Looking Back, Moving Forward

As a glaucoma specialist, I’ve really enjoyed seeing the significant advancement and proliferation of technology over the last few years, both in diagnostics and treatment. And 2018 was no exception. We have seen approvals for new topical glaucoma medications, approvals of new MIGS devices, and recent publications demonstrating new technologies that make it easier to identify glaucoma patients much earlier in the disease.

Over the last few years, there has been an emphasis on earlier detection – and understanding which patients are higher risk of glaucoma progression. A landmark 2018 study looked at the role of corneal hysteresis (CH) as a risk factor for developing glaucoma. (1) With increasing age, both the cornea and the lamina become more rigid and less resilient. The Reichert ocular response analyzer (ORA) (Ametek Reichert Technologies, Depew, NY, USA) measures CH and has been associated with progressive visual field worsening in glaucoma patients. Though earlier studies have demonstrated the link between low CH, glaucoma and response to topical medications, I consider the paper by Carolina Susanna and colleagues to be a landmark study as it is one of the first prospective and longitudinal studies to support the role of CH as a risk factor for developing glaucoma. In our clinical practice, we often use CH to help decide i) if we should initiate treatment in a glaucoma suspect, and ii) how aggressive the treatment should be, regardless of disease severity; after all, the study showed that lower CH measurements were significantly associated with increased risk of developing glaucomatous visual field defects over time.

Along the lines of earlier detection of glaucomatous optic neuropathy, another article published in 2018 caught my attention (2). Glaucoma patients are often diagnosed and treated when irreversible loss of visual function has occurred. Early detection – and therefore appropriate early treatment – are clearly best for such patients. A novel technology called Detection of Apoptosing Retinal Cells (DARC) allows real-time in vivo quantification of apoptosing cells through the use of a fluorescent biomarker and a confocal scanning ophthalmoscope. A recent Phase I clinical trial evaluated the safety of DARC and its ability to detect retinal apoptosis in glaucoma patients and healthy volunteers. Results demonstrate the potential benefits of DARC in the early detection of glaucoma.

In more detail, DARC uses an intravenous injection of an infrared fluorescently labeled ANX (ANX776), followed by retinal imaging using specific wavelengths with the use of a commercially available confocal scanning laser ophthalmoscope (cSLO) and indocyanine green angiography settings. In the Phase I trial, half of the enrolled subjects were eight healthy volunteers and the other half were eight patients with progressive glaucoma. Although the trial was designed primarily to assess the safety and tolerability of ANX776 in patients, it showed that the DARC count was significantly increased in glaucoma patients, compared with healthy volunteers. Furthermore, the DARC count correlated with increasing rates of glaucomatous progression. Phase II trials are underway.

MIGS approvals in the USA

As we have seen, the MIGS space has grown tremendously over the last few years. And 2018 saw the approval of two new MIGS devices. The iStent Inject, which gained FDA approval in the summer, now allows for the implantation of two 0.23 mm x 0.36 mm microstents through the trabecular meshwork (TM) into the Schlemms canal. These devices optimize the natural physiological outflow of aqueous humor by creating two patent bypasses through the trabecular meshwork. The iStent inject cohort achieved a 31 percent mean IOP reduction, or 7.7 mmHg, in unmedicated IOP from an unmedicated mean baseline IOP of 24.8 mmHg to 17.1 mmHg. Also, at 24 months, the overall rate of adverse events for the iStent inject cohort was similar to cataract surgery alone.

Another MIGS approval was the Hydrus microstent. The device not only bypasses TM resistance, but also scaffolds approximately 90 degrees of the patient’s Schlemms canal. The FDA’s approval was based on the 24-month results from the largest MIGS trial to date: HORIZON. The study included 556 mild-to-moderate glaucoma patients randomly assigned to undergo cataract surgery with or without the microstent. More than 77 percent of patients with the implant exhibited a significant decline in unmedicated IOP, compared with 58 percent of the control group. On average, the device reduced IOP by 7.5 mmHg, approximately 2.3 mmHg more than the cataract surgery-only group. Safety was similar to the cataract-only group.

Both of these devices appear to be effective at eliminating or reducing medications, compared with cataract surgery alone. Reducing the medication burden is a key factor when analyzing the effectiveness and overall benefits of MIGS devices.

Since the withdrawal of the Cypass stent, there has been a void in the supraciliary space. Fortunately, there are two other devices undergoing trials, one of which finished enrollment in its IDE trials back in 2017. The iStent SUPRA prospective, randomized clinical trial includes 36 sites and 505 subjects with mild-to-moderate primary open-angle glaucoma and cataracts. Subjects were randomized to receive either iStent SUPRA in combination with cataract surgery or cataract surgery alone. The study has a 24-month primary outcome measure of a 20 percent or greater reduction in intraocular pressure (IOP) from baseline.

Another company, iStar Medical, recently published one-year results of its first-in-human MIGS trial for the MINIject device in a standalone setting. The iStar MINIject system has a medical grade silicone device with precision-pore geometry in a soft, flexible, tissue-friendly material. The company claims exceptional biointegration of the device with surrounding tissue colonizing the porous structure, while preserving in vivo drainage efficacy. The STAR-I trial is a prospective, open, international, multi-center study in which MINIject was implanted in 25 patients with mild-to-moderate primary open angle glaucoma uncontrolled by topical hypotensive medication. Minimal encapsulation was observed, as shown by the absence of a continuous surrounding fibrous capsule, continuous macrophage, and a continuous fibroblast layer. After one year, the STAR-I trial in a standalone setting demonstrated an average 32.6 percent IOP reduction to a mean of 15.6 mmHg at one year. In addition, 75 percent of patients were able to discontinue topical medication usage and remained medication-free at one year. There were no serious ocular adverse events and no patients required subsequent glaucoma surgery. There was minimal change in mean ECD between baseline and one year.  The company will start enrolling subjects in the US sometime in the middle of 2019 for the refractory population.

Medication approvals and commercialization

With the introduction of MIGS, mechanism of action has started to gain more and more traction. We are now paying more attention to outflow resistance and addressing the site of pathology. With this in mind, the approval and commercialization of two new pharmaceuticals was a significant advance in 2018. Both Rhopressa (netarsudil ophthalmic solution 0.02 percent) and Vyzulta (latanoprostene bunod 0.024 percent) were approved for the reduction of intraocular pressure. These drugs are unique as they both demonstrate activity that helps improve outflow through the conventional outflow pathway (the primary site of resistance in POAG patients). There is a possibility these drugs may decrease further pathology in the conventional outflow pathway and may also have a synergistic role with MIGS devices. The added benefit of these eye drops is that they are qd dosing. The introduction of both these new medications and the proliferation in micro-invasive glaucoma surgery have truly inspired a renaissance in the field.

Drug delivery has been a hot topic in the last few years. Three approvals in the cataract surgery space this year have spurred excitement among my colleagues. Dexycu, INVELTYS, and Dextenza are steroid medications that have been approved to reduce postoperative pain and/or inflammation. Dexycu is the first long-acting intracameral product approved by the FDA for treating inflammation following cataract surgery injecting a proprietary drug delivery technology (Verisome) dexamethasone under the iris at the end of the case. In approval studies, a single dose of 5 mcL of Dexycu (equivalent to 517 mcg of dexamethasone), a dose equivalent to 342 mcg of dexamethasone, or a vehicle placebo was administered by the physician at the end of the surgical procedure. The percentage of patients with anterior chamber clearing at day 8 was 20 percent in the placebo group, and 57 percent and 60 percent in the 342 and 517 mcg treatment groups, respectively. The percentage of subjects receiving rescue medication of ocular steroid or nonsteroidal anti-inflammatory drugs was significantly lower on days 3, 8, 15, and 30 in the 342 and 517 mcg treatment groups, compared with placebo.

INVELTYS (loteprednol etabonate) 1 percent ophthalmic suspension is the first ocular steroid approved for twice-daily dosing for post-op pain and inflammation; other ocular postoperative topical steroids are approved for four times daily dosing. INVELTYS uses mucus-penetrating particle (MPP) technology to improve penetration into target tissues of the eye. The technology has demonstrated a greater delivery of the drug into ocular tissues versus current loteprednol etabonate-containing drugs. Data from two Phase 3, multicenter, randomized, double-masked, placebo-controlled trials showed a greater proportion of patients treated with Inveltys having complete resolution of ocular inflammation at day 8 (24 percent vs 13 percent) and day 15 (50 percent vs 27 percent), and complete resolution of pain at day 4 (43 percent vs 25 percent), day 8 (56 percent vs 36 percent), and day 15 (69 percent vs 48 percent) versus placebo (P for both <0.01). In addition, treatment was well-tolerated with no treatment-related serious adverse events reported. INVELTYS will be available as a 1 percent suspension in 5 mL bottles.

Dextenza (dexamethasone ophthalmic insert 0.4 mg) is the first FDA-approved intracanalicular insert to deliver dexamethasone to treat postoperative ocular pain for up to 30 days with one treatment. The device releases drugs into the anterior segment for three to four weeks, and may obviate the need for topical steroids. In two randomized, vehicle-controlled phase 3 studies, a statistically significant number of patients who received Dextenza were free of pain eight days after cataract surgery compared with patients in the vehicle control group. In addition, safety was demonstrated in the two phase 3 studies, as well as a third randomized, vehicle-controlled phase 2 study. Ocular Therapeutix applied for transitional pass-through payment status and intended to apply for a J-code before the January 2019 deadline.

Literature reveals that up to 31 percent of cataract patients have had difficulty inserting drops, and 92 percent used improper techniques. Many of our patients deem the post-op drop regimen the main cause of discontent post cataract surgery. These three approvals benefit patients by decreasing compliance issues and dosing errors associated with the current common post-op regimen of relying on the patient placing drops more frequently following cataract surgery.

In August 2018, the FDA approved the first drug for the treatment of neurotrophic keratitis, Oxervate (cenegermin). Although the prevalence of neurotrophic keratitis is low, it can be a devastating disease. The safety and efficacy of Oxervate, a topical eye drop containing cenegermin, was studied in a total of 151 patients with neurotrophic keratitis in two, eight-week, randomized controlled multi-center, double-masked studies. All eye drops in both studies were given six times a day in the affected eye(s) for eight weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated bilaterally. Across both studies, complete corneal healing in eight weeks was demonstrated in 70 percent of patients treated with Oxervate, compared with 28 percent of patients treated without cenegermin (the active ingredient in Oxervate).

Industry news

Omidria (phenylephrine 1 percent and ketorolac 0.3 percent intraocular solution) received a two-year reinstatement of pass-through status by the CMS that went into effect on October 1. It was important to allow access to the drug until a permanent code is established. The two-year extension was passed into law in March as part of the Consolidated Appropriations Act of 2018. It will remain in effect until October 1, 2020. Omidria is the only FDA-approved product for use during cataract surgery or IOL replacement to maintain pupil size by preventing intraoperative miosis, and to reduce postoperative ocular pain.

Zeiss’ acquisition of Iantech was an exciting announcement at the end of 2018. Iantech is well known for its nuclear disassembly device, the miLOOP, and the company has been working on a new technology to disassemble and remove the cataract from start to finish, without the use of cavitation and phaco energy. The device will likely force the whole industry to re-evaluate the cataract surgery process from a cost, flow, and physics perspective. The Zeiss acquisition also reaffirmed the company's desire to get more involved in the treatment side of the cataract surgery, rather than diagnostics alone.