A new oral therapy under investigation for wet AMD has been shown to improve visual outcomes with a “manageable” safety profile, despite adverse events reported in 80% of study participants.
Published in the journal Eye, the Phase 1 study by Chinese researchers evaluated the efficacy and safety of oral vorolanib for neovascular (wet) age-related macular degeneration (nAMD). The therapy could one day be a more convenient alternative to intravitreal injections of anti-VEGF that can require a high injection frequency over several years, leading to a high treatment burden or complications.
The current standard of care – involving anti-VEGF agents such as bevacizumab, ranibizumab and aflibercept – have also showed worse visual outcomes in real-world studies, possibly due to poor compliance, the researchers noted.
Vorolanib (X-82, CM082) is described as a potent oral VEGF receptor (VEGFR) and PDGF receptor (PDGFR) inhibitor, suggesting a more effective inhibition than anti-VEGF injections alone. In addition, oral vorolanib is more convenient than intravitreal injection.
In the current study, participants received ascending doses of oral vorolanib (25–100 mg daily). In the dose expansion, participants received recommended doses (25 and 50 mg daily).
Between March 2015, and January 019, 41 people were enrolled in six centres in China. At the data cut-off (November 2019), two dose-limiting toxicities (DLTs) were observed during dose escalation (one in the 75 mg cohort and one in the 100 mg cohort).
The maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 33 (80.5%) participants, and grade 3 or higher TRAEs occurred in 12 (29.3%) participants.
No fatal TRAEs were observed – and increases in the mean best-corrected visual acuity (BCVA) from baseline to Day 360 of +7.7 letters (range, −5–29; n = 41) were observed in participants who were administered vorolanib. Corresponding reductions in mean central subfield thickness (CST) and choroidal neovascularization (CNV) area after one year were observed in these three groups.
The researchers concluded that TRAEs after oral administration of vorolanib up to a maximum dose of 100 mg were manageable in the study.
“Given the limitations of the efficacy of anti-VEGF therapy and the burden of repeated intravitreal injections, alternate therapies are being explored. The desire to reduce injection frequency has promoted the development of sustained-release formulations of anti-VEGF drugs, as well as topical and oral formulations,” they wrote.
“Vorolanib, an oral tyrosine kinase inhibitor of both the VEGF and PDGF receptors, does provide important evidence that oral tyrosine kinase inhibitors have efficacy with manageable safety profiles in nAMD. However, we must acknowledge that the systemic adverse profile of vorolanib needs attention, and the potential benefits of vorolanib need to be carefully weighed against the risks.
“Considering that the pathogenesis of CNV formation in nAMD is complex and includes various factors that could be targeted in future treatments, emerging therapies, along with novel anti-VEGF therapies that address treatment burden (including safe oral treatments), are still warranted to provide the retina community with better options for managing nAMD.”
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