 1.39, which is not sufficient to keep up with the vision improvement achieved during the loading phase.”

Patients in the group studied lost vision over time due to these adherence issues.

The discrepancies in guidelines among scientific societies around the world is a sign that there are still open questions on the best treatment regimen with anti-VEGF agents for AMD, Dr. Holz said. – by Michela Cimberle

• Frank G. Holz, MD, can be reached at University of Bonn, Ernst-Abbe-Strasse 2, D-53105 Bonn, Germany; +49-22828715647; fax: +49-22828715603; e-mail: Frank.Holz@ukb.uni-bonn.de.
• Disclosure: Dr. Holz is a consultant for Acucela, Bayer, Genentech, GlaxoSmithKline, Novartis and Pfizer.

The introduction of PRN regimens has enabled us to reduce the number of ranibizumab injections as compared to fixed regimens with monthly administrations. However, re-treatment criteria are still far from being perfect and, as a result, the outcomes of controlled trials with PRN regimens are not as good as those adopting monthly injections.

Paolo Lanzetta

The real-life scenario is usually even worse, because treating patients on a PRN basis has numerous pitfalls. Re-treatment criteria are still imprecise and need a strict organization and a close cooperation with patients, as well as repeated and timely examinations such as visual acuity measurement, OCT and fluorescein angiography.

While research should continue to look for different responder profiles and lesion subtypes, new treatment strategies should be tested based on our current knowledge of ranibizumab pharmacokinetics and previous trials. A fixed regimen with bimonthly administration after the three initial monthly doses could both reduce the number of injections and avoid the burden of unnecessary examinations.

— Paolo Lanzetta, MD
OSN Europe Edition Editorial Board Member
Disclosure: Dr. Lanzetta is a paid consultant of Novartis.