Results from an industry Phase III non-inferiority study of a new single chain antibody fragment (RTH258), designed to inhibit all VEGF-A isoforms, appears to achieve comparable clinical results with less frequent injections than a rival treatment, according to the sponsor. While detailed results have yet to be published, or peer-reviewed, the sponsor of the study, Novartis (NYSE:NVS), claims the drug could ease treatment burdens by extending the injection interval to 12 weeks, compared to Regeneron’s aflibercept’s label of 8 weeks.
Pre-clinical studies of RTH258 (also referred to as brolucizumab, and previously as ESBA 1008) showed that the antibody fragment bound all forms of VEGF-A, including VEGF-165, with no major ocular or systemic toxicity in animal studies. According to the sponsor, RTH258 is the smallest anti-VEGF fragment tested to date in humans, with a molecular weight of 26kDa. In comparison, aflibercept (“Eylea”) is 97kDa, ranibizumab (“Lucentis”) is 48kDa and bevacizumab (“Avastin”) is 149kDa. The smaller the compound, the more efficient the tissue penetration and the higher the target affinity. The small size may facilitate the molecule reaching its site of action relatively faster than larger compounds. Such kinetics may then lead to longer treatment effects and therefore a reduction in the treatment frequency for patients. Clinicians and patients have clear preferences for reduced treatment regimens, all other issues being equal.
In earlier Phase I/II studies of RTH258, the drug demonstrated non-inferiority compared with ranibizumab in the mean change in central subfield thickness (CSFT) from baseline to month 1 for a 4.5- and 6.0-mg dose. According to published results, the difference in CSFT change at month 1 compared to ranibizumab was 22.86 μm (90% confidence interval [CI], −9.28 to 54.99) and 19.40 μm (95% CI, −9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. In addition, the median time to post-baseline therapy (PBT) was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. In the current Phase III studies, termed “HAWK” and “HARRIER”, over 1,800 patients were recruited across 400 centers in a 96-week prospective, randomized, double-masked multi-center trial. According to Novartis, the studies were designed to compare the efficacy and safety of intravitreal injections of 6 mg and 3 mg (HAWK only) RTH258, versus aflibercept 2 mg in patients with neovascular AMD. The primary endpoint for both studies was to confirm that RTH258 is non-inferior to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48, while secondary endpoints included average mean change in BCVA from baseline over the period of week 36-48, the proportion of patients on a 12 week treatment interval at week 48 and anatomical parameters. The company’s press release reported that RTH258 6 mg met the primary and key secondary endpoints but no further details or peer-reviewed results were provided for evaluation.