by William Newton in Texas.

Kala Biopharmaceuticals’ ocular steroid Eysuvis (loteprednol etabonate) has a high probability of attaining the US Food and Drug Administration (FDA) approval for acute exacerbation of dry eye syndrome (DES). However, because stringent FDA requirements have led to only three FDA approvals in DES over the past 20 years, there is still a small chance it will receive a rejection or request for additional data.

Although results were mixed in the previous Phase III STRIDE 1 (NCT02813265) and STRIDE 2 (NCT02819284) studies, the primary endpoints and key secondary endpoints were met in the Phase III STRIDE 3 (NCT03616899), which will likely be enough to address any FDA concerns with the previous body of data.

Eysuvis has a 30 October Prescription Drug User Fee Act (PDUFA) date. Previously, an FDA complete response letter (CRL) sent after the STRIDE 1 and STRIDE 2 trials indicated additional efficacy data from a third Phase III trial would be needed for resubmission, according to an August 2019 company press release.

If approved, Eysuvis will likely gain a niche market share among patients who are using steroids to address DES flare-ups due to its more targeted mechanism of action, quicker onset and improved safety profile compared to traditional topical steroids. However, because steroid use is somewhat uncommon for acute DES, there are mixed views on its potential for market uptake among the large patient population not treated with prescriptions for acute DES.

Analyst reports suggest Eysuvis’ approval is likely and forecast strong market uptake among untreated DES patients with acute exacerbations. A GlobalData consensus forecasts peak sales of $1.76bn in 2026. Kala Biopharmaceuticals has a market cap of $446.8m. The company did not respond to a request for comment.

High approval prospects despite earlier mixed trial results

To gain FDA approval, DES treatments must demonstrate statistically significant improvements in both signs and symptoms, experts said. The FDA accepted Kala Biopharmaceuticals’ New Drug Application (NDA) with data from the Phase III STRIDE 3 trial, which found statistically significant improvement in the primary endpoint of ocular discomfort severity (ODS) and the key secondary endpoint of conjunctival hyperemia, according to a 9 March company press release.

Although Eysuvis will likely be approved based on the results from all three STRIDE trials, with its approval prospects standing at 75%, the FDA’s historically strict requirements for DES approval make it impossible to guarantee, said Dr Parag Majumdar, ophthalmologist, Chicago Cornea Consultants, Illinois. Majumdar, a STRIDE 3 principal investigator who has been involved in more than 20 dry eye trials, noted there have been only three DES approvals in the past 20 years, none of which have been for acute DES.

STRIDE 1 and STRIDE 2 both had coprimary endpoints of change from baseline after 15 days in the signs of conjunctival hyperemia and the symptoms of ODS, according to a January 2018 company press release. STRIDE 1 found statistical significance in both primary endpoints while STRIDE 2 only found statistical significance in the signs primary endpoint, the press release said.

Given the STRIDE-3 positive results, the failure to achieve statistical significance in ODS during STRIDE-2 is unlikely to prevent approval, said Dr Michael Korenfeld, a principal investigator in the STRIDE trials and ophthalmologist, Comprehensive Eye Care, Washington, Missouri. Additionally, the different trial design, which features only symptom primary endpoints, is highly likely to have been based on internal discussions between Kala Biopharmaceuticals and the FDA, said Majumdar and Korenfeld.

As a result, the positive findings in STRIDE-3’s primary and key secondary endpoints will likely address any concerns noted by the FDA in the CRL, both investigators agreed. Additionally, because loteprednol etabonate, marketed as Kala Biopharmaceuticals’ Inveltys, is already approved for the treatment of postoperative inflammation and pain following ocular surgery, this adds confidence in Eysuvis’ approval chances, Majumdar said.

The mostly consistent results from all Phase III trials will likely also be important for regulators given the heterogeneity of the DES patient population, added Korenfeld and Dr Preeya Gupta, associate professor of ophthalmology, Duke University, Durham, North Carolina. Similar to STRIDE 1 (n=918) and STRIDE 2 (n=909), STRIDE 3 (n=901) included both a broad intent-to-treat population and a subset population of patients with more severe DES, according to

Patients in all three STRIDE trials received one to two doses of either Eysuvis or vehicle in each eye, administered four times a day for 14 days, according to

Experts mixed on uptake in broader acute DES population

While uptake among acute DES patients who are already using steroids is likely to be strong, experts have mixed opinions on the extent to which Eysuvis can penetrate the broader DES patient population experiencing flare-ups, including the substantial percentage of patients currently untreated with prescription drugs.

Because of its better-targeted mechanism of action and improved safety profile over traditional topical steroids, most experts said Eysuvis will likely replace most topical corticosteroids. Topical steroids can cause intraocular pressure (IOP) in 6–10% of patients in as little as a few weeks, Majumdar said. Eysuvis is distinct from existing therapies because it penetrates the target tissue of the eye to act on conjunctiva and cornea, reducing the risk of IOP, Gupta added.

Adverse event profiles were similar between placebo and Eysuvis in STRIDE 3, with no patients in either group reaching an IOP of more than 21mmHg stemming from an increase of more than 5mmHg. In STRIDE 1, 0.4% of patients in both the treatment and placebo groups experienced this increase in IOP, and in STRIDE-2, this increase was seen in 1.1% of the treatment group compared to none in the placebo group.

Although Eysuvis could gain market share among topical steroid users in DES, its lack of inflammation-related trial endpoints could limit its uptake for the broader DES population experiencing acute flare-ups, said Dr Louis Tong, associate professor, Singapore National Eye Centre. Physicians are typically more concerned with staining and inflammation endpoints over two- to three-month periods rather than the two-week improvements in ODS and conjunctival hyperemia seen in STRIDE 3, he added. Kala Biopharmaceuticals saw significant results for a secondary endpoint of corneal staining after 15 days in the subset of STRIDE 3 patients (p=0.0042), according to a 9 March company press release.

However, Gupta and Korenfeld disagreed, saying most acute DES treatment prescriptions take place after patients seek care for flare-ups. As a result, positive results for relief over a two-week period, according to patient-centric measurements such as ODS and conjunctival hyperemia, are strong indicators for market success, they said.

While analyst reports project it will have the largest market share among patients with acute DES who are only taking over-the-counter medications, Majumdar said its primary patient population will likely be patients who are already on steroids. Eysuvis’ improved safety profile may mean some prescribers will use it as a first-line treatment for patients with acute DES, he said.

Eysuvis will likely only be an adjuvant therapy in conjunction with chronic treatment options such as Novartis’ Xiidra (lifitegrast) and Allergan’s Restasis (cyclosporine), agreed all interviewed experts. Patients with DES can experience acute exacerbations two to three times per year, Gupta said.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.