Sustained delivery system intended to ease AMD treatment burden

Carl D. Regillo

A new port delivery system may secure sustained, long-term release of anti-VEGF in patients with wet age-related macular degeneration, easing the burden of repeated injections. The implantable device was recently tested in a phase 2 trial with positive outcomes.

“The results of the LADDER (Long Acting Delivery of Ranibizumab) trial exceeded expectations in terms of durability. We are very excited and believe that this device will be a nice potential alternative to regular, frequent injections for patients and doctors,” study investigator Carl D. Regillo, MD, said.

The ranibizumab port delivery system (PDS, Genentech) is a small reservoir-based platform that is secured in a transscleral pars plana location. It requires a short procedure in the operating room, in which a small incision is made in the sclera to insert the tubular part of the device into the vitreous, while a circular diaphragm secures the proximal end to the scleral wall. The conjunctiva is placed over it, and no sutures are needed for the device itself to sit securely in place.

“The PDS is preloaded with a concentrated dose of ranibizumab. After the initial procedure in the OR, it is refilled as needed in the office using a special needle. Basically, you perform an anti-VEGF injection through the conjunctiva into the device rather than placing the drug directly into the vitreous gel,” Regillo, an OSN Retina/Vitreous Board Member, said.

LADDER trial

The LADDER trial was designed to assess the durability and safety of the PDS. Three different concentrations of ranibizumab (10 mg/mL, 40 mg/mL and 100 mg/mL) were tested, with a control group receiving the gold standard, monthly 0.5 mg ranibizumab injection.

“About 220 patients were included in the four arms of the study. Durability was assessed by the time to the first PDS refill in the office. Secondary endpoints included best corrected visual acuity and central foveal thickness change from baseline as well as safety,” Regillo said.

The best results were obtained with the highest concentration of ranibizumab in a dose-dependent fashion. In the 100 mg/mL treatment arm, 80% of the patients maintained the full effect of the drug for 6 months or more. Nearly 69% went 9 months or more without requiring a PDS refill. BCVA and anatomic outcomes were comparable to those of monthly intravitreal ranibizumab. The insertion and refill procedures were well tolerated. Vitreous hemorrhage associated with device insertion occurred relatively frequently at the beginning of the study, but modifications of the surgical technique early on in the course of the trial led to a much lower rate of postoperative hemorrhage thereafter.

“The highest concentration arm had equal vision and anatomic outcomes to monthly injections. This shows that the device provides a comparable amount of drug effect on a day-to-day basis, keeping the disease under an adequate control for at least 6 months,” Regillo said.

Advantages, disadvantages

The advantages are obvious in terms of reducing treatment burden in patients who need frequent injections.

“Many of our patients require frequent treatments, every 4 to 8 weeks. The PDS could be an attractive alternative for them to minimize the number of injections and office visits. The only downside is that an initial procedure in the OR is required, with the related potential increased risks of the surgery itself,” Regillo said.

The initial surgical procedure also involves an additional cost, but taking into account that wet AMD requires indefinite treatment for many years, there is a potential for an overall cost savings over time.

“We don’t know the cost of the device, of the procedure and of the concentrated version of the drug yet, but taking into account the direct and indirect costs related to repeated injections, testing, trips to the office, time given by other family members, days off work and so on, there is a potential for cost savings,” Regillo said.

The lower concentrations of the drug also performed relatively well, but the plan is to move forward to phase 3 testing with only the highest ranibizumab concentration. The ARCHWAY trial, using fixed 100 mg/mL dosing, is planned to start in the last quarter this year. Future projects may also involve other retinal conditions, such as diabetic retinopathy and diabetic macular edema.

“This is not necessarily the best option for all our patients,” Regillo said. “Those who don’t require frequent injections will probably continue to be managed with the current office-based intravitreal injection treatment paradigm. However, the PDS has the potential to be widely utilized just because so many of our patients do need frequent treatments for a very long and indefinite time frame.”

Since the beginning of the anti-VEGF era, the burden of repeated injections has been a major concern, also in terms of compliance and real-life outcomes. A device for sustained release that is effective and safe might represent a true step forward toward a reduced burden for patients and clinics and overall better outcomes, he said. – by Michela Cimberle

Disclosure: Regillo reports he is a consultant for and has received research grant support from Genentech.

Editor's note: This article was updated to include the correct number of patients in the LADDER trial.

Carl D. Regillo

A new port delivery system may secure sustained, long-term release of anti-VEGF in patients with wet age-related macular degeneration, easing the burden of repeated injections. The implantable device was recently tested in a phase 2 trial with positive outcomes.

“The results of the LADDER (Long Acting Delivery of Ranibizumab) trial exceeded expectations in terms of durability. We are very excited and believe that this device will be a nice potential alternative to regular, frequent injections for patients and doctors,” study investigator Carl D. Regillo, MD, said.

The ranibizumab port delivery system (PDS, Genentech) is a small reservoir-based platform that is secured in a transscleral pars plana location. It requires a short procedure in the operating room, in which a small incision is made in the sclera to insert the tubular part of the device into the vitreous, while a circular diaphragm secures the proximal end to the scleral wall. The conjunctiva is placed over it, and no sutures are needed for the device itself to sit securely in place.

“The PDS is preloaded with a concentrated dose of ranibizumab. After the initial procedure in the OR, it is refilled as needed in the office using a special needle. Basically, you perform an anti-VEGF injection through the conjunctiva into the device rather than placing the drug directly into the vitreous gel,” Regillo, an OSN Retina/Vitreous Board Member, said.

LADDER trial

The LADDER trial was designed to assess the durability and safety of the PDS. Three different concentrations of ranibizumab (10 mg/mL, 40 mg/mL and 100 mg/mL) were tested, with a control group receiving the gold standard, monthly 0.5 mg ranibizumab injection.

“About 220 patients were included in the four arms of the study. Durability was assessed by the time to the first PDS refill in the office. Secondary endpoints included best corrected visual acuity and central foveal thickness change from baseline as well as safety,” Regillo said.

The best results were obtained with the highest concentration of ranibizumab in a dose-dependent fashion. In the 100 mg/mL treatment arm, 80% of the patients maintained the full effect of the drug for 6 months or more. Nearly 69% went 9 months or more without requiring a PDS refill. BCVA and anatomic outcomes were comparable to those of monthly intravitreal ranibizumab. The insertion and refill procedures were well tolerated. Vitreous hemorrhage associated with device insertion occurred relatively frequently at the beginning of the study, but modifications of the surgical technique early on in the course of the trial led to a much lower rate of postoperative hemorrhage thereafter.

PAGE BREAK

“The highest concentration arm had equal vision and anatomic outcomes to monthly injections. This shows that the device provides a comparable amount of drug effect on a day-to-day basis, keeping the disease under an adequate control for at least 6 months,” Regillo said.

Advantages, disadvantages

The advantages are obvious in terms of reducing treatment burden in patients who need frequent injections.

“Many of our patients require frequent treatments, every 4 to 8 weeks. The PDS could be an attractive alternative for them to minimize the number of injections and office visits. The only downside is that an initial procedure in the OR is required, with the related potential increased risks of the surgery itself,” Regillo said.

The initial surgical procedure also involves an additional cost, but taking into account that wet AMD requires indefinite treatment for many years, there is a potential for an overall cost savings over time.

“We don’t know the cost of the device, of the procedure and of the concentrated version of the drug yet, but taking into account the direct and indirect costs related to repeated injections, testing, trips to the office, time given by other family members, days off work and so on, there is a potential for cost savings,” Regillo said.

The lower concentrations of the drug also performed relatively well, but the plan is to move forward to phase 3 testing with only the highest ranibizumab concentration. The ARCHWAY trial, using fixed 100 mg/mL dosing, is planned to start in the last quarter this year. Future projects may also involve other retinal conditions, such as diabetic retinopathy and diabetic macular edema.

“This is not necessarily the best option for all our patients,” Regillo said. “Those who don’t require frequent injections will probably continue to be managed with the current office-based intravitreal injection treatment paradigm. However, the PDS has the potential to be widely utilized just because so many of our patients do need frequent treatments for a very long and indefinite time frame.”

Since the beginning of the anti-VEGF era, the burden of repeated injections has been a major concern, also in terms of compliance and real-life outcomes. A device for sustained release that is effective and safe might represent a true step forward toward a reduced burden for patients and clinics and overall better outcomes, he said. – by Michela Cimberle

Disclosure: Regillo reports he is a consultant for and has received research grant support from Genentech.

Editor's note: This article was updated to include the correct number of patients in the LADDER trial.