With positive early phase III data in hand, Clearside Biomedical Inc. plans to file an NDA in the fourth quarter of this year and is probing partnership options outside the U.S. for marketing CLS-TA, a drug-device combo designed to treat patients with macular edema associated with non-infectious uveitis. CLS-TA administers a suspension of the corticosteroid triamcinolone acetonide to the back of the eye via the suprachoroidal space (SCS) with a microinjector.

Shares of Clearside (NASDAQ:CLSD) closed Monday at $10.33, up $2.51, or 32.1 percent, as Wall Street digested the happy news. "We are just receiving our top-line data," which arrived over the weekend, CEO Daniel White said. "We want to go through this information very carefully and, over the next few months, [will] be able to talk more about what we find." Meanwhile, "rather than overstating what we believe we can accomplish," the fourth quarter NDA goal represents "a nice target," he said.

Alpharetta, Ga.-based Clearside said that, in the 160-patient trial called Peachtree, 47 percent of patients given the drug every 12 weeks gained at least 15 letters in best corrected visual acuity (BCVA), as measured using the Early Treatment of Diabetic Retinopathy Study scale, from baseline at week 24, vs. 16 percent of patients who underwent a sham procedure. The improvement, which was the primary endpoint of the trial, was statistically significant (p < 0.001). In BCVA, the mean change from baseline was better in the treatment arm than the sham arm at each monthly evaluation and held true throughout the evaluation period, with 9.6 letters gained at week four and 13.7 letters at week 24 in the active arm, compared to 1.2 letters at week four and 2.9 letters at week 24 in the control arm, respectively.

What's more, CLS-TA resulted in a mean reduction from baseline of 157 microns in central subfield thickness at week 24 in the active arm compared to a 19 micron mean reduction in the sham arm, a result that was also statistically significant (p < 0.001). CLS-TA was generally well-tolerated, with no treatment-related serious adverse events reported in the trial. Through 24 weeks, corticosteroid-related elevated intraocular pressure (IOP) adverse events (AEs) were reported for about 11.5 percent of patients in the CLS-TA treatment group, compared to no patients in the sham group.

Rahul Khurana, an investigator in the Peachtree trial, said during a conference call with investors that uveitic macular edema is a leading cause of vision loss. Local injections with available treatments can lead to IOP problems, and the 11 percent rate in Peachtree "affirms the theoretical benefit" of Clearside's approach, he said. What he found "exciting [about Peachtree] was not only accessing the SCS but really the potential there," especially in patients who need regular injections. "The fact that in the Peachtree trial, they got two treatments in the six-month study and had this pressure profile is very reassuring and is a nice option for us to have in the future," he said, citing more upside in the result that "impact was seen so soon after the first injection." Some treatments take 60 or 90 days to start working, he said.

As for duration of response, compared to options at hand now, he said that "from the data we have, it's hard to make that call."

DME in crosshairs as well

CEO White noted that many other uveitis studies excluded patients with a history of glaucoma or who might be on topical therapy. "It's an important thing to put that into context," he said. "Despite taking these patients that are potentially at high risk for developing pressure, this lower rate is reassuring when you're evaluating this treatment with other treatments out there."

Clearside went public in June 2016, offering 7.2 million common shares priced at $7 apiece to raise $50.4 million. Founded in 2011, the company pulled down a $4 million series A financing the following year from Hatteras Venture Partners to advance the platform, discovered through a multiyear collaboration between the laboratories of Mark Prausnitz, professor of chemical and biomolecular engineering at the Georgia Institute of Technology, and the late Henry Edelhauser, who was professor in the department of ophthalmology at Emory University School of Medicine and director of research for the Emory Eye Center. (See BioWorld Today, June 3, 2016.)

Cowen analyst Boris Peaker last month predicted Peachtree's positive outcome. "To date the company has tested CLS-TA in about 650 administrations to about 400 patients and thus far no serious AEs have been reported," he wrote in a report. "Intravitreal steroid injection is associated with increased IOP and this side effect is particularly concerning clinically, specifically IOP spikes to 40-50 mmHg." Ozurdex (dexamethasone intravitreal implant, Allergan plc), a treatment for uveitis and macular edema, has turned up a 37 percent incidence of any IOP AE and 6 percent of patients with levels of at least 35 mmHg. IOP-lowering procedures, surgical or laser, were used for 1.2 percent of patients in Ozurdex trials. IOP tends to increase with each Ozurdex treatment cycle and return to baseline between cycles.

"We believe that these safety observations for CLS-TA are very important to its approval and commercial adoptions, and will be of high interest to investors," he said.

In November, Clearside offered preliminary data from a phase I/II exploratory trial with CLS-TA for diabetic macular edema (DME) with and without intravitreally injected Eylea (aflibercept, Regeneron Pharmaceuticals Inc.). During the Retina Subspecialty Day of the American Academy of Ophthalmology meeting in New Orleans, results from the Hulk trial showed a visual benefit for patients receiving CLS-TA, with a greater benefit in treatment naïve eyes. Anatomic improvement turned up in all treated eyes, with more than two-thirds of those eyes achieving a greater than 50 percent reduction in excess central retinal thickness based on monthly measurements through six months after initial treatment. In the treatment-naïve group, 40 percent of patients did not require retreatment over the entire six months, with 20 percent needing just one.

DME is the most common cause of vision loss in people with diabetes.

Finding a new way to attack DME has been the ambition, too, of Reykjavik, Iceland-based Oculis SA, which at the start of this year cleared a path for its lead program, OC-118, to become the first non-invasive treatment. The firm raised CHF20 million (then US$20.3 million) in a series B round to enable the finish of an ongoing phase IIb trial and filing of the IND for a U.S. phase III. Success in phase III could lead to approval as soon as 2021, for the first eye drops for treating DME.

OC-118, formulated with nanoparticle delivery technology developed by the scientific co-founders of Oculis, led to a statistically significant and clinically meaningful improvement in visual acuity and a reduction in central macular thickness in two phase IIa trials carried out in Japan. The effect seen in the trials was comparable to that achieved with invasive treatments delivered by intraocular injection or steroid implants, the company said. (See BioWorld, Jan 4, 2018.)

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