Session Title: New Drug Treatment and Technology I
Session Date/Time: Friday 18/09/2015 | 11:00-12:30
Paper Time: 11:56
First Author: : P.Dugel UNITED STATES
Co Author(s): : R. Singh A. Weichselberger W. Schmidt F. Jiang M. Humayun
PURPOSE:An important strategic goal for patients with neovascular age-related macular degeneration (nAMD) is reducing treatment burden. RTH258, a novel single-chain antibody fragment directed against vascular endothelial growth factor A (VEGF-A), has optimized solubility and can be highly concentrated, allowing high protein contents in small injection volumes for intravitreal application. Combined with a novel Posterior MicroPump (PMP) for pulsatile intravitreal drug delivery, RTH258 has potential to significantly reduce treatment burden. Here, we report bench results of RTH258 delivery by PMP, and of the clinical efficacy of RTH258 microvolume (10 µL) application via intravitreal injection or intravitreal infusion in patients with nAMD.
Proof of concept of PMP was demonstrated in several monthly bench tests at body temperature (37°C) over the 6 month period. The microvolume study was a prospective, randomized, multicenter, controlled, assessor-masked, parallel-group study. Patients had untreated, active choroidal neovascularization due to AMD.
To test performance of the PMP, 7 fully assembled pumps were filled with RTH258 and maintained at 37°C. Each pump was programmed to deliver one pre-determined dose (2.05, 4.15 or 8.3 µL) every month for a total of 6 months, generating a total of 42 doses. The volume delivered by the PMP was quantified to evaluate the accuracy of the device. In the clinical study, RTH258 patients were randomized to receive a microvolume intravitreal injection (cohort 1) or microvolume intravitreal infusion (cohort 2). The primary efficacy endpoint was the percentage of responders, defined as achieving at least 3 of the following four criteria: 1) a ≥4-letter gain in best-corrected visual acuity (BCVA) at day 14; 2) a ≥4-letter gain in BCVA at day 28; 3) a ≥80 µm decrease in central subfield thickness (CSFT) at day 14; and 4) a ≥80 µm decrease in CSFT at day 28. A responder rate of 15% represented no relevant treatment effect (null hypothesis).
In the PMP proof of concept study, 40 of the 42 doses were delivered within the specified volume accuracy of ±20%. In two cases only, the pumps delivered outside the specific range (in these cases 22% and 30% respectively). In the clinical study, 26 patients, 13 in each cohort, were randomized. RTH258 produced responder rates of 70% (7/10; 90% CI, 39-91%) when injected and 60% (6/10; 90% CI, 30-85%) when infused, exceeding the 15% responder rate (P≤0.0014). For BCVA, 60% of patients in the RTH258 injection cohort were responders (gaining more than 4 letters at days 14 or 28), while 50% of patients in the infusion cohort were responders. For CSFT, 90% of patients in the RTH258 injection cohort were responders (achieving greater than 80µm decrease in CSFT at days 14 or 28), while 60% of patients in the infusion cohort were responders. The mean changes in BCVA from baseline at day 28 were 7.7 letters in the injection cohort and 5.5 letters in the infusion cohort and in the range of improvements one would expect with effective anti-VEGF agents after the first IVT injection. No safety issues were reported.
The PMP demonstrated its proper functioning at body temperature for a period of up to 6 months on the bench, confirming the essential performance of the device. Microvolumes of RTH258, delivered intravitreally by injection or infusion, are effective in improving BCVA and CSFT in the majority of subjects. A microvolume delivery of RTH258 may permit long term delivery of this drug as well as has the potential to permit simultaneous treatment with other drugs, while maintaining the standard injection volume of 50 µl. The combination of RTH258 delivered as microvolume and the Posterior MicroPump is promising and may address a significant unmet need in the treatment of patients with nAMD in providing a sustainable treatment strategy. Clinical evaluations of microvolumes of RTH258 in the PMP are needed to confirm these results.