It's About Time: Brolucizumab Extends Treatment Effect in Wet AMD

Why do we need another drug for wet age-related macular degeneration (AMD)? There are two good reasons: efficacy and duration. Despite even monthly treatment, a large proportion of patients with wet AMD still have fluid on optical coherence tomography (OCT). The search has therefore continued for a more efficacious drug that also lasts longer in the eye.

Brolucizumab (Beovu), recently approved by the US Food and Drug Administration, may be the drug that meets these clinical needs. A single-chain antibody fragment that inhibits vascular endothelial growth factor (VEGF)-A, brolucizumab's molecular design has the opportunity to penetrate tissue better (being smaller in size) and have a higher molar concentration.

After the OPSREY phase 2 trial showed brolucizumab's safety and efficacy, the HAWK and HARRIER phase 3 trials were undertaken to assess whether it was noninferior to aflibercept. Patients with untreated AMD participating in the trials were randomly assigned to loading doses of brolucizumab (3 or 6 mg) or aflibercept (2 mg) at weeks 0, 4, and 8.

The trial design differed with what we are used to seeing with other AMD trials, in that it represented a real-world clinical situation. Patients in the aflibercept arms received injections every 8 weeks, whereas those in the brolucizumab arms were scheduled to receive injections every 8 or 12 weeks. Patients in the brolucizumab arms, however, were given a "disease activity assessment" at week 16, based on a combination of visual acuity and OCT endpoints specified in the protocol. Those scheduled to receive brolucizumab injections every 12 weeks could be switched to the more frequent every-8-week arm if they met established clinical parameters of disease activity.

At week 16, after identical treatment exposure, fewer eyes treated with 6 mg brolucizumab had disease activity versus those treated with aflibercept. Brolucizumab was noninferior to aflibercept for the trial's primary endpoint of visual outcomes at week 48. However, anatomic outcomes (change in OCT thickness) favored brolucizumab over aflibercept. Over 50% of eyes treated with 6 mg of brolucizumab were maintained on an every-12-week dosing interval through week 48.

These study results are a promising sign that we will be able to decrease the treatment burden for patients with wet AMD.

As we integrate brolucizumab into our clinical practice, it will be interesting to see how we use it. Will it be used initially to try to obtain better outcomes in those patients not controlled with the other anti-VEGF agents? Will it be used to try to extend treatment intervals in those already controlled but who cannot get past a certain time interval? Or will it be used in treatment-naive patients, with a protocol similar to that of the clinical trial? I suspect that a combination of these treatment paradigms will prevail, but time will tell.

Sophie J. Bakri, MD, is a professor in the department of ophthalmology at the Mayo Clinic in Rochester, Minnesota. Her special interests are in diseases and surgery of the retina and vitreous, particularly age-related macular degeneration, diabetic retinopathy, venous occlusive disease, and repair of complex retinal detachments. She also undertakes clinical and translational research in the pathogenesis and treatment of retinal diseases.

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