Novel anti-VEGF agent may provide important advancement in AMD treatment

A novel anti-vascular endothelial growth factor agent, RTH258, produced rapid and sustained improvements in visual acuity and central subfield thickness and was non-inferior to aflibercept in a phase II trial.


Take-home message: A novel anti-vascular endothelial growth factor agent, RTH258, produced rapid and sustained improvements in visual acuity and central subfield thickness and was non-inferior to aflibercept in a phase II trial.



By Cheryl Guttman Krader; Reviewed by Lawrence J. Singerman, MD

Cleveland-Positive results were achieved in a phase II study investigating RTH258 (Alcon Laboratories), a novel anti-vascular endothelial growth factor (VEGF) agent for the treatment of neovascular age-related macular degeneration (AMD).

Dr. SingermanA pivotal trial program will soon be under way, according to Lawrence J. Singerman, MD, clinical professor of ophthalmology, Case Western Reserve University, Cleveland.

Known as the OSPREY trial, the study had a randomized, double-masked design and compared RTH258 6 mg with aflibercept 2 mg (Eylea, Regeneron) in 89 previously untreated patients. Both agents were initially dosed every 8 weeks through week 32, and then the dosing interval was increased to 12 weeks with follow-up continuing to week 56. Throughout the study, patients were evaluated monthly and could receive rescue treatment as needed.

The study met its primary endpoint by demonstrating non-inferiority of RTH258 compared with aflibercept for improving mean visual acuity at week 12.

Comparison of VA gains

Non-inferiority of RTH258 versus aflibercept was also achieved in comparisons of mean visual acuity gain at week 16 and improvements in central subfield thickness, although fewer rescue treatments were needed in the RTH258 arm.

After dosing was switched to every 12 weeks, patients in the RTH258 group continued to require fewer rescue treatments (60 versus 94). Visual acuity gains and central subfield thickness outcomes were again similar in the two study groups at week 56.


The safety analysis showed RTH258 was well tolerated and had a similar adverse event profile compared with aflibercept.

“During the second phase of the OSPREY trial, about half of the patients in the RTH258 group could be maintained with Q12 week dosing,” Dr. Singerman said. “If RTH258 continues to show efficacy with a quarterly dosing schedule in the phase III studies, it will be an important advance for treatment of neovascular AMD.”

Smaller size brings advantages

RTH258 is a humanized, single-chain antibody fragment that is much smaller than commercially available anti-VEGF agents. The molecular weight of RTH258 is only 26 kDa, compared with 50 kDa for ranibizumab (Lucentis, Genentech), 100 to 115 kDa for aflibercept, and 150 kDa for bevacizumab (Avastin, Genentech).

“The smaller size of RTH258 allows for delivery of a higher molar dose in a given volume and should facilitate drug penetration into relevant ocular tissues,” Dr. Singerman said. “In addition, it should reduce systemic exposure because of more rapid elimination and enable formulation in a sustained-release platform in the future.”

Safety review

The safety review in OSPREY showed no differences between groups in ocular, systemic, or serious treatment-emergent adverse events. There was one death in the RTH258 group–a patient who had multiple systemic comorbidities.

“A relationship to RTH258 treatment cannot be ruled out, but it seems remote,” Dr. Singerman said.

A phase II dose-ranging study found RTH258 was non-inferior to ranibizumab for reducing central subfield thickness when comparing the two highest RTH258 doses investigated (4.5 mg and 6 mg).


In addition, RTH258-treated patients had rapid and meaningful gains in visual acuity. Time-to-rescue treatment with standard of care (ranibizumab) was 30 days longer in the RTH258 arm than in ranibizumab-treated patients.

The phase III studies will enroll more than 1,600 patients and will further evaluate RTH258 in comparison with aflibercept.



Lawrence J. Singerman, MD


This article was adapted from Dr. Singerman’s presentation at the 2015 meeting of the Association for Research in Vision and Ophthalmology. Dr. Singerman was an investigator in the OSPREY trial. He receives grant support from Acucela, Alcon Laboratories, Allergan, Genentech, MacTel, National Eye Institute, Novartis, Ohr Pharmaceutical, Ophthotech, and Pfizer, and is a consultant/advisor to and owns equity in ArcticDx, Ohr Pharmaceutical, and Ophthotech.


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