May 19, 2020
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Pharmacokinetic analysis of LADDER trial shows sustained efficacy of ranibizumab refillable implant

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A pharmacokinetic analysis of the LADDER trial indicates that the Port Delivery System filled with the higher 100 mg/mL dose provides continuous release of ranibizumab through at least 16 months.

“Serum concentrations were within the range achieved with monthly intravitreal injections,” Peter Campochiaro, MD, said at the virtual Association for Research in Vision and Ophthalmology meeting.

The Port Delivery System (PDS, Genentech) is a permanent, refillable implant that is surgically inserted through a small incision in the sclera and pars plana, allowing continuous delivery of ranibizumab into the vitreous cavity. In the phase 2 LADDER trial, 220 patients with anti-VEGF-responsive age-related macular degeneration were randomly assigned to one of three PDS doses (10 mg/mL, 40 mg/mL or 100 mg/mL) or monthly intravitreal ranibizumab injections (0.5 mg).

A secondary objective of the study was to perform a pharmacokinetic analysis using serum levels obtained at predefined points. In the monthly injection arm, serum samples were collected at randomization, months 1, 3, 6 and 9, and at the final study visit to assess trough levels. In the PDS arms, serum samples were collected at each monthly visit as well as after implantation and after each refill.

Frequent serum sampling throughout the course of ranibizumab injections showed fluctuation, with a characteristic peak and trough after each injection. In the PDS 100 mg/mL group, the mean serum levels were 243 pg/mL, 160 pg/mL, 101 pg/mL and 50.8 pg/mL at months 6, 9, 12 and 16, showing that the implant continued to release ranibizumab through month 16. The median serum ranibizumab concentration levels were constantly higher than the trough levels of monthly injections.

These findings show that delivery of ranibizumab with the PDS has the potential to reduce the treatment

“These findings explain the median time to first refill of 15.8 months observed in PDS 100 mg/mL patients in the LADDER trial, which was associated with sustained visual gains that were comparable to monthly intravitreal ranibizumab,” Campochiaro said. “They also explain why 80% of PDS 100 mg/mL patients went 6 or more months before meeting refill criteria.”

Sustained delivery of anti-VEGF through the PDS implant has the potential to reduce the treatment burden while improving real-world clinical outcomes for patients with AMD, he said. – by Michela Cimberle

Reference:

Campochiaro P, et al. Pharmacokinetic (PK) profile of the Port Delivery System with ranibizumab (PDS) in the phase 2 Ladder trial. Presented at: Association for Research in Vision and Ophthalmology annual meeting; May 6, 2020 (virtual meeting).

Disclosure: Campochiaro reports he has personal financial interests in Aerpio, Allegro, Applied Genetic Technologies Corporation, AsclepiX Therapeutics, Exonate, Genentech/Roche, Graybug Vision, Merck & Co, Novartis Pharmaceuticals, Perfuse and Wave Life Sciences.