For the last 8 years, retina specialists and patients have had three basic anti-VEGF options for the treatment of wet AMD and no therapies at all for treating the dry form of AMD. While any potential treatments for dry AMD still remain in the future, we are now entering an exciting era in which a new generation of more durable and effective treatments for wet AMD appear poised to enter the US marketplace over the next few years.

The advent of intravitreal anti-VEGF molecules ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron), and off-label bevacizumab (Avastin, Genentech), represent a huge step forward in preserving visual acuity and decreasing neovascular activity in wet AMD when compared to older treatment approaches, such as photocoagulation¹ or photodynamic therapy with verteporfin.² However, real-world results with anti-VEGF have never come close to matching the visual and anatomic improvements attained in pivotal clinical trials.

Recent research aimed at improving the durability and efficacy of wet AMD therapies share an overarching goal: decreasing the total number of necessary interventions while improving final best-corrected visual acuity (BCVA) and central foveal thickness (CFT). Although many phase 1 and 2 trials are also underway, only phase 3 trials will be reviewed here.

BROLUCIZUMAB AND FARICIMAB EXCEL IN DURABILITY

Tentatively expected to launch by the end of 2019, brolucizumab (Novartis) has exhibited promising results in treatment-naïve neovascular AMD patients. Brolucizumab is a single-chain-antibody fragment that is smaller than either ranibizumab or aflibercept molecules and targets all VEGF-A isoforms.

In the HAWK and HARRIER trials, 1,817 patients were randomized to brolucizumab (3mg and 6mg in HAWK; 6mg only in HARRIER) or aflibercept 2mg treatment arms. In both studies, brolucizumab was injected for 3 consecutive months followed by extension to 12 weeks. Also, in both studies, brolucizumab treatment intervals were tightened to 8 weeks if neovascular activity persisted 12 weeks after the last loading dose. Aflibercept dosing was kept at every 8 weeks. The finding BCVA gains were similar in all treatment arms at 48 weeks.

Additional endpoints revealed that 49.4% (brolucizumab 3mg) and 55.6% (brolucizumab 6mg) of patients were able to maintain every 12-week dosing out to 48 weeks.³ The brolucizumab 6mg-arm also exhibited statistically significant reduction in CFT at 48 weeks when compared to the aflibercept arm in both HAWK and HARRIER.

A novel bispecific drug whose phase 3 studies TENAYA and LUCERNE are underway is faricimab (Genentech). The first of its kind, this molecule exhibits dual function by inhibiting two molecules involved in angiogenesis — angiopoietin-2 and VEGF-A. In its phase 2 STAIRWAY study for wet AMD, faricimab 6mg was injected monthly for 4 months followed by extension out to 12 and 16 weeks versus active control with ranibizumab 0.5mg every 4 weeks.

Study results presented in October 2018 revealed similar BCVA gains and CFT reductions in each arm despite longer treatment intervals with faricimab.⁴

ABICIPAR PEGOL DURABLE, BUT WITH AN INFLAMMATION ISSUE

Another unique molecule currently undergoing parallel phase 3 SEQUOIA and CEDAR studies is abicipar (Allergan and Molecular Partners). This drug is a genetically engineered protein known as a DARPin, which functions similarly to an antibody but binds targets with a higher affinity.⁵

Treatment arms include set monthly loading doses of abicipar, followed by extension of treatment intervals to either 8 or 12 weeks, or monthly ranibizumab treatments. Presented results revealed non-inferiority of abicipar to ranibizumab when evaluating mean change in BCVA and mean CFT change at 52 weeks. However, the abicipar arms in both studies reported significantly more intraocular inflammation (average: 15.46%) than ranibizumab arms (average: 0.3%); while most (80%) responded to topical steroid drops.⁵

In the subsequent MAPLE trial, the inflammation rate of abicipar pegol in wet AMD was reduced to 9% following manufacturing changes. The U.S. FDA has accepted a Biologics License Application (BLA) for abicipar and the European Medicines Agency has accepted a Marketing Authorization Application (MAA) for the drug—both are in review.

AN ENTRANT FROM CHINA

Conbercept (Lumitin; Chengdu Kanghong Biotech, China) is an antibody that functions like aflibercept by blocking VEGF-A, VEGF-B, and placental growth factor. Additionally, conbercept’s receptor domains have been fused to include both VEGF receptor 1 and 2 domains, which may extend the drug’s intraocular half-life.⁶ Conbercept’s use has been accepted in China since 2013.

The phase 3 PHOENIX study evaluated the efficacy of conbercept versus sham and revealed that eyes treated with monthly conbercept for 3 months prior to extension to quarterly treatments exhibited statistically significant improvement in BCVA at 3 months. However, these results were not maintained at 12 months, suggesting that more frequent dosing with conbercept may be required.^6,7

Efficacy of conbercept is further being evaluated in the worldwide phase 3 PANDA trial. The study has enrolled 1,143 patients randomized to one of three arms: conbercept 0.5mg monthly for three injections with extension to every 8 weeks thereafter; conbercept 1.0mg monthly for three injections with extension to every 12 weeks thereafter; and aflibercept 2mg for three injections with extension to every 8 weeks thereafter. The primary endpoint of the study is change in mean BCVA from baseline at 36 weeks. Various secondary endpoints will also be evaluated starting at 36 weeks and out to 96 weeks.

PDS SUSTAINED-RELEASE IMPLANT

Another promising approach to the treatment of wet AMD is Genentech’s sustained-release port delivery system (PDS). The tiny reservoir is filled with a concentration of specially formulated ranibizumab and surgically implanted through the sclera/pars plana before its top septum is covered with conjunctiva.

The ranibizumab within passively diffuses from the reservoir into the vitreous, providing continuous dosing of anti-VEGF for months. Reservoirs can be refilled in-office when patients show evidence of recurrent disease activity. Although the phase 2 LADDER study evaluated various concentrations of ranibizumab, the most promising results were with the 100mg/mL concentration; this treatment arm exhibited a mean time to first refill of 15 months while also delivering similar BCVA and CFT outcomes at 9 months when compared to the monthly ranibizumab 0.5mg group.^8-10

Eyes with a PDS did exhibit more early adverse events than control groups, with the most common complication being vitreous hemorrhage. Surgical technique, however, was modified mid-study which significantly reduced rates of vitreous hemorrhage thereafter. The phase 3 ARCHWAY study is ongoing. Treatment arms include PDS implant with ranibizumab 100mg/mL (refilled every 24 weeks) and monthly ranibizumab 0.5mg intravitreal injections.

The primary outcome measure is change in BCVA from baseline at weeks 36 and 40. PORTAL, an extension study, will then follow participants of both LADDER and ARCHWAY who were treated with the ranibizumab 100mg/mL concentration out to 144 weeks to gain more insight into the longer-term adverse effects and outcomes with this treatment modality.

FOVEAL GEOGRAPHIC ATROPHY STILL AN UNMET NEED

Although alterations in diet, optimization of cardiovascular risk factors, and smoking cessation have been shown to reduce progression of nonexudative forms of macular degeneration,¹¹ there is no active treatment available that can halt or regress geographic atrophy GA. This is, however, an area of ongoing research.

Various immune pathways are implicated in the progression of macular degeneration, and many new drug therapies are targeting them. Although many of these therapies have had less-than-promising phase 2 results, a few did make it to phase 3 trials. This included lampalizumab (Genentech), an antigen-binding fragment which inhibits complement factor D. Despite promising early results, the phase 3 SPECTRI and CHROMA studies, which included treatment of 1,881 patients every 4 or 6 weeks with lampalizumab, found no statistical difference in visual function or GA progression between treatment and sham arms at week 48.¹²

Similar negative results were also seen in the phase 2b/3 study evaluating the efficacy of emixustat hydrochloride (Acucela), a molecule that acts at the level of retinal pigment epithelium to reduce the accumulation of retinotoxic biproducts in the visual transduction pathway.³

Lastly, another molecule that functions to reduce an inflammatory pathway will continue investigation this year. APL-2 (Apellis Pharmaceuticals) is a drug that prevents activation of the complement cascade by binding the central complement component C3. It is PEGylated, having been covalently bound to polyethylene glycol (PEG) which increases drug stability and half-life.^13,14 Participants of the parallel phase 3 DERBY and OAKS studies are individuals with geographic atrophy who will be treated with APL-2 15mg either monthly or every other month for 24 months. Treatment arms will be compared to sham controls. Change in GA lesion size from baseline will be evaluated at 12 months (DERBY).

LONG WAIT MAY BE NEARING AN END

While welcoming the advent of life-changing anti-VEGF drugs for retinal disease, both retina specialists and patients have found the current retreatment burden to be onerous and time-consuming.

In the real world, most patients have not been getting the number of retreatments necessary to match the results achieved in clinical trials, leading to undertreatment in many cases. The new generation of more durable intravitreal therapies coupled with the promise of sustained-release concepts should allow real-world results to improve markedly while also lessening the retreatment burden that currently exists. Though we have seen many promising concepts for wet AMD fail over the past 8 years, the new generation of therapies that has made it to phase 3 trials appears to be the strongest group yet to display the potential effectiveness and durability needed for approval. NRP

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