Novartis eyes nAMD

Results from Phase 3 studies support brolucizumab’s less-frequent dosing schedule

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EAST HANOVER, N.J.—In late 2017, Novartis announced positive results from two Phase 3 studies of brolucizumab (RTH258) vs. aflibercept. The results of the head-to-head trials, HAWK and HARRIER, were presented at the American Academy of Ophthalmology 2017 Annual Meeting. Results showed non-inferiority in the primary endpoint, superiority in key retinal health outcomes and long-lasting effect in patients with neovascular age-related macular degeneration (nAMD), a leading cause of blindness.
HAWK and HARRIER are 96-week randomized, double-masked, multi-center studies with more than 1,800 patients across 400 centers worldwide. The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg and 3 mg versus aflibercept 2 mg in patients with nAMD. The primary efficacy objective of HAWK and HARRIER trials was to confirm that brolucizumab is non-inferior to aflibercept in mean change in BCVA from baseline to week 48. Secondary endpoints include average mean change in BCVA from baseline over the period week 36 to 48, the proportion of patients on a 12-week interval at week 48 and anatomical parameters.
Frequent injections into the eye, a standard requirement for nAMD therapies, can be a significant hardship for patients. Brolucizumab is the first and only anti-vascular endothelial growth factor treatment for nAMD to demonstrate robust visual gains with a majority of patients maintained on a less-frequent 12-week (q12w) treatment interval, following the loading phase in clinical trials.
According to a Novartis spokesperson, “Both brolucizumab and aflibercept are vascular endothelial growth factor (VEGF) inhibitors. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases. Brolucizumab is the most clinically advanced humanized single-chain antibody fragment to reach this stage of development.”
In both trials, patients were randomized to either brolucizumab or aflibercept. Following the three-month loading phase, patients in the brolucizumab arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label.
Brolucizumab met the primary efficacy endpoint of non-inferiority to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 in both trials. These results were achieved while a majority of brolucizumab patients—57 percent in HAWK and 52 percent in HARRIER—were maintained on a q12w dosing interval immediately following the loading phase through week 48.
“While the primary endpoint of the trial was non-inferiority vs. aflibercept in mean change in best-corrected visual acuity (BCVA), superiority was shown in three secondary endpoints that are considered key markers of nAMD disease—CST, retinal fluid and disease activity,” notes the Novartis spokesperson. “In these three secondary endpoints, significantly fewer brolucizumab patients showed signs of disease activity as well as retinal fluid (intraretinal fluid and/or subretinal fluid). The most frequent ocular adverse events for brolucizumab (greater than 5 percent of patients in either study) were reduced visual acuity, conjunctival hemorrhage, vitreous floaters and eye pain.”
Brolucizumab 6 mg patients demonstrated superior reductions in central subfield thickness (CST). In nAMD, an elevated CST—as measured by optical coherence tomography (OCT)—is a key indicator of abnormal fluid accumulation in the retina. Significantly improved CST reductions were evident at week 16 and at week 48.
“HAWK and HARRIER demonstrated that brolucizumab has the potential to positively impact disease management and provide long-lasting treatment effect,” said Dr. Pravin U. Dugel, managing partner of Retinal Consultants of Arizona, clinical professor of theRoski Eye Institute at the Keck School of Medicine of the University of Southern California 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. 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.”
Week 16 was an important data point when the treatment assessment for brolucizumab and aflibercept were identical, providing an opportunity to observe how both drugs performed in a matched comparison. At week 16, relative to aflibercept, 35 percent fewer brolucizumab 6 mg patients showed presence of intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) in HAWK, and 33 percent fewer in HARRIER. At week 48, relative to aflibercept, 31 percent fewer patients on brolucizumab 6 mg had IRF and/or SRF in HAWK, and 41 percent fewer in HARRIER. The absence of fluid for patients in the brolucizumab arm suggests the potential for a long-lasting effect and decreased treatment need.
With brolucizumab, fewer patients had active disease at week 16. Active disease was observed in 23.5 percent of brolucizumab 6 mg patients versus 33.5 percent of aflibercept patients in HAWK, and in 21.9 percent of brolucizumab patients versus 31.4 percent of aflibercept patients in HARRIER.
“Having delivered on our non-inferiority 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 at Novartis. “Brolucizumab represents a major scientific and clinical advancement for patients, caregivers and retina specialists around the world.”
In other recent Novartis news, Biospace reports that Novartis has received a priority review voucher in a $130-million agreement with Ultragenyx Pharmaceutical Inc., the second it has gained in the past few months.
“Novartis has provided guidance that it anticipates filing for U.S. regulatory approval in Q4 2018 for an nAMD indication,” concludes the company spokesperson. “With regard to the ongoing Phase 3 studies, it is anticipated that the readout of the two-year data will occur in mid-2018. We [also] look forward to exploring the potential of brolucizumab in a number of indications, including DME and RVO.”

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