Sylentis’ siRNA Therapy Fails to Improve Symptoms of Dry Eye Disease Due to Sjögren’s Syndrome


The phase 3 trial of tivanisiran failed its primary endpoint.

Sylentis’ phase 3 clinical trial (NCT04819269) of tivanisiran RNA therapy has failed the primary endpoint of improving dry eye symptoms associated with Sjögren’s Syndrome. Sylentis is a wholly owned subsidiary of PharmaMar.1

The randomized, double-masked, placebo-controlled trial’s primary endpoints included change from baseline in Corneal Fluorescein Staining (CFS) scale at 85 days post-treatment and change from baseline in Dry Eye Symptom scale at 85 days post-treatment. The trial evaluated the efficacy and safety of daily tivanisiran sodium eye drops versus vehicle for 3 months in participants with signs and symptoms of dry eye disease (DED) due to Sjögren's Syndrome. The trial involved 203 patients across more than 40 hospitals in the United States (US)and 8 in Spain.

Tivanisiran is a small interfering RNA (siRNA) that inhibits the synthesis of Transient Receptor Potential Vanilloid-1 (TRPV1). TRPV1 is involved with the pathophysiology of DED, specifically both the sensation of pain and innate inflammatory response in the eye.

In December 2023, Sylentis announced that the phase 3 FYDES safety trial (NCT05310422) of tivanisiran met its primary endpoint by demonstrating long-term safety in 301 patients with DED recruited from 26 centers in the US. Of these participants, 203 were assigned to the tivanisiran group and 98 to the control arm.2

READ MORE: 4D Molecular Therapeutics’ Wet AMD Gene Therapy 4D-150 Reduces Need for antiVEGF Injections in Interim Phase 2 Trial Data

Investigators found that the overall frequency and percentage of experiencing at least 1 adverse event (AE), including ocular, nonocular, related or unrelated AEs, were similar between both treatment groups, with a 40.4% rate in the tivanisiran group and a 39.8% rate in the control arm. AEs related to tivanisiran included conjunctival hyperemia (1%), eye pruritus (1%), papillary conjunctivitis (0.5%) and blurred vision (0.5%). There were no clinically significant changes in other ocular safety parameters, laboratory values or body temperature after 1 year of treatment.2

Also in Sylentis’ ophthalmologic pipeline is SYL1801, an siRNA therapy being investigated in a phase 2 trial (NCT05637255) in patients with wet age-related macular degeneration (AMD), which is ongoing and recruited its first patient in November 2022.3 SYL1801 is designed to transcriptionally down regulate Nrarp expression, a different vascularization factor than VEGF. The randomized, double-blind trial has 3 parallel groups evaluating different dose levels and has a planned enrollment of 90 patients across European countries. The trial’s primary endpoint is effect on visual acuity of each of the 3 doses of SYL1801 administered as a daily eye drop for 6 weeks. Secondary endpoints are evaluating disease progression and safety.

SYL1801 and tivanisiran, along with the company’s other siRNA therapies, are designed with the use of Sylentis’ SirFinder artificial intelligence system. SirFinder uses neural network-based algorithms, support vector machine, and machine learning to analyze data and rationally design siRNAs.

1. Sylentis, a PharmaMar Group company, announces the results of the Phase III SYL1001_V trial with tivanisiran for the treatment of dry-eye disease associated with Sjögren's Syndrome. News release. PharmaMar. February 9, 2024.
2. Sylentis, a PharmaMar Group company, announces the FYDES study to evaluate the safety of tivanisiran in patients with dry eye disease has met its primary endpoint. News release. December 18, 2023.
3. Sylentis, a PharmaMar Group company, begins a new Phase II trial with SYL1801 for patients with Age-Related Macular Degeneration. News release. PharmaMar. November 23, 2022.
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