Clearside Biomedical sets sights on suprachoroidal drug delivery

(Image Credit: AdobeStock/Sergey Nivens)

Clearside Biomedical, Inc recently hosted a virtual key opinion leader (KOL) event focusing on applicability and real-world experience with suprachoroidal drug delivery, the suprachoroidal space (SCS) as a differentiator in the retinal treatment landscape with a focus on neovascular age-related macular degeneration (wet AMD), and ongoing SCS clinical programs, including potential future development opportunities for the company.

KOL speakers included Glenn Yiu, MD, PhD, professor of ophthalmology at the University of California, Davis and a member of Clearside Biomedical’s scientific advisory board; Victor Chong, MD, MBA, chief medical officer for Clearside Biomedical; and David Brown, MD, director of research at Retina Consultants Houston in Texas.

Clearside President and CEO George Lasezkay, PhD, JD, also participated in the session.

Lasezkay pointed out the company’s focus is delivering on the potential of suprachoroidal drug administration.

“Our proprietary SCS Microinjector has been used in thousands of clinical injections to date,” he said. “Our injection platform has been validated in several ways. We’ve developed the first and only product to receive FDA approval for suprachoroidal administration. We’ve established multiple strategic collaborations with companies that have technologies or expertise that we don’t possess internally.”

In addition to its SCS Microinjector platform, Lasezkay said the company has formulation experience with small molecules for suprachoroidal delivery.

“We have extensive experience in drug device combination regulatory pathway, as evidenced by our track record of obtaining approval from the FDA [for] the first and only SCS-administered product, Xipere [triamcinolone],” he said. “And finally, we received a permanent CPT [Current Procedural Terminology] code for SCS injections to aid physician reimbursement for the use of suprachoroidal products.”

The company also detailed its pipeline, with the development of internal products, strategic partnerships, and CLS-AX, its phase 2b wet AMD product.

Xipere, which was the first product approved for suprachoroidal administration, is currently being commercialized in the US by Bausch+Lomb, and they are currently seeking Canadian approval for the product.

Lasezkay further pointed out the company has 3 key SCS Microinjector collaborations.

Aura is using its viral-like drug conjugate for the treatment of choroidal melanoma. They are exclusively using the SCS Microinjector in an ongoing, global phase 3 trial for the treatment of choroidal melanoma.

REGENIXBIO Inc and AbbVie have recently completed 2 phase 2 studies in diabetic retinopathy as well as wet AMD using Clearside Biomedical’s microinjector, administering their gene-based therapy RGX-314 for both those indications.

Clearside Biomedical’s most recent collaborations with BioCryst focused on the formulation of its small molecule, a plasma kallikrein inhibitor, which they hope to administer suprachoroidally.

Yiu focused on the real-world use of suprachoroidal delivery, a passion of his since he was a fellow more than a decade ago.

Yiu explained that subretinal injections, which are often used for treatments such as gene therapy, require complex vitreoretinal surgery.

“But the suprachoroidal space can be accessed either with microneedles, such as the product from Clearside [Biomedical], or with microcatheterization, which is also a surgical procedure where you extend the cannula through the wall of the eye,” he said.

In recent years, Yiu noted, researchers have demonstrated that when ophthalmologists do a suprachoroidal injection, they can visualize that drug entering that space. First, with work from Charles Wykoff, MD, PhD, showing from anterior segment optical coherence tomography (OCT).

Suprachoroidal triamcinolone acetonide has been tested across a variety of retinal conditions, but Yiu noted that findings from the phase 3 PEACHTREE study (NCT02595398), which randomized 160 patients with uveitic cystoid macular edema to either suprachoroidal triamcinolone vs sham control, demonstrated functional efficacy, where you can see patients who received the treatment gained vision compared with sham and low rates of rescue out to past 6 months.

Yiu also detailed some of the considerations when giving a suprachoroidal injection in the real-world setting.

“First of all, patient selection is important,” he said. “We try to be more mindful of patients who have high myopia or may have evidence of scleral thinning.”

Moreover, Yiu said he would try to err on the side of using the shorter needle.

“[For] things like a history of glaucoma, ocular surgery, particularly if they’ve had a shunt or a tube in the area where you’re injecting, you might want to be mindful of [those],” he said.

Yiu also said he believes setting expectations is most important, at least in his experience.

“Patients who have a history of an intravitreal injection can’t assume this will be a 2-second thing and run out the door like [they would with] an intravitreal injection,” he explained. “I will usually explain to them, ‘It’s going to take a longer period. We have to set you up, and we might have to consider switching needles, and there will be a lot of pressure when the injection is given.’ So I usually tell them that they’ll have the sensation of a pressure wave. It’s not a sharp pain, but…some people call it an ‘ice cream headache.’”

The product comes in 2 needle lengths: 900 μm and 1100 μm.

“We generally prefer the superotemporal to inferotemporal because it’s easier from an ergonomic standpoint, coming from the patient side,” Yiu said. “And this is pretty much the same as what we would do for an intravitreal injection. In both the clinical trials and in most previous studies, a majority of injections can be successful with just a short needle from the superotemporal location, where the sclera is a little bit thinner, a majority of the time.”

Yiu added that a research team he was involved with recently published what they consider to be consensus expert guidance on the best practices for doing these injections.

“Critically, because this is a very short needle, so the more perpendicular you are, the more likely you will access the space more readily and use the full length of the needles of holding the injector perpendicular to the surface is important,” he said.

The procedure requires dimpling and maintaining firm contact during the injection to maintain access to the space and slowly inject it.

“That’s one of the key criteria to minimize discomfort, because usually, any reports of pain or discomfort are because the provider is injecting it a little too quickly,” he said. “And it’s that first of the fluid entering the space. [When] applying it slowly and steadily, many of my patients have been very comfortable with that.”

Yiu added that all the intravitreal biologics have failed for the treatment of geographic atrophy (GA) and that the only ones currently approved are small molecule or aptamers, RNA aptamers, for blocking complements.

“Theoretically, GA is one of those diseases where patients are not interested in repeated treatments, whereas for wet AMD, you are doing an injection, you do OCT, you look at the product [and] the treatment response and you can make a decision to inject or not inject based on them,” he said. “With dry AMD and geographic atrophy, you are just injecting on a regular basis with the hope that it will give you some treatment effect in the long run and you don’t get that personal feedback for every patient.”

And because of that, for GA, it makes more sense to use a gene therapy, where it’s a one-time treatment; you set it and forget it. Yiu said many of these patients are older than typical patients with wet AMD.

“They don’t want to come in for frequent injections,” he said. “So theoretically, a biofactory approach that generates a product that can be helpful for GA will be very important.”

Yiu explained that intravitreal injections generally cause more ocular inflammation, which has been a major limitation for the development of intravitreal gene therapies.

“Subretinal injections, even for wet AMD, have been difficult for patients to accept. It’s still a surgery. It requires vitrectomy,” he said.

Chong shared Clearside Biomedical’s plans over the next few years, pointing out that suprachoroidal injection is potentially safer than intravitreal injection and that researchers believe it has close to no risk of endophthalmitis, an uncommon but serious infection of the eye after intravitreal injection.

“When CLS-AX is approved in a few years’ time, Vabysmo [faricimab] and Eylea [HD; aflibercept] are likely to be the market leader, at least in terms of revenue,” he said. “And we believe patients [with] wet AMD have individual needs, and after the initial loading dose, CLS-AX can be used as a maintenance therapy 2 to 3 times a year in almost all patients [compared with] 3 to 4 times a year in patients with Vabysmo or Eylea [HD]. In terms of the number, [that] might not sound [like] very much, but we were encouraged by the uptick of Vabysmo, showing only a small-duration benefit of Eylea can be rewarded.”

Chong also noted that CLS-AX has flexibility similar to a biologic.

“We are now planning to develop a phase 3 study, which will allow retina specialists to use CLS-AX as a replacement of Vabysmo or Eylea [HD] in the real-world setting,” he said.

Adding to the potential advantage of no risk or very low risk of endophthalmitis as well as CLS-AX is a small molecule.

Chong also detailed the phase 2b ODYSSEY trial (NCT05891548), which featured 60 patients randomly assigned in a 2:1 ratio for comparing CLS-AX with on-label aflibercept.

“CLS-AX can be used again earlier from week 12, if needed, based on selectivity assessment,” Chong said. “However, if there are no disease activities assessed that were detected by week 24, every patient in the CLS-AX group will be redosed at week 24, and our primary end point is at week 36. And we believe that is very important.”

Moreover, Chong noted that each patient in the CLS-AX group will be redosed at least once.

“As wet AMD is a current condition, it is critical to understand the effect of redosing. And it is risky to move to phase 3 without any redosing data in phase 2,” he said. “And we will be the only company using TKI [tyrosine kinase inhibitor] for wet AMD to have those data at phase 2. And we will have those data based on this year.”

The company completed recruitment in December 2023, and every patient has completed 6 months of treatment. As a result, each patient in the CLS-AX group has received at least 2 doses of CLS-AX.

Gauging success, Chong said the team would expect no drug-related serious adverse effects for safety. When it comes to efficacy, the majority of patients in the CLS-AX group should be able to reach week 24 without retreatment.

“We believe that BCVA [best-corrected visual acuity] and CST [contrast sensitivity testing] should be similar in most visits to the aflibercept control arm, in particular at week 24 and week 36,” he said.

Chong added that it is logical for Clearside Biomedical to expand its pipeline into GA.

“Geographic atrophy is more common than wet AMD, so we believe the market size can be larger than [that of] wet AMD,” he said. “It is exciting to have 2 FDA-approved products, but their efficacy can be improved.”

Chong added the company sees a lot of advantage for suprachoroidal delivery in GA.

“We believe suprachoroidal delivery can reach the choroid first, providing the highest drug level, and as geographic atrophy is a primary choroidal disease, that might improve efficacy. And furthermore, small molecule can treat RPE [retinal pigment epithelium] and retina because small molecule can readily diffuse through the Bruch membrane.”

Chong also detailed that suprachoroidal sterile suspension has already demonstrated duration of 6 months.

“We have seen low risk of inflammation, and some of our efficacy have already seen in our partner in gene therapy delivery anti-VEGF,” he said. “And furthermore, we have seen the level of inflammation with suprachoroidal gene therapy is also significantly lower than [that with] intravitreal.”

Chong added there is a need for better understanding of the potential target pathway of GA.

“Clearside [Biomedical, by] looking into the changes in the choroid in several groups, has identified specific immune cells present around geographic atrophy lesion, mast cell, microglia cells, and macrophages,” he concluded. “So targeting damaged cells, to me, is low-hanging fruit.”

Brown pointed out that whether performing a routine procedure or working in the operating theater, retinal surgeons must learn how to work more quickly.

“[For] the suprachoroidal injection, the first time you do it, you do have some nuances,” he explained. “I did several hundred, and it doesn’t take me much longer than an intravitreal injection.”

For the patient, it is just a small part of the entire process, and Brown said he has been able to become more efficient in his clinic.

“Our average visits, we’re happy if we can get them below an hour and a half,” he said. “This implies that my visits are 40 minutes. And even then, injection as a percentage of the whole time is a very small fraction of that. It’s even smaller in real life.”

In his experience with drug trials, Brown pointed out that if there is confidence that the drug works, it should have a real-world treatment criterion.

“A treatment criterion that’s more real-world is what you need to know if your drug works,” he said. “In a trial, we’re totally comfortable seeing patients more frequently and having tighter criteria because it’s better care for the treatment. Again, we’ve got good drugs out there. Faricimab is a great drug. Aflibercept 8 mg is a good drug. But you have no idea how many patients can go 12 weeks or even 8 weeks if you rely on patients having…preset criteria that are nowhere near what we do in the clinic.”

Brown added that a lot has been learned from injections. Although the average patient can have 8-week dosing, he noted that in his clinic, 40% to 50% needed 4- or 5-week dosing.

“Why is that?” he asked. “I made a pretty good case at Retina Society and in the poster I showed at ASRS [American Society of Retina Specialists] that the main reason with our clinicians is drug clearance.”

Brown explained that if you look at the faricimab filing data, 10% of the patients have a half-life less than 5 days and 10% of the patients have a half-life of more than 11 days.

“And if you have patients with a long half-life, they can go 8, 10 weeks with 2 mg aflibercept,” Brown said. “However, if you [have] a 5-day half-life, you are barely going 28 days with either faricimab or aflibercept. Eight milligrams would give you, by definition, 2 extra half-lives for that patient with a 5-day half-life that’s only 10 extra days.”

Brown also discussed adaptation issues when CLS-AX is approved.

“From our perspective, if you can get these patients who are requiring faricimab every 4 weeks or 5 weeks…to 12 weeks, they’ll put up with whatever it takes,” he said.

Brown noted that the procedure is straightforward and easy. Generally, it is not much different from an intravitreal procedure.

“You have some patients who don’t want to look the way you want them to look, or they have very tight lids, or they have very thick sclera and [you] have to change the needle; [that’s] where it does take a little more,” Brown said. “But if we’re doing this injection 10 times, 15 times a day, it will become as routine as an intravitreal injection.”