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Cyclosporine Intracanalicular Insert Stalls
Phase 2 study fails to meet primary efficacy endpoint after novel product shows encouraging efficacy signals in earlier trial. Cheryl Guttman Krader reports
Asustained-release cyclosporine intracanalicular insert, OTX-CSI (Ocular Therapeutix), demonstrated a favourable tolerability profile and rapid onset of action for improving dry eye disease (DED) signs and symptoms in a phase 1 study. However, a phase 2 study showed no statistically superior improvement from baseline to 12 weeks compared to controls.
In the phase 2 study, two OTX-CSI formulations showed favourable safety profiles and good tolerability as well as an association with early and sustained improvements in corneal fluorescein staining (CFS) and DED symptoms. The study sponsor, Ocular Therapeutix, announced in an October 22, 2021, press release the company will continue to review the study data for additional information that may inform future development of the OTX-CSI program.
Mitchell A Jackson MD is an investigator in the OTX-CSI clinical trial program. Earlier in October, he presented the results from the phase 1 study at the 39th Congress of the ESCRS in Amsterdam, the Netherlands.
“Intolerable side effects and slow onset of action represent some of the biggest complaints that patients have about the commercially available products used for the chronic treatment of DED. The ocular surface side effects—namely, stinging, burning, and irritation—often lead to non-compliance and therapy discontinuation. In addition, the slow onset of action can be frustrating for patients and lead to early drop-out,” Dr Jackson told EuroTimes.
“It is worthwhile to continue exploring OTX-CSI not only for its potential to address the unmet need for effective chronic DED treatments but also because of its promise of overcoming the issue of poor compliance with topical medications. In my opinion, poor compliance is one of the biggest culprits explaining why available therapies are not entirely effective in the real world of patient care.”
OTX-CSI incorporates cyclosporine in a preservative-free, fully biodegradable, polyethylene glycol hydrogel rod. Designed to provide prolonged cyclosporine release, the insert also offers a second treatment modality for DED—punctal occlusion, Dr Jackson said.
The phase 1 and phase 2 trials investigating OTX-CSI were US-based. The phase 1 study had an open-label design and enrolled five adults who had the device inserted bilaterally at week zero after a 14-day washout period. Patients were eligible for enrolment if they had bilateral DED for at least six months, a severity Eye Dryness Score (EDS) ≥30 rated on a visual analogue scale of 0 to 100, total CFS score (NEI scale) ≥6 and <15, and an unanaesthetised Schirmer score >0 to ≤5 mm/5 min.
The trial’s safety data showed no serious adverse events, treatment-related adverse events, or reports of stinging, burning, or dysgeusia. Efficacy data showed improvements from baseline in Schirmer score, CFS score, EDS severity and frequency, and scores on two DED symptom questionnaires.
Improvements in efficacy measures were observed starting at the first follow-up visit at two weeks post-insertion of OTX-CSI and lasted up to 16 weeks for both the Schirmer test and DED symptom assessments. Mean Schirmer test score improved from 4.2 mm/5 min at baseline to 8.2 mm/5 min at week 12 and 8.5 mm/5 min at week 16. Mean total CFS score was 6.7 at baseline and fell to 2.7 at week 12. Mean scores for EDS severity and EDS frequency were 51 at baseline and fell to approximately 23 and 28, respectively, at week 16.
WHAT HAPPENED IN PHASE 2? The phase 2 study was a double-masked, multicentre trial that randomised 147 patients into one of four groups to receive one of two formulations of OTX-CSI or one of two vehicle inserts. The two OTX-CSI inserts contained the same amount of cyclosporine but differed in their expected release duration (two-to-three months or three-to-four months), and the vehicle inserts had expected durations of three-to-four months and one week.
At the primary efficacy endpoint visit conducted at week 12 post-insertion, change from baseline Schirmer score was 1.98 mm/5 min for the shorter duration OTX-CSI group, 1.91 mm/5 min for the longer duration OTX-CSI group, 2.24 mm/5 min for the longer duration vehicle group, and 3.08 mm/5 min for the shorter duration vehicle group.
Other efficacy analyses showed improvements from baseline in both OTX-CSI groups in both total CFS and EDS as early as two weeks after insertion. At 12 weeks, however, the improvements from baseline in CFS, EDS severity, and EDS frequency were not statistically significant compared with those achieved in the vehicle groups.
OTX-CSI continued to demonstrate favourable safety and tolerability. There were no ocular serious adverse events, and no study participant withdrew because of adverse events. Ocular pruritus was the most common ocular adverse event recorded, affecting 16% of patients treated with OTX-CSI. The reported rate of ocular discomfort or pain was less than 3%.
