For this issue of Retina Minute, I am speaking with my dear friend, professor Tien Wong, about the PULSAR extension trial.

Dr. Wong, recently at Angiogenesis and Macula Society, you presented details on the PULSAR extension trial. Who was involved in the study, and what did the researchers find?

PULSAR was a pivotal study that evaluated 8 mg aflibercept (Eylea HD; Regeneron) vs. the conventional 2 mg dose of aflibercept in patients with treatment-naive neovascular age-related macular degeneration (AMD). The initial PULSAR study lasted 2 years, and patients were voluntarily given the option to continue into the third year of the extension study. The extension was open-label, so they were not masked, and the patients who were originally on a 2 mg dose were switched to an 8 mg dose. In other words, the control group in the original PULSAR study was switched to an 8 mg dose, and those who were on the 8 mg dose in the first 2 years continued on that dose in the extension trial. We compared outcomes with 8 mg for 2 years with the standard 2 mg dose and found that visual acuity and structural outcomes were shown to be equivalent for patients in both groups.

Patients in the 8 mg group in the PULSAR study could also be extended. In fact, 80% of patients extended to 12 weeks or longer in the initial 2-year study. In the PULSAR extension trial, we evaluated whether patients who were in the 8 mg group could continue to be extended without vision loss and whether they could maintain retinal structure up to 3 years. In other words, we looked at whether the same efficacy in the initial PULSAR study was maintained throughout the additional third year in the extension trial.

The second aim was to see whether patients who were on the 2 mg dose could be switched to 8 mg after 2 years of treatment, whether they did well, and whether they could be extended. The PULSAR extension study showed that those who switched could maintain their vision and extend beyond the 2 mg, two monthly treatments in the original PULSAR study.

Another important outcome was to see whether there were new or persisting safety signals in the 8 mg group or in patients who were switched from 2 mg. Specifically, there was concern that the higher volume would lead to glaucoma or changes in intraocular pressure, but we did not see safety signals in that aspect or other systemic safety signals over 3 years. We also did not see any vasculitis or other retinal occlusive events. 

The PULSAR extension study showed the benefits of 8 mg high-dose aflibercept for the treatment of neovascular AMD up to 3 years, with 80% extension.

I think the extension study is applicable to our patients in normal clinical practice who are currently on a 2 mg dose and who may benefit from the higher 8 mg dose.

Was there a change in patients’ central subfield thickness when they switched from 2 mg to 8 mg?

Yes, there was a drop in central subfield thickness and a reduction in fluid that was seen at the first 8 mg dose. This decrease was maintained up to 8 weeks before they were given the injection at 12 weeks, which suggests that you will see some reduction in fluid and maintenance of visual acuity, even with a longer duration, in patients who switch from 2 mg to 8 mg of aflibercept.

What did you find in the subset of patients who were in the 20- or 24-week groups in the initial PULSAR study?

The maximum dosing interval that could be extended in this trial was 24 weeks, so we do not know what happens after that yet, but I think this study has shown the possibility of having not only most patients (80%) beyond 12 weeks, but also having approximately half of patients—40% to 50%—beyond 20 weeks. That is an extension of almost 5 months, which I think is excellent.

As high-dose aflibercept becomes more utilized in Asia, how do you plan on using it in your treatment of nAMD patients?

I think many patients will be offered the 8 mg option from the beginning, if they are treatment-naive. Patients on 2 mg aflibercept or other drugs can also be given the option of changing to 8 mg aflibercept because of the data from PULSAR that shows they can still achieve some fluid reduction. I think physicians could also consider switching patients who are on 2 mg and could not be extended previously or who still have residual subretinal fluid to the 8 mg dose.   

Dr. Wong, thank you so much for making time. This is fascinating data that adds to the ever-growing body of evidence that the second-generation medicines really have a play in terms of increasing duration while maintaining safety. They could give us more options for our wet macular degeneration and diabetic macular edema patients who are fatigued by more frequent injections.

Tien Wong, MD, PhD is a physician scientist at Tsinghua University in Beijing, China.

Michael A. Singer, MD is a board-certified vitreoretinal specialist and director of clinical research at Medical Center Ophthalmology Associates in San Antonio, TX. He is currently the clinical professor of ophthalmology at the University of Texas Health Science Center in San Antonio.