VANCOUVER, Canada — An experimental implant that delivers ranibizumab controls the progression of neovascular age-related macular degeneration as well as injections, results from the phase 2 LADDER trial show.
Port delivery system with ranibizumab implant.
"To be able to offer our patients the outcomes achieved with monthly injections, but with a device that eliminates the need for those monthly injections, is very exciting," said Carl Awh, MD, from Tennessee Retina in Nashville.
"This could change the landscape," he told Medscape Medical News.
In the real world, outcomes in patients with neovascular age-related macular degeneration often fall short of those achieved in clinical trials of vascular endothelial growth factor (VEGF) inhibitors, said Awh. Patients are often elderly, have trouble getting to physicians' offices on a monthly basis, and can find the injections uncomfortable.
In the LADDER study, most patients went at least 6 months before the ranibizumab port delivery system, developed by Genentech, had to be refilled, and only made monthly doctor visits for monitoring.
Awh presented results from the first successful phase 2 trial of a long-acting implant here at the American Society of Retina Specialists 2018 Annual Meeting.
The port delivery system, which is slightly longer than a grain of rice, is implanted in the pars plana during a surgical procedure that can be performed in an operating room with local anesthesia, Awh explained. Once implanted, the system remains covered by the capsule of Tenon and the conjunctiva indefinitely, and continuously diffuses ranibizumab into the vitreous cavity.
It is refilled with a customized needle in an office-based procedure that is slightly more complicated than an intravitreal injection because the needle must be perpendicular to the device and in its center.
LADDER Trial
Carl Awh
In the LADDER trial, Awh and his colleagues randomly assigned 179 patients to different doses of ranibizumab delivered through the port system — 58 patients to 10 mg/mL, 62 to 40 mg/mL, 59 to 100 mg/mL — and 41 patients, who served as the control group, to monthly intravitreal injections of ranibizumab 0.05 mg.
All participants — two-thirds of whom were women — had been diagnosed with neovascular age-related macular degeneration in the 9 months before screening for study eligibility, and all had received at least two treatments with a VEGF inhibitor. The patients ranged in age from 50 to 92 years (mean, about 74 years).
Clinicians refilled the devices if there was a significant increase in central foveal thickness (CFT), a decrease in best-corrected visual acuity, or new macular hemorrhage.
In 80% of patients, the devices did not need to be refilled for at least 6 months.
Outcomes were comparable in the four treatment groups. As would be expected, the greater the concentration of ranibizumab in the implant, the longer it lasted.
| Table. Outcomes With Ranibizumab Delivered by the Port System or Injection | ||||
| Port Delivery System | Injection | |||
|---|---|---|---|---|
| Measures | 10 mg/mL | 40 mg/mL | 100 mg/mL | 0.05 mg |
| Median time to first refill, months | 8.7 | 13.0 | 15.0 | — |
| Mean baseline ETDRS letters | 69.3 | 69.3 | 69.9 | 70.6 |
| Mean change in ETDRS letters | –3.2 | –0.5 | 4.3 | 3.3 |
| Mean baseline CFT, µm | 194.4 | 181.8 | 183.1 | 185.0 |
| Mean change in CFT, µm | 28.0 | 2.9 | –3.4 | –6.9 |
| At least 1 systemic adverse event, % | 75.9 | 79.0 | 78.0 | 78.0 |
"The data are incredibly exciting," said session moderator Timothy Murray, MD, from Murray Ocular Oncology and Retina in Miami.
"I don't think the data could have been any stronger," he told Medscape Medical News.
Half of the first 22 patients, implanted during the first month, experienced vitreous hemorrhage, and some required surgery to clear the blood. But with experience, the surgeons improved their techniques and, after the first month, only 5.5% of the patients experienced vitreous hemorrhage.
Implant surgery led to endophthalmitis in 1.6% of patients. In addition, a small number of surgeries resulted in cataract, conjunctival bleb, conjunctival erosion, rhegmatogenous retinal detachment, tractional retinal detachment, hyphema, conjunctival retraction, or conjunctival filtering bleb leak.
"For something brand new — a new device, a new surgical technique — these are acceptable complication rates, and it's likely they will diminish as we gain more experience," said Awh.
During his presentation, Awh played videos of the implant technique and the refill procedure. "For a vitreoretinal surgeon, it looked uncomplex," Murray said. And refilling the port delivery system might be less uncomfortable for patients than an intravitreal injection because the needle doesn't go through the sclera, he added.
The LADDER participants were monitored on a monthly basis. If the device is approved, fewer office visits might be required, Awh pointed out. The longest the port delivery system has been implanted so far is 34 months, he reported.
Genentech has plans to launch a phase 3 trial — dubbed Archway — later this year. "The study patients I've spoken with have been happy with the device and are delighted they can keep it in the ongoing trial," Awh said.
Pivotal Moment
"If we are truly able to get to a point where we only need to fill this implant once or twice a year, that's a game changer for people with wet macular degeneration," said Roger Goldberg, MD, from Bay Area Retina Associates in Walnut Creek, California.
He said he is looking forward to trying out the new device in some of his patients in the phase 3 trial.
"So far we only have 9 months of data in visual and anatomic outcomes. It will be great to see longer-term data," he added. "Fortunately, we will get those data as we follow the outcomes from patients in the LADDER study over a longer time period and certainly we'll see that in the larger-scale phase 3 results."
In addition to the larger dataset that the phase 3 trial will provide, Murray said he looks forward to learning how much the device will cost and what codes surgeons will use to bill for it.
If phase 3 results support the use of the port delivery system in patients with neovascular age-related macular degeneration, it could also be a turning point for patients with other conditions, such as diabetic macular edema, he added.
The study was funded by Genentech. Awh reports financial relationships with Genentech, Allergan, Apellis Pharmaceuticals, ArcticDX, Bausch + Lomb, GlaxoSmithKline, Hoffman-La Roche, Katalyst, Merck Pharmaceuticals, Ophthotec, PanOptica, Regeneron, and Volk. Goldberg reports a financial relationship with Genentech. Murray reports relationships with Alcon surgical and Regeneron.
American Society of Retina Specialists (ASRS) 2018 Annual Meeting. Presented July 25, 2018.
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Cite this: Implant Poised to Transform Macular Degeneration Treatment - Medscape - Jul 27, 2018.
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