Kala Pharmaceuticals Inc. plans to use its positive phase III data in dry eye disease (DED) with KPI-121 (loteprednol etabonate ophthalmic suspension 0.25%) as the basis for the resubmission of its NDA in the second quarter of 2020. Shares of the Waltham, Mass.-based company (NASDAQ:KALA) closed 26% higher, or $1.65, at $7.93 on word of top-line results from Stride 3, investigating the compound that Kala hopes to commercialize as Eysuvis.

Stride 3 met both of its primary efficacy endpoints, turning up a statistically significant improvement in the symptom endpoint of ocular discomfort severity (ODS) at day 15 in the overall intent-to-treat (ITT) population (p=0.0002) and in the predefined subgroup of ITT patients with more severe ocular discomfort at baseline (p=0.0007). Statistical significance was also met in the key secondary endpoints of conjunctival hyperemia at day 15 in the ITT population (p<0.0001) and ODS at the eighth day in the ITT population (p=0.0282). Significant results were shown, too, for total corneal staining at day 15 in the ITT population (p=0.0042). Loteprednol, a corticosteroid, proved well-tolerated, with adverse events and intraocular pressure increases comparable to vehicle.

Kala expects a six-month review by the FDA, which in the summer of 2019 smacked Kala with a complete response letter (CRL), asking for efficacy data from another study. The CRL wasn’t much of a shock to some, since Dublin-based Shire plc’s DED therapy, lifitegrast, was run through a similar gauntlet by U.S. regulators. In October 2015, the FDA said it wanted Shire to provide data from another phase III study. As it happened, Shire had just completed one, with data soon rolled out. Lifitegrast came to Shire by way of the $300 million buyout of Foresight Biotherapeutics Inc., of New York, in August 2015. The FDA gave its go-ahead for the drug, branded Xiidra, in July 2016. Osaka, Japan-based Takeda Pharmaceutical Co. Ltd. gained Xiidra in the takeover of Shire, but sold the drug to Novartis AG, of Basel, Switzerland, in May 2019. Also available for DED is Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan plc).

The original NDA for Eysuvis-to-be included data from one phase II and two phase III efficacy and safety trials, Stride 1 and Stride 2, in about 2,000 DED patients. In Stride 1, statistical significance was achieved for the primary sign endpoint (conjunctival hyperemia change from baseline to day 15) in the ITT population (p<0.0001) and the primary symptom endpoint (ODS change from baseline to day 15) in the ITT population (p<0.0001). In Stride 2, statistical significance was hit for the primary sign endpoint in the ITT population (p<0.0001), but not for the primary symptom endpoint in the ITT population (p=0.1298). Inclusion and exclusion criteria were modified to better Stride 3’s chances of doing what the FDA seemed especially interested in, i.e., hitting the symptom endpoint. It did.

Kala won approval in 2018 of Inveltys (loteprednol etabonate ophthalmic suspension 1%) to treat inflammation and pain following ocular surgery. During Kala’s conference call with investors regarding data on Eysuvis, J.P. Morgan analyst Christopher Schott wanted to know more about the strategy with the latter drug if it’s approved – whether the company would first take aim at about 500,000 patients already using off-label steroids and then broaden the push or go for the whole enchilada right off. Chief Operating Officer Todd Bazemore said he believes the firm can pursue “the entire market straight away. Certainly, you would expect very rapid early adoption from patients that are already using or have used corticosteroids in the past for their DED, but we believe from our interactions with both patients and physicians and market research that we will very quickly be able to penetrate into the over-the-counter market as well, because the vast majority of those patients are already visiting an eye care professional” on average two to three times per year, “and almost half of the office visits that they show up for is because they are experiencing a DED flare. Currently, there is no FDA-approved short-term treatment for those patients.” About 33 million people suffer from DED in the U.S., “of which over 17 million have been diagnosed and are managed by an eye care professional. Quantitative market research study suggests that approximately 80% to 90% of these patients experience episodic dry eye flares, rather than continual symptoms.”

On the subject of potential partnerships, CEO Mark Iwicki said that, in the U.S., the commercial infrastructure is already built, “and it's a terrific team of really experienced ophthalmology sales professionals, leadership, management, marketing – all across the board. I think we're really well poised to launch Eysuvis ourselves. Of course, we're always open to evaluating opportunities, but right now, our plans are to do this inside the U.S. In Europe, we've had several conversations with regulators, and those have been positive conversations. We've been waiting for this trial to come in, and we're going to continue to advance those discussions as well. I think on the backs of having a clear line of sight as to the opportunities in Europe, we will also be really interested in seeking out any potential partnerships for the European market.”

Among other players in DED is Palatin Technologies Inc., of Cranbury, N.J., which said Feb. 19 that it had enrolled the first patient in a phase II trial testing PL-9643, a melanocortin 1/5 receptor agonist that would attack DED “at the core, not just symptoms,” said Wainwright analyst Joseph Pantginis. “By being designed to treat both the signs of the eye damage and the physical symptoms experienced by patients with DED, PL-9643 may significantly benefit the market by offering a differentiated profile based on optimal safety without discomfort, which should increase patients’ compliance; comparable if not higher efficacy than commercially available drugs; and overall faster activity, which should favor the adoption,” Pantginis wrote in a report as the phase II study began.

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