Pam Harrison

August 27, 2013

TORONTO, Ontario — As-needed ranibizumab is an appropriate strategy for most treatment-naive patients with subfoveal neovascular age-related macular degeneration, suggest new 2-year data from the HARBOR trial.

The long-term study shows that 93% of patients treated with as-needed ranibizumab 0.5 mg did not require monthly dosing at 24 months. Over the 24-month study period, these patients received an average of 13.3 injections (range, 3 to 24).

During the first 12 months of the study, patients required a mean of 7.7 injections; this dropped to a mean of 5.6 injections during the second 12 months. After the initial monthly loading doses of ranibizumab, the average treatment interval between as-needed doses was 9.9 weeks.

"All groups in the HARBOR trial had clinically meaningful visual gains over the first year of the study, ranging from a gain of 10.1 letters in the 0.5 mg monthly group to 8.2 letters in the 0.5 mg PRN group," reported lead study author Brandon Busbee, MD, from Tennessee Retina in Nashville.

These data suggest that there is an individualized response to treatment and a need to individualize it in this patient cohort," Dr. Busbee explained.

He presented the HARBOR results here at the 31st Annual Meeting of the American Society of Retina Specialists.

 
All groups in the HARBOR trial had clinically meaningful visual gains over the first year of the study.
 

HARBOR was a prospective multicenter study that enrolled 4 equal groups. For 12 months, 2 groups received monthly ranibizumab at doses of either 0.5 mg or 2.0 mg, and 2 groups received the same doses, but each on an as-needed basis after 3 monthly loading doses of ranibizumab.

The primary end point of the study was mean change from baseline in best-corrected visual acuity at 12 months. The secondary end point was mean change in best-corrected visual acuity at 24 months.

At 12 months, the mean change in visual acuity was similar in the 4 treatment groups, although it was slightly lower in the 0.5 mg as-needed group. At 24 months, most patients had lost approximately 1 letter from month 12, but patients in the 0.5 mg as-needed group lost only 0.3 letters.

Table. Mean Gains in Visual Acuity With Ranibizumab

Group 12 Months 24 Months
0.5 mg monthly 10.1 9.1
0.5 mg as needed 8.2 7.9
2.0 mg monthly 9.2 8.0
2.0 mg as needed 8.6 7.6

 

During the first 12 months of the study, approximately one third of patients gained 15 letters or more in all 4 groups. This proportion increased in each group by month 24.

After 24 months, the ocular and systemic safety profile of ranibizumab was similar in all treatment groups, and serious ocular adverse events were rare. There was no evidence that dose response or dose exposure was related to key ocular or nonocular adverse events.

In other HARBOR data presented at the meeting, patient perception of vision-related function paralleled results for visual acuity in all dosing groups, reported Neil Bressler, MD, from the Wilmer Eye Institute and Johns Hopkins University School of Medicine in Baltimore.

"This was equally true for monthly and PRN dosing over the 24-month study interval," Dr. Bressler said. Patients in the as-needed dosing groups required approximately half as many injections as those in the monthly dosing groups.

Other HARBOR Analyses

Karl Csaky, MD, from Texas Retina Associates in Dallas, presented a subanalysis of the HARBOR data in which investigators examined the presence of antitherapeutic antibodies and treatment response 12 and 24 months after the introduction of ranibizumab.

"We all know that biologics generate antitherapeutic antibodies and that there is a perceived decrease in vascular endothelial growth factor [VEGF] response over time," but the cause of this is unclear, Dr. Csaky explained.

In all 4 HARBOR treatment groups, the incidence of antitherapeutic antibodies was between 6% and 12%, but there was no difference in the incidence of these antibodies at 12 and 24 months, he added.

Furthermore, the appearance of antitherapeutic antibodies did not have any effect on visual acuity at month 24; there was no perceptible difference in mean visual acuity values between antibody-negative and antibody-positive patients.

There was also no detectable effect of antiranibizumab antibodies on the percent of patients who gained 3 or more lines of letters at 24 months. Dr. Csaky concluded that although antiranibizumab antibodies can be detected in patients on treatment, they do not appear to affect clinical outcomes.

John Kitchens, MD, from Retina Associates of Kentucky in Lexington, presented data showing that both monthly and as-needed ranibizumab led to a consistent reduction in total lesion and choroidal neovascular membrane area in most eyes during the 24-month study period.

The classic choroidal neovascularization component was the most sensitive to ranibizumab treatment. Complete regression in the neovascularization area was observed in almost all patients in all groups.

Regimented Dosing

"I think the HARBOR study tells us several things," said Pravin Dugel, MD, from Retinal Consultants of Arizona in Phoenix, who was asked by Medscape Medical News to comment on this study. It shows the medical community that a regimented dose schedule is "probably not a good thing" when it comes to treating wet age-related macular degeneration with ranibizumab.

"It also shows that there is a huge variability in dosing," said Dr. Dugel, who is also clinical associate professor of ophthalmology at the Doheny Eye Institute, Keck School of Medicine of the University of Southern California at Los Angeles. "If we individualize treatment, we'll probably get as good results and decrease treatment burden," he pointed out. At the same time, there are clearly different populations of patients with wet macular degeneration. Some require very little treatment to improve visual acuity and others require much more. "Unfortunately, we don't yet know who they are," Dr. Dugel said.

Until groups are better differentiated, patients will require careful follow-up and monitoring to ensure that VEGF activity is adequately kept in check with as-needed dosing.

The HARBOR study was sponsored by Genentech. Dr. Busbee, Dr. Bressler, Dr. Csaky, and Dr. Kitchens report financial interests with a number of pharmaceutical companies, including Genentech.

31st Annual Meeting of the American Society of Retina Specialists. Presented August 25, 2013.

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