HARBOR results lead to ranibizumab label change

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Findings from the HARBOR study on ranibizumab for wet macular degeneration prompted new labeling for a potentially less frequent than monthly dosing, depending on individual responses to treatments.

By Michelle Dalton, ELS; Reviewed by Brandon G. Busbee, MD

Nashville, TN-Results from the HARBOR study an anti-vascular endothelial growth factor (VEGF) drug approved for various retina disorders, has led to the drug’s third label update in 18 months.

“In the HARBOR study, it’s astounding that 93% of the patients in the [ranibizumab (Lucentis, Genentech)] 0.5 mg arm did not need monthly injections over the 2-year study,” said Brandon G. Busbee, MD, in private practice, Nashville, TN. “HARBOR-along with the other AMD studies-really confirmed that in order to get clinically meaningful vision results, patients do not need to have monthly injections.”

After the initial three loading doses, Dr. Busbee said HARBOR also confirmed what many clinicians believe-“there’s definitely an individualized response to ranibizumab.” In HARBOR, the average injection frequency over 2 years for patients in the PRN arm was 9.9 weeks, with a mean gain of 7.9 letters.

Although patients may not be dosed monthly, they’re still being seen monthly during a PRN regimen “because you’re waiting for fluid to come back and vision to decrease. You really can’t afford to have those patients out of your office for too long,” Dr. Busbee said.

The new label for ranibizumab now notes the drug is recommended for intravitreal injection once a month for the treatment of neovascular age-related macular degeneration (AMD), but “although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment.” The approved label notes that in the subsequent 9 months after initial dose-loading, “frequent dosing with 4 to 5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1 to 2 letter gain.”

The label continues to note that “patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average.” In the latter two dosing regimens, patients should be assessed regularly.

What the HARBOR results found

Patients in HARBOR were randomly assigned into one of four groups: ranibizumab 0.5 mg monthly (n = 275), ranibizumab 0.5 mg PRN after three loading doses (n = 275), ranibizumab 2 mg monthly (n = 274), and ranibizumab 2 mg PRN after three loading doses (n = 273).

Starting at month 3, PRN groups were evaluated for re-treatment monthly and treated if there was a >5 letter decrease from previous visit or any evidence of disease activity on spectral-domain optical coherence tomography.

Key efficacy endpoints included mean change from baseline in best-corrected visual acuity (BCVA) at month 12, and a superiority comparison between the two ranibizumab doses. Secondary endpoints included mean change in BCVA at month 24, mean number of injections, mean change in foveal thickness over time, and proportion of patients who gained 15 letters or more.

In all four groups, vision was maintained at year 2; the two monthly dosing arms had more letter gains than the two PRN arms, but those intra-arm differences were not statistically or clinically relevant.

In year 2, the ranibizumab 0.5mg PRN group received a mean of 5.6 injections, compared with 4.3 mean injections in the ranibizumab 2 mg PRN group (the monthly groups received a mean of about 10 injections).

“What’s even more impressive is that the 93% who did not require monthly dosing still gained 7.9 letters,” Dr. Busbee said.

There were no safety issues in year 2, he added, an “no evident dose response or dose exposure relationship with respect to any key ocular or non-ocular adverse event.”

Real-world implications

What the HARBOR results confirm is that clinicians should be comfortable with optimizing treatment strategies on an individual basis, Dr. Busbee said.

“We have a drug that has phenomenal results, whether dosed monthly, PRN, or longer,” he said. “These treatment strategies really are the key to decrease the burden, not only for the patient, but for the families as well. That’s where studies like HARBOR really help. We now have hard data to show that patients only need 13 injections over 24 months, and some patients can have a successful visual outcome with even fewer treatments.”

Because of HARBOR, if patients have consistently good visits, Dr. Busbee may delay seeing them for upward of 8 weeks.

The end game is always the patient’s vision, Dr. Busbee said.

“Visual acuity is the ultimate determinant of success or failure,” he said. “We’re always looking for any change on OCT or vision with every exam.”

If one or the other seems to be decreasing from the previous visit, Dr. Busbee recommends moving the patient back to a more intensive treatment schedule until the eye has stabilized again.

Brandon G. Busbee, MD

P: 615/983-6000

Dr. Busbee is a consultant to Genentech, Regeneron, Synergetics, and ThromboGenics.