For our patients with primary open-angle glaucoma (POAG), medical/topical therapy remains our first-line treatment. Yet, we all have patients who are non-adherent or cannot tolerate these medications and others who still have visual field loss despite adequate IOP control. Although we prescribe the prostaglandin class of drugs as first-line therapy, no class of drugs has been able to reverse the visual field loss or disease progression.

As glaucoma specialists, we know substantially more patients will be overwhelming our offices as Americans age. For the time being, topical medications will continue to have a major role in our treatment of patients with POAG.

But, for those patients who have only moderate disease, the potential for surgical intervention with minimally invasive glaucoma surgery (MIGS) devices shows great promise, and many of these devices are approved for use and implantation in the United States at the time of cataract surgery. These devices were developed to address the gap between topical medications and conventional glaucoma surgery. The presumption was that efficacy would not be as good as trabeculectomy or shunts, but have a much better safety profile and adverse event profile as well as the ability to lower the number of topical medications patients need.

For those with more advanced disease who are already on maximal therapy, trabeculectomy is still a viable option.

We need all of these options, but the way that we use them might change. Traditionally, we initiated treatment with topical drugs, then moved onto lasers (laser trabeculoplasty) then surgery. I believe that is no longer a realistic view of treatment. We are going to start seeing very specific treatments, and individualized treatments, depending on the age and severity of disease. Here’s what I mean.

TREATMENT PARADIGMS

If the patient has a visually significant cataract and concurrent mild POAG, MIGS might be a first step. We will start to see more pinpoint utilization of pharmaceutical products rather than just a “this is what we always do first” methodology.

That noted, there are still three big “buckets” of treatment on the shelf:

1. Topical drops (pharmaceuticals).
2. Surgery, including MIGS.
3. “Guided administration of pharmaceuticals,” or GAPS.

I equate this third bucket to coated stents used in cardiology. It is the idea of medicine and surgery starting to blend together. External GAPS (or E-GAPS) include punctal plug delivery (those being developed by Ocular Therapeutix and Mati) or the Allergan bimatoprost ring. These are external “deliverative” medicines. Internal GAPS (or I-GAPS), that is, the internal delivery of medicines, would include the iDose (Glaukos) and Bimatoprost SR (Allergan).

THE BIG BLEND

Allergan has recently reported on Bimatoprost SR, a first-in-class, sustained-release, biodegradable implant designed to lower IOP for at least four months.¹ The first Phase 3 study showed similar efficacy to topical bimatoprost (about a 30% reduction in IOP) but without the compliance issues involved with daily dosing.¹ The second Phase 3 study will have a readout early this year.

The upshot is that the dividing line between straight pharmaceuticals or straight surgical device is blurring. Topical medications will continue to be used, but how we administer the medications may be different. Industry is starting to blend pharmaceuticals and surgical as well. For example, Allergan started as a pharmaceutical company in glaucoma but is now delivering medication via a device. Conversely, Glaukos started as a device company and is now developing products to deliver pharmaceuticals.

This blending is providing a great opportunity for individual clinicians to choose from a large menu with continually increasing offerings. For patients, it provides additional opportunities to receive better individualized treatment.

Pharmaceutical products to treat glaucoma are not going to be displaced by MIGS or another device category. We may deliver them differently, which could improve compliance and and side effect profiles, including reduced corneal toxicity and external lid changes induced by prostaglandins. And, for seniors on Medicare Part D, they could be more affordable — we are all too familiar with the challenges patients face when filling their drop prescriptions.

One last advantage of delivered-internally pharmaceutical product: They could obtain the desired effect with substantially less active ingredient than when the same medication is applied topically.

BEYOND POAG

All of the glaucoma pharmaceutical products approved in the United States are indicated to treat either ocular hypertension or open-angle glaucoma. But, about 20% of people with open-angle glaucoma have low-tension glaucoma. While no restrictions exist for how we prescribe these agents, they do not have a specific indication for low- or normal-tension glaucoma.

Certain classes of medications, however, may be more effective than others in patients with lower starting IOPs. Two examples may be the most recently approved drugs, Vyzulta (latanoprostene bunod, Bausch + Lomb), a nitric oxide-donating prostaglandin analog with a dual mechanism of action, and Rhopressa (netarsudil, Aerie Pharmaceuticals), which is a once-daily therapy. As glaucoma specialists, we may see better patient outcomes simply because our pharmaceutical armamentarium is expanding.

For our patients with angle-closure glaucoma, treatment will likely remain a mix of surgical intervention laser and medications.

The combination of surgery and pharmaceuticals is becoming more individualized and precise. It is becoming more dependent upon where we meet the patient on the continuum of the disease.

FUTURE MEDICATIONS

More treatments are in the pipeline. The furthest along is Rocklatan, Aerie’s netarsudil and latanoprost combination, which has a PDUFA date of March 14 and would be the first combination with a prostaglandin drug in the United States.

Rocklatan has demonstrated incredible efficacy in the Mercury studies in the pivotal trials. For example, in Mercury 2, Rocklatan achieved its primary efficacy endpoint of demonstrating statistical superiority over each of its components, with an additional 1 to 3 mm Hg decrease when compared to either latanoprost or netarsudil throughout the duration of the study.² Plus, Rocklatan reduced mean diurnal IOPs to 16 mm Hg or lower in 56% of patients, a significantly higher percentage than observed in the two comparator arms.²

Another in-the-pipeline drug is Santen’s omidenepag isopropyl. This EP2 receptor agonist has shown a stable IOP reduction over a 52-week period in both open-angle and normal-tension glaucoma, both as monotherapy and in combination with timolol.³ Preclinical and early stage studies found this compound to have significant ocular hypotensive effects.^4-7

One of the potential benefits of this EP2 receptor agonist is that it would provide a similar type of efficacy as a prostaglandin but potentially reduce some of the side effect profiles. For example, iris color change and periorbital pigmentation may occur much less commonly. In addition, there may be responders to EP receptor agonists that don’t respond to prostaglandin FP receptors. Also, a population of patients may do well with this drug and not with prostaglandin.

CONCLUSION

This ever-changing field is introducing more technique and newer classes of drugs to treat our ever-growing glaucoma population. Between the developing trends and new therapies detailed above, we can expect glaucoma treatment to become more interesting as well as more effective. OM

REFERENCES

1. Allergan. Allergan Announces Positive Topline Phase 3 Clinical Data for Bimatoprost SR (Sustained-Release) Implant for IOP Lowering in Patients with Open-Angle Glaucoma or Ocular Hypertension. https://tinyurl.com/y763sagr . Accessed Dec. 21, 2018.
2. Aerie Pharmaceuticals. Aerie Pharmaceuticals Reports Positive Roclatan (netarsudil/latanoprost ophthalmic solution) 0.02%/0.005% Phase 3 Topline Efficacy Results. https://tinyurl.com/y9ojn37c . Accessed Dec. 21, 2018.
3. Aihara M, Lu F, Kawata H, et al. 12-month efficacy and safety study of a novel selective EP2 agonist omidenepag isopropyl in OAG and OHT: the RENGE study. Presented at American Academy of Ophthalmology. Chicago, IL, Oct 27-30, 2018.
4. Iwamura R, Tanaka M, Okanari E, et al. Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl. J Med Chem 2018;61:6869-6891.
5. Fuwa M, Toris CB, Fan S, et al. Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys. J Ocul Pharmacol Ther 2018;34:531-537.
6. Kalouche G, Beguier F, Bakria M, et al. Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci 2016;57:1816-1825.
7. Kirihara T, Taniguchi T, Yamamura K, et al. Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent. Invest Ophthalmol Vis Sci 2018;59:145-153.

About the Author

Jason Bacharach, MD has been a glaucoma consultant in Sonoma County, Calif., since 1993. He is the founding partner and medical & research director of North Bay Eye Associates, Inc., a multi-subspecialty ophthalmology practice, and co-chair of the Department of Glaucoma at California Pacific Medical Center, in San Francisco.
Dr. Bacharach has been a primary investigator in more than 200 Phase 1 through 4 clinical trials in ophthalmology.
Disclosure: Dr. Bacharach is an investigator and/or consultant for Aerie, Allergan, Bausch + Lomb, Glaukos and Santen.