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A phase II clinical trial evaluating suprachoroidal CLS-TA used with intravitreally administered aflibercept in patients with diabetic macular edema (DME) over a 6-month evaluation period-has met both primary and secondary endpoints of vision and anatomic improvement.
Tybee-a phase II clinical trial evaluating suprachoroidal CLS-TA used with intravitreally administered aflibercept in patients with diabetic macular edema (DME) over a 6-month evaluation period-has met both primary and secondary endpoints of vision and anatomic improvement, according to Clearside Biomedical in a prepared statement.
Suprachoroidal CLS-TA is a proprietary preservative-free, suspension of triamcinolone acetonide formulated for administration to the back of the eye via the suprachoroidal space.
Clearside has said that the suprachoroidal treatment approach is designed “to enable rapid dispersion of a high amount of medicine” to the posterior segment.
Whereas most studies investigate one drug in each arm, “this approach is unique,” said Charles C. Wykoff, MD, PhD, of Retina Consultants of Houston. “It's using combination therapy in DME patients to determine if we can do better from both an efficacy and durability perspective compared with monotherapy alone.”
On their own, both anti-vascular endothelial growth factor (VEGF) agents and steroids manage exudative retinal diseases, but “a core challenge is that most patients require repeated anti-VEGF injections over long-periods to achieve optimal outcomes,” adding substantially to the treatment burden, Dr. Wykoff said.
Tybee hoped to show that delivering 2 mg of aflibercept on the same day as 4 mg CLS-TA would achieve maximal outcomes while substantially decreasing treatment burden. The study enrolled 71 treatment-naÃ¯ve DME patients with baseline best-corrected visual acuity (BCVA) of 20/40-20/200 and center-involved macular edema of more than 300 Î¼m.
The trial met its primary endpoint of mean improvement in BCVA from baseline over 6 months. Patients in the combination arm gained an average of 12.3 ETDRS letters compared with 13.5 ETDRS letters in the aflibercept alone control arm (p = 0.664).
In this multicenter, randomized, masked, controlled phase II trial patients were randomly assigned 1:1 to receive either quarterly treatments of suprachoroidal CLS-TA together with intravitreal aflibercept (months 0 and 3; the combination arm) or 4 monthly treatments of intravitreal aflibercept plus a sham suprachoroidal procedure (months 0, 1, 2 and 3; the control arm), with patients in either arm receiving intravitreal aflibercept treatment at months 4 and 5 as needed.
The study also met secondary endpoints, with a mean reduction from baseline of 208 Î¼m in central subfield thickness (CST) at 6 months in the combination arm, compared with a 177 Î¼m mean reduction in the control arm (p = 0.156).
Further, 93% of patients in the combination arm had a greater than 50% reduction in excess CST at 6 months, compared with 73% of patients in the control arm.
There were no treatment-related serious adverse events reported through the 24-week evaluation period. Elevated IOP adverse events were reported for 8.3% of patients in the combination arm, compared to 2.9% of patients in the control arm.
Both the combination and control arms reported cataract adverse events, with about 5.6% of patients in the combination arm and 2.9% of patients in the control arm developing or showing progression of cataracts.
Both arms of the study “did well,” Dr. Wykoff said, “and the study met the pre-specified primary endpoint at week 24, which is critical. This trial used a direct head-to-head comparison for similarity between the arms, with a 90% confidence interval for the evaluation.”
From the clinician’s perspective, once a study shows visual outcomes to be similar, a major clinical consideration is treatment burden, because many patients dislike the time commitment needed for frequent injections, he noted.
In the clinic, the durability of a treatment is often defined by anatomic response, Dr. Wykoff said.
“In Tybee, the combination arm performed substantially better at every time point from an anatomic perspective,” he said. “For instance, at month 1, 21% of the control arm (aflibercept-only) demonstrated resolution of fluid, while 47% of patients in the combination arm had resolution of fluid. That’s likely a clinically-meaningful difference.”
Although the difference in resolution narrowed at 6 months (41% in the control arm compared with 59% in the combination arm), outcomes still favored the combination arm.
Dr. Wykoff added that the number of additional aflibercept injections during the PRN phase of the trial also showed a significant difference, with the control arm needing an additional 23 injections compared to 10 injections needed in the combination arm (p = 0.03).
From a safety perspective, “as with any steroid trial, we need to look at IOP elevations,” Dr. Wykoff said. One patient in the control arm and three in the combination arm (2.9% versus 8.3%, respectively) had elevated IOPs.
“Along with the modest signal of IOP elevation, when evaluating for cataracts there was also a slight difference in the two arms,” he said, with one patient in the control arm and two patients in the combination arm developing cataracts.
CLS-TA is also under evaluation for the treatment of retinal vein occlusion (RVO) and non-infectious uveitis (NIU).
In RVO, the phase II Tanzanite study showed the combination arm provided better vision, faster onset of action, and a longer duration of action than treatment with intravitreal aflibercept alone. Clearside just finished enrollment in the phase II Sapphire study, which is evaluating CLS-TA with aflibercept for the potential treatment of RVO.
In the Peachtree trial for NIU patients with macular edema, 47% of patients who received suprachoroidal CLS-TA every 12 weeks gained at least 15 letters in BCVA from baseline at week 24, compared with 16% of patients who underwent a sham procedure. The mean improvement from baseline was maintained throughout the evaluation period, with 9.6 letters gained at week 4 and 13.8 letters at week 24 in the active arm, compared with 1.2 letters at week 4 and 3.0 letters at week 24 in the control arm, respectively.
The company said it plans to file a New Drug Application with the FDA for CLS-TA as monotherapy for the treatment of macular edema associated with NIU.
“The phase II Tybee study met its primary endpoint and the secondary analyses all point toward an anatomic benefit beyond anti-VEGF monotherapy,” Dr. Wykoff said. “These signals support continued evaluation for a potential pivotal phase III program.”
Dr. Wykoff is a clinical investigator for Clearside Biomedical.
1. Campochiaro PA, Wykoff CC, Brown DM, et al. for the Tanzanite Study Group. Suprachoroidal Triamcinolone Acetonide for Retinal Vein Occlusion: Results of the Tanzanite Study. Ophthalmology Retina. 2018;2:320-328.