You could say getting drugs to the back of the eye has been retina specialists’ Everest, but that wouldn’t be fair to the Sherpas who guide climbers up world’s highest summit. After all, thousands have stood on that summit, whereas the best solution science has had for getting drugs to the retina is intravitreal administration of anti-VEGF agents and corticosteroids. That typically involves serial injections because the concentration of the drug dissipates in the vitreous and washes out over time.
Clearside Biomedical (Alpharetta, Ga.) is taking a different route to the back of the eye—that is, via the suprachoroidal space. While not at the summit, it is somewhere on the mountain. Clearside uses a proprietary injector that penetrates the sclera, to uniquely access the suprachoroidal space, depositing a proprietary suspension formulation of triamcinolone acetonide. Called CLS-TA, the platform has been in multiple clinical trials, but the most noteworthy so far is the Phase II trial in noninfectious uveitis, which Steven Yeh, MD, reported on at the 34th annual meeting of the American Society of Retina Specialists in San Francisco.
In the trial, 22 eyes of 22 people with macular edema associated with noninfectious uveitis each received a single suprachoroidal injection of CLS-TA—a 4-mg dose in 17 people and an 0.8-mg dose in five. The primary efficacy endpoint was reduction in central subfield thickness, which averaged a 164-μm change from baseline (p=0.002) in the 4-mg group. The trial was only powered for the higher 4-mg dose and achieved a secondary efficacy endpoint—an average gain of 9.2 letters in best-corrected visual acuity from baseline. As for safety endpoints, no subjects showed steroid-induced increases in intraocular pressure or serious adverse events in this study.
“The outcomes from our Phase II trial provide preliminary evidence that CLS-TA has a positive effect in subjects with uveitis when it was administered suprachoroidally,” says Glenn Noronha, PhD, chief scientific officer of Clearside. Here, Dr. Noronha provides insight into CLS-TA.
The mechanism of action in his own words:
Triamcinolone is a synthetic glucocorticoid with known anti-inflammatory and immunomodulatory properties, so the effect of this molecule in uveitis is reasonable. Specific to reduction of macular edema, there is speculation about suppression of vascular endothelial growth factor expression and restoration of the blood-retina barrier playing a role. None of the mechanistic aspects of how CLS-TA works in noninfectious uveitis will be unique in our product.
What is unique is not how CLS-TA works, but that in this approach to therapy the drug is administered through the suprachoroidal space, and that there is potential to provide safe and efficacious treatment as seen from the results of this trial. CLS-TA apparently achieves adequate ocular levels in the retina and choroid over the time period of the trial, and that could explain the efficacy reported in this Phase II study.
Why target macular edema in noninfectious uveitis?
Macular edema is the dominant cause of vision impairment and loss in uveitis. This trial targeted macular edema due to uveitis because of a unique opportunity to treat subjects with any etiology of uveitis, and with disease affecting any geographic location in the eye including anterior, intermediate, posterior and panuveitis.
The presumed advantages of suprachoroidal injection:
The advantages span from efficacy and duration, as well as the possibility for better safety. What happens after suprachoroidal administration of the drug is that it distributes dominantly into the retina and choroid, sparing the anterior chamber. Concentrations are high in the relevant parts of the eye, providing potential for good efficacy. Clinical trial data have been consistent with that expectation so far.
How the unique injector works:
The injector itself uses a needle about 1,000 μm in length. The sclera has a limited capacity to expand on account of its structure, and therefore injection of fluid through a needle into the sclera encounters resistance. However, as a needle extends towards the base of the sclera, resistance to expansion of the region between the base of the sclera and the underlying choroid—the suprachoroidal space—is far less. As a result, fluid containing the drug enters the space. Tactile and visual feedback assist in completing the injection.
Following suprachoroidal injection, fluid flows posteriorly and absorbs dominantly in the choroid and retina within minutes, based on observations from preclinical ex vivo models and animal studies. The expectation is that a rapid and selective distribution of drug would occur in human eyes in a similar manner to that seen in preclinical studies. The procedure has been relatively straightforward in more than 50 human subjects who have received these injections in Phase I/II studies.
The take home of the Phase II trial:
The trial observed good and consistent efficacy that includes visual acuity improvement and macular edema reduction; the objective is to see if a larger patient population will continue to show similar results when CLS-TA is dosed suprachoroidally to treat uveitis.
The big question the Phase II trial answers:
This study was a controlled, masked, randomized study that met the primary endpoint, which was a significant reduction in macular edema. Visual acuity also improved.
In uveitis, the trial showed that the suprachoroidal space is drugable and that there is potential to develop therapies by administering drugs through this space. The intention is to systemically define advantages of treatments via the suprachoroidal space through systematic developmental efforts. So the big question is, can you dose human eyes through the suprachoroidal space in this and other ocular disease states using CLS-TA and with other agents, and can you effectively treat eye diseases in this manner?
The next steps:
The first next step, a Phase III trial in uveitis, is currently enrolling. The second next step is to look at other disease conditions. To that end, a Phase II trial in retinal vein occlusion has already been completed. Those data will be shared soon for the first time. RS