In June, Novartis reported that initial 48-week data for its large-scale, phase 3 HAWK and HARRIER clinical trials of its anti-VEGF brolucizumab (RTH258) for wet AMD demonstrated a durable 12-week retreatment interval for a majority of patients in the 2 studies. The company released additional HAWK and HARRIER results at the recent AAO meeting in New Orleans, showing impressive efficacy in both eliminating retinal fluid and reducing central subfield thickness in a head-to-head comparison with aflibercept (Eylea; Regeneron).
Given this highly positive data, Novartis now plans to file for FDA approval of the wet AMD indication in late 2018 and begin clinical trials for DME and RVO in 2018 as well. It’s also possible that brolucizumab will be tried in combination therapy in the future and also in a sustained-release format.
Novartis describes brolucizumab as a humanized single-chain antibody fragment and the most clinically advanced, humanized single-chain antibody fragment to reach this stage of development. The company says single-chain antibody fragments offer the advantages of small size, enhanced tissue penetration, rapid clearance from systemic circulation, and versatility in drug delivery.
At week 48, relative to aflibercept, 31% fewer patients on brolucizumab 6 mg had intraretinal fluid and/or subretinal fluid in HAWK, and 41% fewer in HARRIER. Novartis said the absence of fluid for patients in the brolucizumab arm suggests the potential for a long-lasting effect and decreased treatment need.
Additionally, brolucizumab 6 mg patients demonstrated superior reductions in central subfield thickness. Significantly improved CST reductions were evident in both HAWK and HARRIER at week 16 and at week 48.
Brolucizumab also met the primary efficacy endpoint of noninferiority to aflibercept in mean change in BCVA from baseline to week 48 in both trials. These results were achieved while a majority of brolucizumab patients — 57% in HAWK and 52% in HARRIER — were maintained on a 12-week dosing interval immediately following the loading phase through week 48. Brolucizumab is now the first anti-VEGF treatment for wet AMD to demonstrate robust visual gains with a majority of patients maintained on a less-frequent 12-week treatment interval immediately following the loading phase in randomized clinical trials.
"HAWK and HARRIER demonstrated that brolucizumab has the potential to positively impact disease management and provide long-lasting treatment effect," said Pravin U. Dugel, MD, a vitreoretinal specialist with Retinal Consultants of Arizona in Phoenix and principal investigator of both trials. "HAWK and HARRIER showed that brolucizumab outperformed aflibercept on disease activity assessments, including key measures of disease progression seen on OCT, which forms the basis of a clinician's treatment decisions,” Dr. Dugel told Retinal Physician.
“Importantly, improvements in these key OCT measures were seen as early as week 16 and maintained at week 48, with a majority of brolucizumab patients on a 12-week treatment interval,” he added. “This is the first prospective, randomized study to show that patients can be extended to 12 weeks; it’s a far higher level of data and scientific scrutiny than we’ve had with post hoc analyses and case studies. Importantly, the consistency of the data in the HAWK and HARRIER phase 3 studies as well as the OSPREY phase 2 study gives us confidence in the potential benefit of this drug.”
“Consistent data in a variable disease deserves emphasis,” he noted. “The preponderance of data points in the same direction, and that direction is the potential for better disease control,” he added. “If you have a drug that gives superior structural anatomic outcome, it suggests better disease control. It also could offer a more sustainable treatment strategy. The hope is that we can manage patients better and more sustainably.”
"Having delivered on our noninferiority endpoint with a majority of patients on a q12-week interval, we're truly excited to share these data showing that brolucizumab clearly improves key anatomical outcomes that are biomarkers of disease," said Vas Narasimhan, global head of drug development and chief medical officer for Novartis.