Fewer Injections With New Wet Macular Degeneration Therapies

Laird Harrison

October 28, 2018

CHICAGO — The number of injections required for the successful treatment of neovascular age-related macular degeneration could be reduced considerably with experimental therapies, new research shows.

Treatments in the late stages of development could be administered every 3 months instead of monthly or bimonthly. And data from a phase 1 study of gene therapy foreshadow a day when a single treatment could control the disease indefinitely.

"Drugs that last longer have been the Holy Grail ever since anti-VEGFs were introduced," said Julia Haller, MD, from Wills Eye Hospital in Philadelphia, who moderated the session during which the trial data were presented.

That goal "is definitely closer now," she told Medscape Medical News.

Frequency is an issue because many patients find it difficult or inconvenient to visit a clinic for monthly eye injections. "We know that, left to their own devices and given the vicissitudes of life, patients will not come in as often as they should," Haller said here at the American Academy of Ophthalmology 2018 Annual Meeting.

Brolucizumab (Alcon and Novartis), a humanized, single-chain antibody fragment inhibitor of VEGF A, has cleared the most hurdles. Researchers believe that it works better than the VEGF inhibitors currently on the market because it is a smaller molecule, allowing greater tissue penetration and the administration of higher drug concentrations.

Two-year data from the phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) trials presented show that best-corrected visual acuity (BCVA) and safety profile are comparable with brolucizumab administered every 12 weeks and aflibercept administered every 8 weeks. And brolucizumab outperforms aflibercept on disease progression measured with optical coherence tomography.

At 48 weeks, there were 370 patients in the brolucizumab group and 369 in the aflibercept group. By 96 weeks, fewer patients in the brolucizumab group than in the aflibercept group had discontinued treatment (28 vs 40).

Table 1. Vision Changes at 48 and 96 Weeks in HARRIER
Variable Brolucizumab Aflibercept
Dosing interval, weeks 12 8
Mean change in BCVA, letter    
At 48 weeks 6.1 6.6
At 96 weeks 5.9 5.3

Data from the phase 3 SEQUOIA (NCT02462486) and CEDAR (NCT02462928) trials of abicipar (Molecular Partners and Allergan) were also presented. The agent uses DARPin technology to create small molecules capable of binding to multiple targets, in this case, VEGF and platelet-derived growth factor (PDGF) receptors.

At 1 year, the effectiveness of abicipar administered every 8 to 12 weeks was similar to that of ranibizumab administered every 4 weeks. And reductions in central retinal thickness were similar with the two drugs.

Although the rate of inflammation was higher with abicipar than with ranibizumab (15.3% vs 0.3%), most was mild and controlled with topical corticosteroids.

Table 2. Vision Changes at 52 Weeks in SEQUOIA
Variable Abicipar (n = 265) Ranibizumab (n = 299)
Dosing interval, weeks 12 4
Mean change in BCVA, letters 7.3 8.3

Not as far along in the drug development pipeline is faricimab (Genentech and Roche), a "bispecific" molecule engineered to bind to both VEGF and angiopoietin (Ang)-2 receptors. Although VEGF causes vessels to proliferate, Ang-2 causes them to become unstable and leaky, said Arshad Khanani, MD, from Sierra Eye Associates in Reno, Nevada. The molecule is engineered to reduce the risk for inflammation and systemic exposure, he explained.

Data from the phase 2 STAIRWAY (NCT03038880) trial show that faricimab administered every 12 to 16 weeks was as safe and effective as ranibizumab administered every 4 weeks.

Table 3. Vision Changes at 52 Weeks in STAIRWAY
Variable Faricimab (n = 31) Ranibizumab (n = 16)
Dosing interval, weeks 16 4
Mean change in BCVA, letters 11.4 9.6

In faricimab, "I think we have a drug that can reduce the treatment dosing and maintain visual acuity," Khanani told Medscape Medical News.

Gene Therapy

With RGX-314, a therapy being developed by Regenxbio, genes injected into the subretinal space cause cells to produce a protein similar to that in currently approved VEGF inhibitors. Unlike classic gene therapy, which repairs or replaces a defective gene, RGX-314 inserts an artificial gene designed to produce medication.

The treatment uses the NAV AAV8 virus as a vector to insert genes encoded to bind to and neutralize VEGF activity. The virus does not replicate and is not known to cause disease.

During a standard small-gauge vitrectomy, with the patient under local anesthesia, RGX-314 is delivered through a cannula and a subretinal bleb is created in a healthy area of the retina.

The 18 patients in the study had been treated for neovascular age-related macular degeneration with at least 34 injections of VEGF inhibitors. The investigators administered one of three doses of RGX-314 and found that that the more virus they administered, the more protein they could detect in the patients' eyes.

The six patients who received the largest dose saw the greatest improvement in BCVA over 6 months, gaining eight letters. The six patients who received the middle dose gained seven letters, and the six patients who received the lowest dose lost two letters.

The data on central retinal thickness data were more ambiguous: patients who received the lowest and highest doses lost 14 µm of thickness, but those who received the middle dose gained 26 µm.

The average number of rescue injections of a VEGF inhibitor required during the 6-month study was 1.3 in the high-dose group, 3.8 in the middle-dose group, and 4.7 in the low-dose group. Three patients in the high-dose group received no rescue injections at all.

Five adverse events — one a peripheral retinal detachment that was repaired without sequelae — occurred in three patients, but none were related to the drug.

"The highest-dose cohort in the phase 1 study has shown durable drug production inside the eye for 6 months," RGX-314 researcher Allen Ho, MD, from Thomas Jefferson University in Philadelphia.

"I think it's so cool," he told Medscape Medical News.

Recently, the team initiated a fourth cohort of six patients at a higher dose, and REGENXBIO is planning a phase 2 trial of RGX-314 in 2019.

Each of the trials was funded by the relevant drug manufacturer. Khanani reports relationships with Aerpio, Allergan, Clearside Biomedical, Genentech, Novartis, Ophthotech, Opthea, Oxurion, Verana Health, Alimera, Notal Vision, Polyphotonix, Recens Medical, Roche, and Santen. Haller has disclosed no relevant financial relationships. Ho reports financial relationships with Regenxbio, Allergan, Alcon, Genentech, and Iconic.

American Academy of Ophthalmology (AAO) 2018 Annual Meeting. Presented October 26, 2018.

Follow Medscape on Twitter @Medscape and Laird Harrison @LairdH

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