Novel drug therapies making progress to extend wet AMD treatment

Experimental treatments could slash the number of injections needed to successfully treat neovascular age-related macular degeneration (nAMD).
By adding new twists to the established anti-vascular endothelial growth factor (VEGF) approach, some pharmaceutical manufacturers have created formulations that can be administered as little as once every 16 weeks.

At the 2018 meeting of the American Academy of Ophthalmology (AAO), researchers presented phase III data on Novartis' brolucizumab and Allergan's abicipar pegol, and phase II data on Roche's faricimab.

Visual acuity gains for the three new drugs were comparable to the anti-VEGF drugs already on the market.

The three anti-VEGF drugs currently available for nAMD have made dramatic improvements in many patients' lives, allowing them to read, drive, and play with their grandchildren.

But of these drugs, bevacizumab (Avastin, Roche) and ranibizumab (Lucentis, Novartis) are labeled for monthly intravitreal injections and aflibercept (Eylea, Regeneron) is labeled for bimonthly intravitreal. Many patients find the injections uncomfortable and have difficulty getting to appointments that often.
At this meeting, researchers presented the full 2 years of data on brolucizumab, making it the closest of the three new drugs to the market.

Brolucizumab is a humanized, single-chain antibody fragment inhibitor of VEGF-A.  Researchers believe it works better than the anti-VEGF treatments currently on the market because it is a smaller molecule, allowing greater tissue penetration and administration of higher drug concentrations.

"Over two years, brolucizumab consistently dried retinal fluid better than aflibercept while keeping many patients on a quarterly dosing schedule," said Shreeram Aradhye, global head of medical affairs and chief medical officer at Novartis, in a prepared statement. "Additionally, the robust visual gains shown in year one with brolucizumab were maintained in year 2."

The HAWK and HARRIER trials showed fewer patients with intra-retinal fluid (IRF) and/or subretinal fluid (SRF) - key markers used by physicians to determine injection frequency in clinical practice - with brolucizumab 6 mg versus aflibercept at week 96: 24% for brolucizumab 6 mg versus 37% for aflibercept in HAWK (p = 0.0001); 24% versus 39%, respectively, in HARRIER (p < 0.0001).

Absolute reductions in CST from baseline were -175 µm for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (p = 0.0057) and -198 µm versus -155 µm, respectively, in HARRIER (p < 0.0001).

Also at week 96, fewer brolucizumab 6 mg patients had subretinal pigment epithelium (sub-RPE) fluid (11% for brolucizumab 6 mg versus 15% for aflibercept in HAWK; 17% versus 22%, respectively, in HARRIER).

Of the patients on brolucizumab 6 mg who successfully completed year one on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year 2.

Brolucizumab maintained robust visual gains in year 2, with mean change in best-corrected visual acuity of 5.9 letters for brolucizumab 6 mg versus 5.3 letters for aflibercept in HAWK, and 6.1 letters versus 6.6 letters, respectively, in HARRIER.

Safety data for brolucizumab was comparable to that of aflibercept.

Close behind brolucizumab in the drug development pipeline comes abicipar. Abicipar is based on the DARPin technology, created by Molecular Partners of Zurich, Switzerland, for creating small molecules that bind to multiple targets. Abicipar binds to both VEGF and platelet-derived growth factor (PDGF) receptors.

In two global phase III studies, SEQUOIA and CEDAR, a total of more than 1,800 patients with nAMD were treated with a fixed treatment regimen of either 2 mg abicipar every 12 weeks (2q12) or every 8 weeks (2q8) or the comparator, monthly ranibizumab.

BCVA gains were comparable for abicipar and ranibizumab, and these gains for abicipar fixed 2q12 and fixed 2q8 were maintained throughout week 52.
The anatomical data (OCT) on abicipar-treated patients showed reductions of central retinal thickness (CRT) in all arms in both studies in the same range as for ranibizumab.

However, patients treated with abicipar showed more inflammation than patients treated with ranibizumab.

“We are very impressed by the vision and anatomical data presented,” said Michael Stumpp, chief operating officer of Molecular Partners, in a prepared statement. “These data underline that abicipar has the potential to become the first fixed 12-week anti-VEGF therapeutic.”

Farther back in the drug development pipeline, faricimab is a "bispecific" molecule engineered to bind to receptors for both VEGF and Ang-2. While VEGF causes vessels to proliferate, Ang-2 causes them to become unstable and leaky, according to Roche. The molecule is also engineered to reduce the risk of inflammation and systemic exposure, the company said.

At 52 weeks, faricimab patients dosed either every 16 weeks or every 12 weeks demonstrated sustained vision outcomes comparable to ranibizumab dosed every four weeks.

“The STAIRWAY data show the potential of faricimab to allow fewer injections while achieving and sustaining the same visual gains seen with a current standard of care," said Sandra Horning, Roche’s chief medical officer and head of global product development, in a prepared statement. "Based on these data, we will be initiating a global phase III programme for faricimab in neovascular AMD.”

Safety data for faricimab was comparable to that of ranibizumab.