Sylentis, a PharmaMar Group company, has announced positive topline results from its Phase IIa dose-ranging study of SYL1801 for the treatment of neovascular age-related macular degeneration (nAMD). The investigational siRNA therapy, administered as eye drops rather than traditional intravitreal injections, successfully met its primary endpoint with more than 71% of patients in the mid-dose cohort maintaining visual acuity over the 6-week study period.
The double-blind study evaluated three parallel dose levels of SYL1801 in 99 treatment-naïve nAMD patients who were followed for 42 days. The primary endpoint assessed the change from baseline to end of treatment in best corrected visual acuity (BCVA) score. All dose levels maintained visual acuity similarly, with the middle concentration of 25mg/ml achieving statistically significant improvement at the 42-day mark.
"With these data from this explorative study of SYL1801, we are encouraged to put efforts into the subsequent clinical research program with proper guidance from the patient outcomes in the concluded study," said Andreas Segerros, CEO of Sylentis.
A Novel Approach to AMD Treatment
SYL1801 represents a breakthrough in ophthalmology drug development through gene silencing technology based on RNA interference (RNAi). The eye drop formulation blocks the synthesis of the NRARP receptor (Notch-Regulated Ankyrin Repeat Domain Proteins), which plays a critical role in choroidal neovascularization—a key pathological process in AMD.
This approach could potentially transform AMD treatment, which currently relies on regular intravitreal injections of anti-VEGF agents. These injections are uncomfortable for patients and resource-intensive for healthcare systems.
Ana Isabel Jiménez, COO and Research & Development Director at Sylentis, previously noted that "the drugs traditionally used to treat retinal diseases are antibodies, large molecules that cannot reach the retina from the ocular surface. This is why they are administered by intravitreal injections." She explained that "siRNAs, such as SYL1801, are much smaller than antibodies, allowing them to penetrate the retina and inhibit the formation of new blood vessels after being applied as eye drops on the ocular surface."
Clinical Development Journey
The positive Phase IIa results follow a successful Phase I trial completed in March 2022, which involved 36 healthy volunteers who received SYL1801 eye drops in both single ascending dose (SAD) and multiple ascending dose (MAD) formats. That study demonstrated that SYL1801 was safe and well-tolerated at all tested doses.
The Phase IIa trial was initiated in November 2022 as a randomized, double-blind study with three parallel groups receiving different dose levels. The study enrolled 90 patients across multiple European centers, with the primary objective of evaluating the effect on visual acuity after 6 weeks of daily administration.
The Burden of Age-Related Macular Degeneration
AMD is a significant global health concern, with an estimated 288 million individuals expected to be affected by 2040. It remains the leading cause of irreversible visual impairment in the elderly population of developed countries, accounting for 8% of all cases of blindness worldwide. The overall prevalence of AMD among adults aged 45-85 is approximately 8.7%.
The disease is characterized by a gradual loss of visual acuity that can progress to blindness in severe cases. Current standard treatments involve regular hospital visits for intravitreal injections, which are associated with patient discomfort, potential complications, and substantial healthcare costs.
RNA Interference Technology
SYL1801 utilizes RNA interference, a natural cellular mechanism that occurs in plants, animals, and humans. This technology allows for the rational design of specific therapies that silence genes by eliminating messenger RNA (mRNA), the molecular precursors of proteins.
The RNAi approach represents a significant advancement in treating diseases caused by protein malfunctioning or overproduction. Compounds based on RNAi technology tend to have longer-lasting effects than traditional drugs and fewer side effects due to their high specificity.
Sylentis has established itself as a leader in applying RNAi technology to ophthalmology, with SYL1801 being one of several candidates in its pipeline. The company also has tivanisiran in Phase III clinical trials for the treatment of dry eye.
The positive results from the Phase IIa study were presented at the 2025 Association for Research in Vision and Ophthalmology (ARVO) annual meeting in Salt Lake City, highlighting the potential of this innovative approach to transform AMD treatment.
