New anti-VEGF agent completes phase 2 trial

Results suggest that a 3-month induction-loading dose regimen may be important with anti-VEGF therapy, investigator says.

Issue: January 10, 2009

Early results of a new anti-VEGF agent using an induction-loading dose protocol indicate encouraging improvements in visual acuity, as well as possible improvements of biological measurements of neovascular disease in patients with wet age-related macular degeneration.

The phase 2 trial met its primary and secondary endpoints in reducing central retinal or lesion thickness, as well as showing improvements in best corrected visual acuity under conditions that investigator David M. Brown, MD, FACS, a retinal surgeon at Methodist Hospital, Houston, called real world as-needed dosing.

For the study, patients received either 0.5 mg or 2 mg of VEGF Trap-Eye (Regeneron and Bayer HealthCare) at baseline and again every 4 weeks for the first 12 weeks followed by dosing on an as-needed basis, starting at week 16. Other patients in the study received 0.5 mg, 2 mg or 4 mg at baseline and again at week 12, followed by as-needed dosing at week 16.

“For re-injection, investigators were asked to look for evidence of new hemorrhage on clinical exam or any fluid on OCT or [fundus fluorescein angiography] in or under the retina,” Dr. Brown said. “Most of us truly believe that persistence of fluid, or any fluid recurrence, is bad for the retina and will ultimately lead to worse visual outcomes. Regeneron designed this very liberal re-treatment criteria to try and simulate the way we treat patients in the clinic.”

David M. Brown

In the primary outcome analysis, mean reduction in central retinal thickness was statistically significant in all groups. From baseline, central retinal thickness was reduced a mean 143 µm in patients receiving 2 mg with an initial 3-month induction-loading dosing and a mean 125 µm in patients receiving 0.5 mg with this regimen.

Patients in the 2-mg induction-load cohort had a mean improvement in visual acuity of nine letters at the end of 1 year (P < .0001), and patients in the 0.5-mg induction-load cohort had an improvement of 5.4 letters compared with baseline (P < .085). Improvements in visual acuity were also achieved in patients receiving the quarterly dosing followed by as-needed dosing, but results were not as significant, and this group never caught up to final visual outcomes of those who received the initial monthly dosing induction regimen, Dr. Brown said.

“What I glean from this data is that if it takes three monthly injections to get the best outcomes with VEGF Trap-Eye, which has an extremely high affinity for VEGF, then it is very likely that this induction-loading phase is probably at least as important for treatment with ranibizumab, which has an affinity 300 times less than VEGF Trap-Eye, and bevacizumab, which has an affinity 1,600 times less than VEGF Trap-Eye,” he said.

“As it regards to the overall potential of VEGF Trap-Eye, to have a visual acuity curve analogous to our monthly dosing ANCHOR/MARINA data showing efficacy, with a true [as-needed] strategy, is very encouraging,” Dr. Brown said. “Most of us think that [as-needed] dosing and treat-and-extend dosing strategies are compromises that probably decrease outcomes compared to sustained monthly dosing, so I’m really excited to see the results of this agent in the true monthly dosing cohort in the enrolling phase 3 trial.”

Encouraging results

Patients receiving a 2-mg dose with the initial three-monthly induction-loading injections received a mean 1.55 injections during the as-needed dosing phase of the trial, which was lower than in patients receiving 0.5 mg with this induction load (2.52 injections) or any of the groups receiving a dose at baseline and at week 12 (mean 1.84 injections for the 0.5 group; mean 2.48 injections for the 2-mg group; and mean 1.7 injections for the 4-mg group).

The time to re-injection during the as-needed dosing phase may be an indicator that the increased affinity of VEGF-trap for VEGF may be leading to an improved sustainability of action over current anti-VEGF agents, Dr. Brown said. Time to re-injection was a median 110 days, and the median number of days to re-injection in the group receiving 4 mg at baseline with monthly dosing was 150 days.

However, the trial was not designed for head-to-head comparison, and the trial did not look at sustainability of gains in visual acuity or decreases in central retinal thickness, he said.

“You can’t directly compare the results to any study that has ever been done, but if you compare them to what a lot of us see in the clinic with ranibizumab and bevacizumab, it seems like this agent may really be a longer-acting therapy. I’m biased by the fact that I want find something that is better for my patients (and my waiting room), but it is definitely encouraging. Many phase 2 trials look great. We really won’t know for sure until we see the head-to-head data from the phase 3 trial,” Dr. Brown said.

Phase 3 trials

Regeneron and Bayer are currently enrolling a phase 3 trial in the United States. The U.S. trial, called VIEW-1 (VEGF-Trap: Investigation of efficacy and safety in wet age-related macular degeneration), will evaluate safety and efficacy and compare Trap-Eye with Lucentis (ranibizumab, Genentech), according to the Regeneron Web site.

Results from the trial are expected in about 1.5 years.

A second phase 3 trial, VIEW-2, will enroll about 1,200 patients in up to 200 centers in Europe, Asia-Pacific, Japan and Latin America, according to a release on the Regeneron Web site. – by Bryan Bechtel

David M. Brown, MD, FACS, is a retinal surgeon at Methodist Hospital in Houston. He can be reached at Vitreoretinal Consultants at 713-524-3434; e-mail: dmbmd@houstonretina.com.
Dr. Brown is a consultant for Regeneron and serves on the U.S. and international steering committees for the VIEW-1 and VIEW-2 trials. He is also a consultant for Genentech, Allergan, Alcon, Novartis, NeoVista and other companies with competing therapies, and is a consultant for Heidelberg Engineering and Carl Zeiss Meditec for imaging technologies used in the treatments of macular disease.