GLAUCOMA & THE ROLE OF NITRIC OXIDE

GLAUCOMA & THE ROLE OF NITRIC OXIDE

September 27, 2021

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Catalyzed by endothelial nitric oxide (NO) synthase (eNOS) activity, NO is a gaseous signaling molecule maintaining endothelial and cardiovascular homeostasis.

Principally, NO regulates the contractility of vascular smooth muscle cells and permeability of endothelial cells in response to either biochemical or biomechanical cues.

In the conventional outflow pathway of the eye, the smooth muscle-like trabecular meshwork (TM) cells and Schlemm's canal (SC) endothelium control aqueous humor outflow resistance, and therefore intraocular pressure (IOP).

The mechanisms by which outflow resistance is regulated are complicated, but NO appears to be a key player as enhancement or inhibition of NO signaling dramatically affects outflow function; and polymorphisms in NOS3, the gene that encodes eNOS modifies the relation between various environmental exposures and glaucoma.

Nitric oxide (NO), a small molecule generated ubiquitously, targets a plethora of tissues to regulate both physiological and pathophysiological functions.

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NO overproduction, stimulated by microenvironmental conditions, is the main component that dysregulates the tight balance between its beneficial and damaging roles in ocular homeostasis.

Considering the protective functions of NO against glaucoma, its endogenous release facilitates aqueous humor drainage and regulates ocular blood flow, maintaining a normal intraocular pressure.

NO overproduction generates free radicals, such as peroxynitrite, which induce a vicious circle of vascular disharmony and dysregulation, transient ischemia, nitrosative stress, neuronal degeneration, and permanent glaucomatic injury

Helicobacter pylori (Hp) is considered a burdening factor of glaucoma. NO overproduction and possible systematic dispersion in Hp infection (Hp-I) could suggest a potential pathophysiological bridge between these conditions.

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NITRIC OXIDE

What is nitric oxide?

Endogenous signaling molecule

• Generated by nitric oxide synthases

• Regulates many functions throughout the body

• One key role: vascular smooth muscle relaxation to regulate blood flow Nitric oxide in the eye

• Contributes to IOP regulation

• Activates cGMP signaling pathway

• Relaxes cells in trabecular meshwork

• Increases aqueous humor outflow

• Reduced levels found in eyes of patients with glaucoma

Nitric Oxide Contributes to Regulation of Intraocular Pressure

During this discussion, we will review why this is important. We will discuss the role nitric oxide plays in regulating IOP in normal eyes and the deficiency of nitric oxide markers in glaucomatous eyes. We also explore the dual action of VYZULTA and how it lowers IOP.

Louis Pasquale, MD: Elevated intraocular pressure (IOP) is a major risk factor for the development of primary open-angle glaucoma, a disease which affects more than 75 million people around the world.

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Today’s therapeutic options lower IOP to help prevent progressive vision loss from glaucoma. Prostaglandin analogs, by virtue of their effectiveness in lowering IOP and once-a-day dosing, have been a valuable treatment option for physicians treating glaucoma and their patients.

In 2017, VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024% was approved by the FDA.

VYZULTA, indicated for the reduction of IOP in patients with open-angle glaucoma or ocular hypertension, is the first prostaglandin analog that is metabolized into latanoprost acid and butanediol mononitrate, a nitric oxide-releasing moiety.

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W. Daniel Stamer, PhD: Nitric oxide is an endogenous signaling molecule known for its role as a mediator of smooth muscle relaxation and vasodilation.

It helps to regulate many physiologic functions in the body, including learning and memory, pulmonary and systemic vascular smooth muscle tone, platelet adhesion, sexual potency and erection, cell proliferation and matrix deposition in wound healing, peristalsis in the gut, and innate and adaptive immune responses.

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Nitric oxide is produced by three different nitric oxide synthase enzymes, which are present primarily in neurons, macrophages, and endothelial cells. We are most familiar with the endothelial cell synthase, which controls the flow of blood to the various tissues in the body.

When nitric oxide is released by this synthase, it causes the smooth muscle cells that wrap endothelial cells to relax. As a result, blood flow to the tissue increases. A similar process occurs in the trabecular meshwork. It is easy to imagine how that is important in aqueous humor outflow.

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Nitric Oxide as a Regulator of IOP

Dr. Pasquale: What role does nitric oxide play in IOP regulation?

Robert Feldman, MD: In normal eyes, nitric oxide is part of the homeostatic mechanism of IOP control.

Endothelial cells in Schlemms’s canal produce nitric oxide in response to elevated IOP, and it is involved in regulating the canal volume and outflow facility. Nitric oxide relaxes the cells of the trabecular meshwork, most likely through alterations in the cytoskeletal network.

This increases tissue permeability and, ultimately, the outflow of aqueous humor.

Dr. Pasquale: How does nitric oxide work at the cellular level in the trabecular meshwork?

Donald Budenz, MD, MPH: Nitric oxide activates the cyclic guanosine monophosphate (cGMP) signaling pathway, which initiates a cascade of events, including inhibition of Rho-kinase and reduction of intracellular calcium levels.

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These events decrease cell contractility and volume in the cytoskeleton and, thus, relaxation of trabecular meshwork cells, which are quite contracted in glaucoma, and increase flow of aqueous humor.

Dr. Pasquale: Studies have shown that anterior chambers of glaucomatous eyes have reduced nitric oxide levels relative to normal eyes.

Dr. Stamer: Yes. Evidence suggests that lower levels of nitric oxide may be causally related to glaucoma or may be a manifestation of the disease.

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Studies from about 15 years ago showed lower amounts of nitric oxide in the aqueous humor and bloodstream of glaucoma patients as well as less synthase activity in the outflow pathway.

Also, as Dr. Pasquale knows quite well, evidence from genetic studies involving relatively large numbers of patients indicates that single amino acid changes in the endothelial nitric oxide synthase, i.e., the nitric oxide synthase present in the aqueous outflow pathway, increase the risk for glaucoma.

In addition, Dr. Pasquale and colleagues have published a study on dietary nitrate intake and its association with primary open-angle glaucoma risk.

Dr. Pasquale: Correct. Thank you for pointing out the work we’ve done with regard to nitric oxide synthase polymorphisms in relation to glaucoma.

An interesting aspect of our work was that we showed that the association between environmental factors and behaviors, such as post-menopausal hormone use by women, and glaucoma can depend on nitric oxide synthase gene variants.

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Other groups, too, have discovered the relationship between candidate polymorphisms and nitric oxide synthase and the development of glaucoma. We’ve also been studying nutritional epidemiology, considering a variety of factors that might modify the risk of open-angle glaucoma.

The strongest evidence we found, analyzing data from the Nurses’ Health Study and the Health Professionals Follow-up Study, was that higher dietary nitrate and green leafy vegetable intake was associated with a 20% to 30% lower risk for primary open-angle glaucoma.

Dr. Stamer, can you elaborate on the dysfunction that occurs in the soluble guanylate cyclase (sGC)/cGMP/ protein kinase G signaling pathway when a patient is experiencing elevated IOP

Dr. Stamer: We’ve done work in our laboratory at Duke and in collaboration with Darryl Overby, PhD, in the Department of Bioengineering at the Imperial College of London.

This work shows that the conventional aqueous outflow pathway (the trabecular meshwork) is pressure-sensitive tissue.

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As IOP increases, the tissue is pushed toward the outer wall of Schlemm’s canal, which starts to collapse. In a normal eye, this process stimulates endogenous nitric oxide production.

But in a glaucomatous eye, the tissue is stiffer and less responsive to the pressure elevation. Therefore, less nitric oxide is produced.

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Dr. Pasquale: Should we consider the role of nitric oxide when we’re treating patients with glaucoma?

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Dr. Feldman: Nitric oxide could be a useful adjunct to the IOP-lowering armamentarium because it’s clearly involved in the homeostatic mechanisms of IOP regulation.

It could be an important factor in glaucoma patients in that they have less nitric oxide and, therefore, less stimulation of permeability of the trabecular meshwork.

Dr. Pasquale: What causes contraction in the trabecular meshwork and why is it a problem?

Dr. Budenz: There appear to be two main causes of trabecular meshwork contraction.

The first is increased Rho-kinase activity. The second is calcium signaling. If those two processes are active, the trabecular meshwork becomes contracted, which decreases the ability of aqueous humor to flow into Schlemm’s canal.

The importance of nitric oxide is in inhibiting those pathways, thereby allowing the trabecular meshwork to relax and fluid to flow better.

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Dr. Pasquale: Why is permeability of the trabecular meshwork so important?

Dr. Stamer: The permeability in the trabecular meshwork is a function of its geometry. The tissue is unique, because it’s under tension all the time. Elastic ligaments that extend from the ciliary muscle into the trabecular meshwork anchor into the inner wall of Schlemm’s canal.

The cells are very contractile in order to maintain a tone in the tissue at all times. So, if you either contract the ciliary muscle or relax the trabecular meshwork, the net result is an increase in the permeability of the tissue.

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This is particularly important in the area where the trabecular meshwork and Schlemm’s canal interact.

Dr. Feldman: As glaucoma specialists, we’ve been classically taught that the disease occurs because of a decrease in the permeability of the trabecular meshwork that brought about increased IOP.

Therefore, anything that can increase that permeability would be an important approach to controlling IOP.

Dr. Budenz: It is worth reiterating that the main resistance to aqueous humor outflow is the trabecular meshwork, and the ability to increase permeability through the meshwork has been a breakthrough in our field.  

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Dr. Pasquale: I agree. We had very little previously that allowed us to accomplish this biochemically.

Dr. Budenz: True. While some prostaglandin analogs act on the trabecular meshwork, pilocarpine acts on the ciliary body to stretch the “beams” open, but that’s an indirect mechanism.

We’re able to use nitric oxide to work directly on the trabecular meshwork to loosen it up and increase permeability.

Dr. Pasquale: Primary open-angle glaucoma is a complex disease that happens across a spectrum of IOP levels. It’s great to have a drug that acts directly on the trabecular meshwork, which brings us to VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024%.

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As we know, VYZULTA releases nitric oxide. What is the significance of that? Significance of a Glaucoma Medication that Releases Nitric Oxide

Dr. Feldman: VYZULTA gives us a pharmacologic agent that works on two aqueous outflow pathways. One outflow pathway, which has been the target of primary therapies since the introduction of latanoprost, is the unconventional or uveoscleral pathway.

The primary outflow pathway, which VYZULTA also addresses, is the trabecular meshwork.

Dr. Pasquale: How does nitric oxide released by VYZULTA work at the cellular level to help relax the trabecular meshwork cells and why does that matter?

Dr. Stamer: Along with the increased outflow of aqueous humor, VYZULTA delivers nitric oxide to the tissues that aren’t receiving it from the endogenous source, Schlemm’s canal. As such, at the cellular level nitric oxide is interacting with sGC to produce more cGMP, and cGMP has two important functions.

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One of the functions is to bind to membrane channels that either affect potassium or calcium flux. As Dr. Budenz mentioned earlier, as a result, the calcium is being shut off. The second important function of cGMP is to bind to and inhibit protein kinase G.

The kinase inhibition causes myosin light chain dephosphorylation. This is where cytoskeleton rearrangement affects the contractile machinery in the cell.

When the machinery is dephosphorylated, it doesn’t bind to actin and act in a contractile way. Therefore, the trabecular meshwork is relaxed and outflow through the trabecular meshwork is improved.

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Dr. Pasquale: How is VYZULTA different from other prostaglandin analogs? There is, in fact, a very important distinction between latanoprost and latanoprostene bunod.

Dr. Budenz: Once the molecule gets inside the eye, it is metabolized into latanoprost acid and butanediol mononitrate. The latanoprost acid carries out its wellknown mechanism to primarily increase unconventional outflow.

The butanediol mononitrate metabolizes into 1,4-butanediol and nitric oxide. The nitric oxide is of course what VYZULTA delivers that other prostaglandin analogs do not, even those that also have some activity on the trabecular meshwork.

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And, by the mechanisms we’ve described, the nitric oxide acts directly on the trabecular meshwork to increase outflow.

This dual mechanism of action is likely why VYZULTA was shown to lower mean diurnal IOP 1.23 mmHg more than latanoprost 0.005% ophthalmic solution (Xalatan, Pfizer) at day 28 in the VOYAGER study.

VYZULTA lowered IOP 34.6% from baseline, while Xalatan 0.005% lowered IOP from baseline 29.8%, which is what we would expect with latanoprost. What this means for clinical practice is that the additive effect of nitric oxide may allow us to achieve our target IOP for more patients.

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If we’re starting with IOP of 26 mmHg and looking for a 30% reduction, we can reach 18 mmHg or less in approximately 64% of patients by using VYZULTA compared with approximately 50% of patients if we’re using Xalatan 0.005%.

In a post-hoc analysis, 42% of patients achieved a reduction of at least 2 mmHg more than the mean diurnal IOP reduction for Xalatan 0.005% (mean diurnal IOP reduction of 7.8 mmHg).

Dr. Pasquale: How do we know the nitric oxide is working in VYZULTA and its not just the four-timeshigher concentration of latanoprost?

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Dr. Feldman: If we go back to previous studies, including the paper published by Eveleth and colleagues, no significant additional reduction in IOP was observed with higher concentrations of latanoprost, up to .0125%, in patients with open-angle glaucoma and ocular hypertension.

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Dr. Pasquale: In preclinical research, rabbits, which are typically nonresponsive to prostaglandin analogs, responded to VYZULTA. Help us better understand the significance of this result.

Dr. Stamer: As you correctly point out, rabbits aren’t typically responsive to prostaglandins. However, in one study involving rabbits with saline-induced ocular hypertension, VYZULTA blunted the IOP increase in the rabbits.

Another study, which utilized an FP receptor knockout mouse model, found those animals, despite not having the receptor for the prostaglandin, were responsive to VYZULTA.

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Whereas latanoprost had no IOP-lowering effect, as would be expected in this scenario, VYZULTA lowered IOP from 0.45 to 1.23 mmHg.

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Dr. Pasquale: Given all of the glaucoma medications available to us, in which situations do you choose VYZULTA as a first-line treatment option and why?

Dr. Budenz: For me, the perfect time to use VYZULTA is when I’m treating patients with manifest glaucoma, i.e., patients with definite glaucoma and visual field defects.

For them, I want to initially decrease IOP by 30% or more. In pooled data from all tested time points in phase III trials of VYZULTA, an average pressure reduction of 32% was seen at month 3.

VYZULTA achieved the primary objective of noninferiority to timolol 0.5% and also demonstrated superior IOP reduction versus timolol 0.5% at month 3.

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In addition, the VOYAGER study, as we mentioned, showed superiority to latanoprost as well, with VYZULTA lowering IOP 34.6% from baseline compared to 29.8% with XALATAN (latanoprost) 0.005%.

The ability to achieve IOP goals with a single agent with VYZULTA is very attractive. An interesting aspect of the VOYAGER results is that VYZULTA and XALATAN (latanoprost) 0.005% were similar in terms of side effects.

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In the APOLLO and LUNAR phase III studies, 6 out of 811 patients discontinued due to ocular adverse events (0.6% discontinuation rate). The rate of conjunctival hyperemia, which was the most frequently reported side effect, was 6%.

The JUPITER study evaluated the longer-term safety of VYZULTA in Japanese patients with openangle glaucoma or ocular hypertension. It had an acceptable safety profile when used for up to 1 year. Efficacy was also significant in JUPITER.

Mean IOP was statistically significantly reduced to 14.4 mmHg (from 19.6 mmHg at baseline) at 12 months, a reduction of 26.5%.

Considering the safety and efficacy of VYZULTA, it is a great first-line choice for patients with manifest glaucoma.

Dr. Feldman: I agree; it’s all about target pressure. It’s about setting a goal and choosing the right therapy that may be more likely to help your patients reach it.

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The VOYAGER study provided me with evidence that VYZULTA could be a first-line therapy option instead of latanoprost for many of my patients. For some of my patients, it is helpful if they can stay on a once-daily drop and get more IOP reduction.

Dr. Pasquale: When a patient doesn’t reach target IOP on monotherapy, what is your next course of action?

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Dr. Budenz: I was never a big proponent of switching between prostaglandins for patients who are not controlled on their current therapy.

Historically, no solid evidence supported switching as a beneficial therapeutic maneuver. When I did make a switch from one prostaglandin to another, I wasn’t seeing additional pressure lowering.

But the VOYAGER study clearly showed that VYZULTA can get pressure more than 1 mm Hg lower than latanoprost on average, and for that reason, I think it’s reasonable to consider VYZULTA if the patient is close to his or her target pressure but not quite there yet.

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Furthermore, the average achievement of IOP of 1.23 mmHg lower with VYZULTA compared with latanoprost is just that, an average. Some patients may have achieved IOP greater than 2 mmHg lower with VYZULTA.

Therefore, in my opinion, it’s reasonable to consider VYZULTA in an effort to further lower IOP.

Dr. Feldman: That’s my thought process as well. When I’m considering what to do next for a patient who’s using a prostaglandin analog but not where I want them to be pressure-wise, I consider how close we are to the target pressure.

If we’re only 1 mmHg off or 2 mmHg off, it’s certainly worth considering VYZULTA. On the other hand, if the target pressure is 4 mmHg or 5 mmHg away, another agent is likely going to be required.

Dr. Pasquale: What type of patients are good candidates for treatment with VYZULTA?

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Dr. Budenz: Theoretically, VYZULTA should be used early in the course of the disease. Chronic use of aqueous suppressants isn’t beneficial in my opinion.

Therefore, using an outflow drug such as VYZULTA early in the course of the disease makes more sense to me than using an aqueous suppressant.

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I’m not sure patients with advanced disease benefit as much from VYZULTA as they do at the beginning of the disease prior to being bombarded with aqueous suppressants for decades.

Dr. Feldman: I agree. Over the past several years, we’ve all come to understand that later in the course of glaucoma, the trabecular meshwork is not the only issue.

Issues arise further downstream from the meshwork and more resistance develops elsewhere. And our collective experience with some of the minimally invasive glaucoma surgery (MIGS) devices and their IOP-lowering efficacy indicates that we should improve trabecular outflow earlier.

Better post-trabecular outflow capacity is likely helpful when we want to utilize MIGS. Therefore, again, it’s probably better to use VYZULTA earlier rather than later.

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Dr. Pasquale: To add my personal perspective, I think back to the American Academy of Ophthalmology meeting 2 years ago.

At that meeting, I spoke about primary open-angle glaucoma as a heterogenous group of diseases and how useful it would be to specifically identify a nitric oxide-deficient type of open-angle glaucoma.

Although there is by no means a clear-cut, definitive subset of patients, I think it would be beneficial to increase the nitric oxide in glaucomatous eyes. They don’t necessarily have low IOP or high IOP.

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Their IOP may be somewhere between 18 mmHg and 24 mmHg, which is probably too high for them in terms of the increased vulnerability of their optic nerves.

Those are the kind of patients who may benefit the most from first-line treatment with a drug such as VYZULTA (latanoprostene bunod ophthalmic solution), 0.024%.

Latanoprostene Bunod in Normal-tension Glaucoma

Dr. Pasquale: Why is VYZULTA a good option for patients with normal-tension glaucoma?

Dr. Budenz: I think we all agree that patients who have normal-tension glaucoma are the most difficult patients to manage.

It’s difficult to reduce their IOP by 30%. The lower the starting IOP, the smaller the effect of a drug.

However, in the JUPITER study, patients who started with an average pressure of 19.6 mmHg were able to achieve a 26% decrease, to 14.4 mmHg. That’s a big response for a normal-tension glaucoma patient using only one medication.

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While JUPITER was a 1-year study in Japanese patients, who we know have a higher prevalence of normal tension glaucoma, the results are applicable to our patients.

The struggle is getting patients to the target pressure, and VYZULTA® appeared to be able to do this in this patient population.

Dr. Feldman: As we know, the available evidence on how best to manage normal-tension glaucoma isn’t clear-cut. Basically, we try to bring these patients to the lowest IOP possible with minimal side effects.

That being the case, when I’m choosing a first-line agent, VYZULTA or latanoprost, I know I’m likely to get more of an IOP-lowering effect with VYZULTA, so starting there makes the most sense.

I try to get as low as possible because even with low pressures, these patients sometimes progress, making it necessary to reduce the IOP even further. It’s better to be aggressive early because the target is often going to be down in the low teens or even single digits.

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Dr. Pasquale: VYZULTA presents an exciting opportunity. We can recall in the Collaborative Normal Tension Glaucoma Study that the goal was to achieve very low IOP, and 50% of the patients needed adjunctive laser treatment or incisional surgery to reach the goal.

It would be interesting if that kind of study could be repeated today with VYZULTA. It may be that we’d have far more patients achieving their target pressures.

Time will tell. Leveraging the Properties of Nitric Oxide in Glaucoma Care

Dr. Pasquale: All of us learned about the therapeutic value of nitric oxide in medical school, but it wasn’t relevant to our ophthalmic practices until the FDA approved VYZULTA.

Have you experienced an aha moment about nitric oxide as it relates to glaucoma treatment that you’d like to share with our peers?

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Dr. Stamer: Yes. It happened in 2010 when I was learning how to perfuse mouse eyes. Significantly, mice have similar outflow pathway anatomy to humans, including a true Schlemm’s canal; thus, it is a good model to functionally isolate the conventional outflow pathway.

You can imagine how, in a mouse, the flow rates are quite small, but you have the advantage of the known genetics. We had mice that were over-expressing endothelial nitric oxide synthase (eNOS).

We were studying them because eNOS is sensitive to shear stress and we were interested in the shear stress in Schlemm’s canal at elevated IOP.

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In the course of studying that aspect, we were perfusing the eyes and discovered that outflow was twice that of controls. Immediately, we knew nitric oxide was important to outflow.

Up until that point, we knew that nitric oxide lowered IOP in patients and in animal models, but we didn’t know how. That 2010 study was the first that actually showed us exactly where the nitric oxide works.

Dr. Feldman: My nitric oxide moment is more clinical. It relates to how I had been using latanoprost throughout the years. I remember the first patient I put on latanoprost.

He was already using all of the other options, including pilocarpine at the time, and his pressure went up to 50 mmHg instead of going down.

The pilocarpine was reducing uveoscleral outflow and preventing any further effect from latanoprost. Since VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024% has been available, I’ve used it in the same situation and it has been successful.

This is a strong indication that VYZULTA is working via a different mechanism than its predecessors and that we can use it for situations in which latanoprost wasn’t enough.

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Dr. Budenz: My nitric oxide moment was in thinking about how the cells of the trabecular meshwork behave similarly to smooth muscle cells and blood vessels.

Nitric oxide is effective in other disease states for relaxing smooth muscle cells, so why wouldn’t it be effective in the trabecular meshwork for glaucoma?

That was the connection for me between what I learned about nitric oxide in medical school and what we’re seeing now in the eye.

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Dr. Pasquale: From my point of view, the 150-yearold debate over whether glaucoma is purely a trabecular meshwork problem or whether it has an optic nerve vulnerability aspect has always generated more heat than light. I’m excited that we have VYZULTA as a therapy to help our appropriate patients.

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