Two new options will make glaucoma therapy safer
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`Two new options will make glaucoma
`therapy safer
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`Primary Care Optometry News, July 1996
`
`---Alan Robin, MD
`
`Alan Robin, MD, an associate professor at Johns Hopkins
`University, Baltimore, is probably best known for his work with
`apraclonidine (Iopidine, Alcon) and laser therapy for glaucoma. Here the
`glaucoma specialist and Primary Care Optometry News Editorial Board
`member discusses with Staff Writer Susan Biro the coming revolution in
`medical therapy of glaucoma. Shortly after this interview, the Food and
`Drug Administration approved Pharmacia & Upjohn's Xalatan (latanoprost)
`for treating open-angle glaucoma and ocular hypertension in patients who
`are either intolerant of other intraocular pressure-lowering medications or
`insufficiently responsive to another pressure-lowering medication.
`
`--- Treating glaucoma: Standard therapy for glaucoma,
`which is indicated in this videoangiogram of retinal
`circulation, may change with Food and Drug Administration
`approval of a new treatment option.
`
`Primary Care Optometry News: Before we talk about the
`new glaucoma drugs moving into clinical use, can you tell us what you think the
`last major change in glaucoma therapy was?
`
`Alan Robin, MD: The medical therapy of glaucoma was drastically changed in
`1978 with the advent of nonselective beta-blockers. Prior to that, glaucoma
`therapies caused terrible systemic or local side effects. Pilocarpine caused
`significant browache, miosis and blurred vision, carbonic anhydrase inhibitors
`had about a 50% acceptability and the original epinephrine drugs had a high
`rate of allergy.
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`Two new options will make glaucoma therapy safer
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`When timolol came on the market, it was almost as though we had a panacea. It
`wasn't until approximately 4 years later that we recognized the clinical problems,
`including depression, bradycardia and decreased pulmonary function. Non-
`selective beta-blockers alter blood lipids and may increase the long-term risk of
`stroke and heart disease. Now in all fairness, timolol is very safe in most of
`those who use it. But its systemic profile and the fact that it is a twice-a-day drug
`in most individuals are limitations.
`
`PCON: So that brings us to the newest era of post beta-blocker drugs. What are
`they and what has been your experience with them?
`
`Robin: The most exciting new drug is latanoprost, brand name Xalatan,
`marketed by Pharmacia & Upjohn. I was one of the investigators in the U.S.
`studies.
`
`Xalatan is a much more powerful drug than timolol. Timolol given twice a day
`has a mean eye pressure lowering effect of 25%. Latanoprost given once a day
`has a mean intraocular pressure (IOP) lowering of about 35%, so it's a third
`more powerful. It also adds well to most of the other medications that we have.
`
`PCON: Why is that?
`
`Robin: It works by a different mechanism of action than any of the other classes
`of drugs we have. Beta-blockers, alpha agonists and carbonic anhydrase
`inhibitors basically "turn the faucet down," or decrease the production of
`aqueous humor. Pilocarpine "opens the drain" by letting more fluid exit through
`the trabecular meshwork. Latanoprost works by increasing the outflow of fluid
`through a new pathway: uveoscleral outflow.
`
`This is an escape path where fluid basically goes behind the iris through the
`suprachoroidal space. Latanoprost allows this outflow by relaxing ciliary muscle
`fibers in a dose-dependent way and also by increasing the intracellular spaces
`within the trabecular meshwork. It is not dependent on episcleral venous
`pressure. It may be ideal in low-tension glaucoma patients.
`
`I was also involved with a compassionate-use study that enrolled patients on
`maximal medical therapy who were surgical candidates but didn't want surgery.
`Prostaglandins worked beautifully on that kind of patient. Latanoprost also has
`no effect on blood flow, on blood-aqueous barrier or the retinal vasculature.
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`It's also an ideal prodrug in that there is no backward flow within the tear cell.
`This minimizes systemic side effects that might occur through systemic
`absorption.
`
`PCON: Does it have any adverse effects?
`
`Robin: There are three potential complications with this drug. One is hyperemia.
`In earlier models of prostaglandins hyperemia was a real problem. Patients' eye-
`pressure lowering was great, but they had terribly red eyes. With latanoprost,
`the redness is about 0.5 on a scale of 0 to 5. The injection peaks at about a half
`hour after it's given and is gone within an hour and a half. And because it's given
`once a day—at nighttime, because it seems be more efficacious then—the
`patient is sleeping during most of the time the eye is red.
`
`Another potential complication in about 3% of patients—those with bluish brown,
`greenish brown or hazel eyes— is that the eye can turn more brown.
`
`PCON: Is this part of an ongoing change in the eye?
`
`Robin: No, this is not a premalignant condition. It's just an eye color change of
`the type that has been seen with prostaglandin use in dermatology. It's
`something that patients should be aware of. However, most patients accept it
`because they realize the gravity of their disease and because they can get a
`once-a-day eye drop.
`
`The third potential problem with prostaglandins is that they can cause
`inflammation. We looked carefully for signs of inflammation but have not been
`able to find any significant inflammation associated with latanoprost, which is
`really exciting. I think it's the most exciting new drug to enter the field of
`glaucoma therapy in the last 20 years.
`
`PCON: Where will it fit into your plan for primary open-angle glaucoma
`treatment?
`
`Robin: My feeling is that unless somebody is young and has blue-green eyes,
`today, with the knowledge I have, I would rather be on latanoprost than a beta-
`blocker. One of the problems with the nonselective beta blockers is that they all
`decrease exercise-induced tachycardia. The blunting of exercise-induced
`tachycardia makes it harder for the body to cope with normal daily activities and
`stress.
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`In most patients, latanoprost will become my first drug of choice. If it is not
`adequate, I would probably add a cardioselective beta-blocker, such as
`betaxolol.
`
`PCON: You said latanoprost adds well to most other current glaucoma
`medications. Are there any drugs to which it is not additive?
`
`Robin: There are some human data from Scandinavia indicating that it adds to
`pilocarpine, but other data with 4% pilocarpine showed that it does not add any
`effect. It is still being studied.
`
`PCON: The other new drug, still in clinical trials, is Allergan's brimonidine
`tartrate.
`
`Robin: Brimonidine is actually an old drug. It's an alpha agonist that has been
`available for many years, but no ophthalmic work was done until about the last
`10 years.
`
`Clonidine was sort of the classic alpha-2 agonist. It was originally looked at as a
`nasal decongestant, but in early studies volunteers were fainting because their
`blood pressures dropped suddenly. So it was used as a blood-pressure lowering
`medicine. Then it was noticed that systemic clonidine also lowered eye
`pressure. Since that worked, someone decided to try it as eye drops.
`
`In 1981, Elizabeth A. Hodapp, MD, compared topical clonidine to pilocarpine 2%
`and it worked very well, except for the large drops in blood pressure. Clonidine
`is no longer used as a therapy in the United States, but it's still currently
`available in Germany.
`
`Next came apraclonidine, brand name Iopidine, marketed by Alcon. I did much
`of the clinical work on apraclonidine, a relatively selective alpha-2 agonist. It is
`probably the safest drug we have seen so far in the therapy of glaucoma. The
`only disadvantage to apraclonidine is that 15%-25% of patients develop a
`localized allergy involving the eyes, the eyelids and surrounding skin. It is a self
`limiting allergy, but it's disconcerting.
`
`With regard to the more serious side effect of the class of alpha
`agonists—systemic hypotension—the concept of therapeutic index comes into
`play.
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`Therapeutic index is a measure of the difference between the safety of a certain
`drug's concentration and its efficacy. Apraclonidine has a large difference
`between its effective dose and the level that causes side effects. So it's a very
`safe drug.
`
`PCON: Did you participate in the studies of brimonidine as well?
`
`Robin: I was involved with both the design and clinical evaluations of some of
`the original dose-response studies for brimonidine, both safety studies and post-
`laser use studies. I have not been involved with the chronic-care studies, but I
`am familiar with some of their results. I've also been involved with a
`compassionate-use study with brimonidine.
`
`My clinical experience has been limited, but in this limited experience I have had
`a few patients who became drowsy. Some of these patients have been
`rechallenged with the drops, and without the drops they feel fine. Start them on
`the drops again, and they're falling asleep. But the 1-year studies of brimonidine
`do not seem to have this as a major finding.
`
`The allergy problem is much less than is seen with apraclonidine. But the blood
`pressure effects and central nervous system effects both potentially concern me.
`
`PCON: What kind of therapeutic index does brimonidine have?
`
`Robin: Fairly tight. In the initial studies for the post-laser indications, a 0.5%
`concentration was used. With 0.5%, there was a statistically significant drop in
`blood pressure even with one drop. The 0.2% solution appears to be much
`safer, so that is what is in clinical trials now.
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