June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Long-term safety studies of tivanisiran for the treatment of Dry Eye Disease (DED)
Author Affiliations & Notes
  • Anne-Marie Bleau
    Sylentis, Madrid, Spain
  • Veronica Ruz
    Sylentis, Madrid, Spain
  • Beatriz Vargas
    Sylentis, Madrid, Spain
  • Ana Isabel Jimenez
    Sylentis, Madrid, Spain
  • Footnotes
    Commercial Relationships   Anne-Marie Bleau None; Veronica Ruz None; Beatriz Vargas None; Ana Isabel Jimenez None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3954. doi:
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      Anne-Marie Bleau, Veronica Ruz, Beatriz Vargas, Ana Isabel Jimenez; Long-term safety studies of tivanisiran for the treatment of Dry Eye Disease (DED). Invest. Ophthalmol. Vis. Sci. 2023;64(8):3954.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Long-term non-clinical and clinical studies were designed to collect safety data of tivanisiran, a small interfering ribonucleic acid (siRNA) intended to be administered chronically in eye drops for the treatment of DED.

Methods : FDA guidance on DED recommends a clinical program of 400 patients, including at least 300 and 100 patients with a 6-week and 1-year follow-up, respectively, at concentrations similar to the clinical dose. Conversely, high concentrations are tested in toxicology studies to determine potential toxicity in target and non-target organs.
Long-term non-clinical development was carried out in two animal species: New Zealand White (NZW) rabbits (6 months) and Beagle Dogs (9 months). Animals were administered in both eyes with either vehicle (PBS) or increasing doses of tivanisiran to establish the relationship between toxicity, exposure and recovery.
A 1-year clinical trial to explore long-term safety in 300 subjects with DED is ongoing in US. FYDES is a phase 3, multicenter, double-masked, randomized (2:1; tivanisiran: vehicle) clinical trial to study the safety of 1.125% tivanisiran when administered bilaterally once daily as eye drops.

Results : No tivanisiran-related effects on clinical signs, laboratory parameters, organ weight and gross pathology were seen in response to any of the doses tested, regardless animal model.
Ocular instillation of tivanisiran was generally well tolerated in both species. Ocular findings in Beagle dogs were limited to microscopic evidence of minimal to moderate periocular inflammation in a few eyes of animals treated with the highest dose-levels (conjunctival erosion, loss of goblet cells and epithelial degeneration). Inflammation resolved by the end of a 4-week recovery period. The only tivanisiran-related finding in NZW rabbits was minimal to mild hypertrophy/hyperplasia in the epithelium of nasolacrimal ducts after 28 days of treatment. These effects were not observed after 6 months of treatment of after recovery period.
FYDES is still ongoing and data is masked. No drug-related Serious Adverse Events have been reported yet in any of the 301 randomized subjects.

Conclusions : These observations suggest that sustained exposure to 1.125% tivanisiran solution does not produce clinically significant local or systemic Adverse Events nor in non-clinical or clinical studies.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.


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