Novel Drug Checks All the Boxes as Dry Eye Treatment

SAN DIEGO -- A novel inflammation inhibitor quickly and significantly increased tear production in patients with dry eye disease (DED), according to a randomized trial reported here.

The reactive aldehyde species (RASP) inhibitor reproxalap led to almost a 2-mm increase in the Schirmer score for tear production after the first day of dosing, whereas patients randomized to vehicle had a decrease in tear production. Twice as many patients had at least a 10-mm increase from baseline on the first day.

Ocular discomfort and DED symptoms decreased significantly with reproxalap versus vehicle, reported Eric Donnenfeld, MD, of OCLI Vision in Garden City, New York, during the American Society of Cataract and Refractive Surgery meeting.

"What I found particularly interesting about reproxalap was that, for me, for a dry eye treatment to be successful, it has to work rapidly, work in one day, it has to be efficacious in terms of Schirmer scores, and it has to be well tolerated. These are all the things we're looking for," said Donnenfeld.

RASP are thought to be involved at the top of the inflammatory cascade, binding to various molecules to induce cytokine and T-cell activation. The phase III TRANQUILITY-2 trial evaluated the safety and efficacy of reproxalap to improve tear production in patients with DED. The trial involved 361 patients randomized to reproxalap or vehicle, self-applied four times daily.

The primary endpoint was change in Schirmer score after the fourth dose on day 1, and the key secondary endpoint was the proportion of patients who had at least a 10-mm improvement in Schirmer score. The results showed a mean improvement of 1.8 mm in the reproxalap group versus a loss of 0.5 mm in the vehicle arm (P<0.0001). Additionally, 16% of patients in the reproxalap group versus 8% in the vehicle arm had a 10-mm improvement (P<0.0001). Ocular discomfort and symptoms were significantly less with reproxalap (P=0.0176).

Combination Outperforms Cyclosporine for Anterior Surface Normalization

Also reported at the meeting, eye drops containing cyclosporine 0.1% and the steroid loteprednol 0.2% (CsA/LE) significantly improved higher order aberrations (HOAs) versus cyclosporine alone, a small randomized trial showed.

After 2 weeks of treatment, patients randomized to the combination had a statistically significant shift toward resolution of HOAs and a more favorable ocular anatomy. The improvement resulted in 60% of patients in the CsA/LE arm qualifying for trifocal intraocular lenses (HOA ≤0.5 µ) at 4 weeks versus 43% in the CsA group.

Patients in both groups had significant improvement in the Standard Patient Evaluation of Eye Dryness (SPEED) score for ocular symptoms (P<0.003 at 2 weeks, P<0.0001 at 4 weeks for CsA/LE, and P<0.01 at 4 weeks for CsA).

"We've done studies in the past on the effectiveness of cyclosporine and lifitegrast, and these products take awhile to work, up to a month to really have the ocular surface in shape for treatment," said John Hovanesian, MD, of Harvard Eye Associates in Orange County, California. "A month may be too long for pre-cataract treatment."

HOAs arise from a variety of factors, including traumatic injury, severe dry eye, ocular surgery, and cataract. The aberrations are associated with multiple vision disorders, such as diplopia, contrast issues, glare, starbursts, halos, and limited night vision.

The investigators hypothesized that the combination of CsA/LE would lead to better, more rapid improvement in HOAs and signs/symptoms of dry eye, as compared with CsA alone. The team enrolled 60 patients and randomized them 2:1 to CsA/LE or CsA. In addition to improved ocular anatomy and SPEED score, tear breakup time improved significantly (P<0.003 and P<0.0001 for CsA/LE at 2 and 4 weeks, and P<0.01 for CsA at 4 weeks).

Nasal Spray for Dry Eye Falls Short in Post-Op Study

Intranasal varenicline (Tyrvaya) for postoperative dry eye failed to improve corneal healing faster than placebo but showed enough promise to warrant consideration of continued study, a small randomized trial showed.

Seven days after treatment, patients randomized to varenicline or vehicle exhibited 100% epithelial healing over baseline in both eyes. The nasal spray led to faster healing during the first 24 hours after treatment, but otherwise the healing rates did not differ during the first 7 days.

Varenicline-treated patients had numerical improvement in secondary endpoints, including symptom score, osmolarity, and tear breakup time at 84 days, and all patients in the varenicline arm discontinued use of artificial tears by day 63, reported Brandon Baartman, MD, of Vance Thompson Vision in Omaha, Nebraska.

"We know the prevalence of dry eyes is common in refractive surgery, and OC-01 [intranasal varenicline] could represent a favorable treatment option, mitigating some of the dry eye symptoms and signs following PRK [photorefractive keratectomy]," said Baartman. "While the results of this study weren't reaching statistical significance, the results did signify directional trends toward benefit of OC-01 for dry eye symptoms. Future work may include a larger sample size that would likely reveal a statistically significant benefit of OC-01 in the treatment of dry eye following PRK."

The FDA approved varenicline nasal spray in 2021 as a treatment option for signs and symptoms of dry eye disease. The drug stimulates natural tear production by activating the trigeminal nerve pathway, increasing production of all three tear-film components, said Baartman. The therapy demonstrated safety and efficacy for dry eye in clinical trials involving more than 1,000 patients.

A total of 50-75% of patients undergoing refractive surgery develop dry eye postoperatively, Baartman continued. The investigators conducted a randomized trial to evaluate the efficacy and tolerability of OC-01 in patients who had undergone PRK. The study involved 41 patients scheduled for PRK. They were randomized and initiated treatment (varenicline or vehicle) 28 days before surgery and continuing to 84 days afterward. Most of the patients had normal dry-eye parameters prior to surgery.

Patients received varenicline or vehicle twice daily. The primary outcomes were change in corneal epithelial healing 7 days after PRK and change in the National Eye Institute Visual Function Questionnaire to day 84.