COMMENTARY

New Data on RTH258 Show Promise

Parth Shah; Sophie J. Bakri, MD

Disclosures

August 24, 2016

Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration: A Randomized Controlled Study

Holz FG, Dugel PU, Weissgerber G, et al
Ophthalmology. 2016;123:1080-1089

A Promising Alternative

Current treatment modalities for neovascular age-related macular degeneration (AMD) are centered around intravitreal anti-vascular endothelial growth factor (VEGF) injections and include ranibizumab, bevacizumab, and aflibercept. These anti-VEGF agents, in addition to improved diagnostic modalities, have provided drastic improvements in the management of patients with neovascular AMD.

Nevertheless, patients often receive monthly or bi-monthly injections and have to make multiple clinic visits to assess treatment response. This can be taxing on patient lifestyle and increases the risk for reduced patient compliance, as demonstrated in the AURA trial.[1]

RTH258, an anti-VEGF single-chain antibody fragment, aims to overcome the limitations of current therapies. RTH258 has a small 26 kDa size, compared with 48 kDa for ranibizumab and 115 kDa for aflibercept, allowing for better ocular tissue penetration and concentrations of up to 120 mg/mL to deliver a higher dose per injection. Moreover, animal studies demonstrated faster systemic clearance and a fourfold reduced systemic exposure compared with ranibizumab and bevacizumab.[2,3]

As a promising alternative, RTH258 was the basis of a 6-month prospective proof-of-concept phase 1/2 trial.

Study Summary

This study aimed to assess the safety, tolerability, and effect of treatment on ocular outcomes of different doses of a single intravitreal injection of RTH258 in comparison with ranibizumab 0.5 mg in patients with neovascular AMD.

The study included 194 treatment-naive patients older than 50 years who had primary subfoveal choroidal neovascularization secondary to AMD. The study had two phases, the first of which was a dose-escalation phase of RTH258 to the maximum feasible dose in which patients received 0.5 mg, 3 mg, or 4.5 mg of RTH258 or 0.5 mg of ranibizumab. The second phase was a maximum feasible dose expansion phase in which patients received either 0.5 mg, 3 mg, or 6 mg of RTH258 or 0.5 mg of ranibizumab.

The primary efficacy endpoint to assess treatment outcomes was the change in central subfield thickness (CSFT) from baseline to 1 month, as measured by spectral-domain optical coherence tomography (SD OCT). The secondary efficacy endpoint was the time from initial treatment to post-baseline therapy (PBT). PBT was at the discretion of the investigator and was given at day 14 if there was a decrease in change from baseline in CSFT < 50 μm, new intraocular hemorrhage, or vision loss of seven or more letters of best-corrected visual acuity (BCVA) associated with retinal fluid accumulation. PBT was given at 1 month if there was a > 340-μm CSFT on SD OCT, new intraocular hemorrhage, or vision loss of seven or more letters of BCVA associated with retinal fluid accumulation. Safety was assessed by examining the adverse events that occurred in the study eye within 7 days of intravitreal injection. Statistical analysis in regard to efficacy was conducted using an ad hoc efficacy analysis based on the actual treatment received instead of the intent-to-treat patient set. In examining the change in CSFT, the authors concluded that noninferiority of RTH258 for the 4.5-mg and 6-mg doses, compared with ranibizumab 0.5 mg, would be established if the lower limit of the two-sided 90% confidence interval was greater than -40 μm. The secondary efficacy outcome that examined time to PBT was analyzed using the Kaplan-Meier method.

The results were encouraging, with the least squares mean difference showing a 21.49-μm and a 10.34-μm larger reduction in the mean change in CSFT, the primary efficacy outcome, from baseline to 1 month for the RTH 4.5-mg and RTH 6-mg groups, respectively, compared with ranibizumab 0.5 mg. The lower limit of the confidence interval was also greater than -40 μm, demonstrating noninferiority to ranibizumab 0.5 mg. Examining the time from initial treatment to PBT, the secondary efficacy outcome, all groups except RTH258 0.5 mg had a longer duration of effect than the median time of 45 days for ranibizumab 0.5 mg. The 3-mg and 6-mg groups had promising median times to PBT of 75 days each. When examining BCVA, the RTH258 6-mg group demonstrated larger mean changes from baseline in BCVA compared with ranibizumab 0.5 mg at all post-baseline visits.

The most common adverse events were conjunctival hemorrhage, eye pain, and conjunctival hyperemia. No patients discontinued treatment due to adverse events.

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