Tolerability and safety of GS‐101 eye drops, an antisense oligonucleotide to insulin receptor substrate‐1: a ‘first in man’ Phase I investigation
Bibliographic record
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Corneal proliferative angiogenesis is an orphan disease leading to cornea loss. • Today's therapeutic approach is not clearly established, although essentially based on topical corticosteroids. • There is therefore a need for new therapeutic alternatives specifically targeting angiogenesis. WHAT THIS PAPER ADDS • Preclinical data demonstrated the efficacy of GS‐101, an antisense oligonucleotide inhibiting insulin receptor substrate‐1 expression, at inhibiting experimental corneal angiogenesis. • This study demonstrates the excellent safety and tolerability profile of GS‐101 applied as eye drops three times daily in this ‘first‐in‐man’ study. • Upon validation in human of its immediate benefit, GS‐101 would offer an alternative to antivascular endothelial growth factor therapies in the treatment of corneal angiogenesis. AIMS GS‐101 (GeneSignal, Epalinges, Switzerland) is an antisense oligonucleotide that inhibits the expression of the scaffold protein insulin receptor substrate‐1 (IRS‐1). Inhibition of IRS‐1 results in the prevention of neovascular growth and was shown to prevent the angiogenic process in preclinical in vitro and in vivo experiments. There is therefore a strong therapeutic rational for targeting angiogenesis in pathological neovascularization. We aimed to investigate the safety, tolerability and bioavailability of GS‐101 eye drops. METHODS This was a Phase I open‐label study. The investigation was performed in two steps. Local ocular tolerability was first assessed with the application of one single low dose in one eye. After no signs of intolerance were observed in the subjects, the dose escalation phase of the study was initiated, and the remaining subjects received three times daily escalating doses of GS‐101 in one eye for 14 days. RESULTS The 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS‐101 from 43 to 430 µg per day. Other than itching, experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed. CONCLUSIONS The tolerability profile obtained from this study suggests that GS‐101 is safe for human use. Further clinical evaluations in diseases related to abnormal angiogenesis are being targeted. In particular, the neovascularization‐related orphan indications of corneal graft rejection, retinopathy of pre‐maturity and neovascular glaucoma are currently under Phase II clinical investigation and are showing promising results.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".