Article

CLINICAL TRIAL DOWNLOAD: Two-Year Brolucizumab Data

Results reinforce the drug’s potential.

EDITED BY PRAVIN U. DUGEL, MD

Related

At the 2018 American Academy of Ophthalmology annual meeting, additional phase 3 results from year 2 for the HAWK and HARRIER trials of brolucizumab (Novartis) were presented, which reinforced the drug’s positive year 1 findings. Brolucizumab met its primary endpoint of noninferiority vs aflibercept (Eylea; Regeneron) in BCVA and exhibited superiority in key retinal outcomes at year 1 while maintaining robust visual gains in year 2 in patients with wet AMD. Relative to aflibercept, fewer brolucizumab 6 mg patients with wet AMD had intraretinal fluid and/or subretinal fluid at year 2 (24% for brolucizumab 6 mg vs 37% for aflibercept in the HAWK study and 24% vs 39% in the HARRIER study). Of the patients receiving brolucizumab 6 mg who successfully completed year 1 on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year 2. Adverse events for brolucizumab continued to be comparable to aflibercept, with the overall incidence balanced across all treatment groups in both studies. Importantly, anatomic superiority was maintained. In this column, Retinal Physician seeks initial reactions to the data from several retina experts.

Judy E. Kim, MD, Professor of Ophthalmology, Vitreoretinal Diseases and Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

It is encouraging to see that the visual gain noninferiority and anatomic superiority of brolucizumab 6 mg compared to aflibercept was maintained to week 96 in the HAWK and HARRIER trials in neovascular AMD. While this is exciting, the flip side is that nearly a quarter of subjects in the brolucizumab group still had fluid. Although it is not known whether we need to dry the fluid completely in every patient, it is possible that some patients may require modulation of factors other than suppression of VEGF-A alone to dry the retina.

Another encouraging result was that of the subjects on brolucizumab 6 mg who successfully completed year 1 on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year 2. It is exciting to know that once we identify early on which patients can be maintained at quarterly dosing, we can expect that the majority can be maintained at this extended dosing. However, we should remember that only 57% of HAWK and 52% of HARRIER patients treated with brolucizumab 6 mg were maintained on a 12-week interval at week 48. While it is encouraging that brolucizumab may reduce treatment burden in over half of patients, the remaining patients still need a shorter treatment interval. Furthermore, there are other drugs that are showing efficacy at quarterly dosing, so it will be interesting to see which one clinicians will use in the future. It may be based on efficacy and safety data as well as the drug cost.

Brolucizumab Phase 3 Year 2 Data

  • Fewer patients with nAMD had intraretinal fluid and subretinal fluid: 24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (P=.0001); 24% vs 39%, respectively, in HARRIER P<.0001).
  • Reductions in central subfield thickness from baseline were -175 µm for brolucizumab 6 mg vs -149 µm for aflibercept in HAWK (P=.0057) and -198 µm vs -155 µm, respectively, in HARRIER (P<.0001).
  • Fewer brolucizumab 6 mg patients had subretinal pigment epithelium fluid: 11% for brolucizumab 6 mg vs 15% for aflibercept in HAWK; 17% vs 22%, respectively, in HARRIER.
  • Of the patients on brolucizumab 6 mg who successfully completed year 1 on a 12-week dosing interval (57% in HAWK and 52% in HARRIER), 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year 2.

Jonathan L. Prenner, MD, Clinical Professor and Chairman, Department of Ophthalmology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey

The 2-year data from HAWK and HARRIER are extremely impressive, particularly given the unmet need seen in busy clinical practices. While I generally tend to place my faith exclusively in prespecified, alpha protected, primary endpoints, the uniform directionality of the secondary endpoint data in these trials is encouraging. I was pleased to see that there continues to be a favorable safety profile with extended drug exposure and I look forward to having the drug in my hands in the near future.

Ramin Tadayoni, MD, PhD, Chairman, Professor of Ophthalmology, Université Paris 7 (Sorbonne Paris Cité), Lariboisière, Saint Louis & Cochin Hospitals, OphtalmoPôle Paris, Académie Nationale de Chirurgie, Paris, France

My gut reaction to these data are threefold. First, because we are looking at a study that evaluates a new drug and a new protocol in the same trial, we must ask how the investigators distinguish the effect of the drug and the protocol. Second, as a whole, brolucizumab performed better, with fewer injections and less fluid. But we don’t have the full picture yet. Third, legitimate moderation may have led to an underestimation of a preferred goal: some retinal physicians prefer longer treatment intervals and therefore patients have more subretinal fluid, and others prefer less subretinal fluid and therefore patients receive a higher number of injections. In my opinion, patients do best when physicians can discuss these variations in practice. RP