Friday, January 06, 2006

Advances in the Treatment of Glaucoma

This report was part of the Industry Overview published by OptiStock in the Summer/Fall of 2001.
(An addendum on AMD was added by the OptiStock editors.)

Irving J. Arons
Managing Director
Spectrum Consulting

Glaucoma continues to represent a significant healthcare issue, with millions of people worldwide at risk for vision loss. However, over the past decade, glaucoma detection and treatment has progressed, especially with the introduction of advanced new drugs and surgical techniques. Going forward, we anticipate a continued evolution in the management of this vision deteriorating disease, possibly leading to the management of the underlying cause(s) and thus preventing the progression to blindness.

Glaucoma -- The Problem and Incidence

Glaucoma is a general term given to a progressive neuropathy disease, with a gradual (or sometimes rapid) buildup of pressure within the eye as one of several well characterized risk factors. If the buildup of pressure is not treated, it can gradually cause a total loss of vision through deterioration of the optic nerve. The disease is typically associated with aging, as its frequency increases as people reach the age of 60. Glaucoma is estimated to affect 1%-2% of the U.S. population and an estimated 67 million people worldwide. It is the second leading cause of blindness in Caucasians and leading cause in people of African descent. Fortunately, there are drug and surgical therapies that can help stabilize this condition after detection, although, for many of the most common forms, there is no absolute cure.

There are two broad classifications of glaucoma: open-angle and angle-closure (or closed-angle). Open-angle glaucoma is the most prevalent in U.S. and African people, while angle-closure appears most frequently in people in Asian countries.

Since there is no outward sign or pain associated with this "thief of sight" and, especially with the open-angle form, there is a gradual loss of vision until the effects become pronounced. Angle-closure glaucoma produces similar vision loss, but in many cases, can progress rapidly to an irreversible damage point where vision loss can occur in just a few days after diagnosis.

Primary open-angle glaucoma (POAG) is associated with a rise in intraocular pressure (IOP), as the aqueous humor produced by the ciliary body, used to nourish the anterior portion of the inner eye, cannot adequately drain out through the trabecular meshwork into the bloodstream. As IOP rises, the eye weakens at its most vulnerable point, the optic nerve, causing damage and eventually blindness. Normal IOP is between 12-21 mmHg. As the IOP rises, the patient is deemed hypertensive and the risk of developing POAG increases. Normal tension POAG accounts for as much as 30% to 50% of people with the disease.

The exact cause of POAG is not known. It has been postulated that as a person ages, the trabecular meshwork loses its ability to regulate the volume of aqueous humor within the eye. Another recent theory proposes that as a lack of nourishment begins to damage the optic nerve's ganglion cells, they send a "death signal" to other ganglion cells, thereby creating a domino effect.

Primary open-angle glaucoma accounts for approximately 90% of the total glaucoma cases, or about 3.6 million Americans, with an estimated 63,000 new cases diagnosed annually.

Angle-closure glaucoma occurs when the iris moves over the trabecular meshwork, effectively "narrowing" the angle between the iris and the cornea, blocking the exit channel for the aqueous humor. Angle-closure glaucoma accounts for approximately 10% of the total glaucoma population, or about 330,000 people in the U.S., with an estimated 16,500 to 17,500 new cases developing annually.

Detection/Diagnosis

Standard Screening Techniques

Detection of elevated IOP (more than 21 mmhg) is critical to early intervention. The most commonly used diagnostic tool is the tonometer, which is usually administered during an eye exam by sending a puff of air onto the corneal surface and measuring the resulting eye pressure. As noted, "normal" IOP is between 12-21 mmHg. A reading of greater than 21 mmHg is not necessarily an indication of glaucoma, but rather suggests ocular hypertension. Approximately 2%-4% of the general population has ocular hypertension, while 1%-2% has glaucoma. Hypertensive people generally progress to glaucoma at the rate of 1% per year. Also, HCFA has recently announced that it will cover the cost of examinations for people with a family history or predisposed to getting glaucoma. This will lead to many more people at risk obtaining examinations over the next several years.

If a patient presents with a "high" IOP reading, the ophthalmologist can perform an ophthalmoscopy, by reflecting light off of the back of the retina, creating a picture of the optic nerve. This can be used to determine if any damage has occurred to the optic nerve due to the onset of raised IOP.

With increased IOP and suspected glaucoma, the ophthalmologist will also view the angle between the iris and the cornea, using a gonioscope, a mirrored lens placed on the cornea, to determine whether open-angle or closed-angle glaucoma is present.

Laser-Imaging Technologies

Because some normal-tension patients account for a significant proportion of glaucoma patients, there arose a need for more advanced diagnostic tools. Since it is widely believed that the retinal nerve fiber layer and the optic nerve provide important information about the presence and progression of the disease, several innovative imaging technologies that can provide quantitative information about the retinal nerve fiber layer and the optic nerve have been developed and are now available to the ophthalmologist. These automated technologies may help in detecting glaucoma at an earlier stage, increasing the potential for limiting irreversible damage and preserving vision. Several of the newer technologies are described below.

Scanning laser polarimetry (SLP) -- Laser Diagnostics Technologies has developed and is marketing its GDx Nerve Fiber Analyzer. The GDx device provides a precise measurement of the nerve fiber layer which can then be compared to a normative database and allow for very early detection of glaucoma. Image acquisition occurs in 0.7 seconds and provides an automated alignment of baseline images for follow-up analysis, allowing the tracking of small changes over time.

Scanning laser topography/ophthalmoscopy (SLT/SLO) -- At least three companies produce SLT/SLO devices: Heidelberg Engineering, with its Heidelberg Retinal Tomograph, the HRT II; Rodenstock with its SLO; and Odyssey Optical Systems also with an SLO, now distributed by Keeler Ltd. These SLT/SLO devices measure the surface structure of the optic nerve in less that 2 seconds, using computerized axial tomography. The systems are capable of providing automated alignment of follow-up images to baseline, again, useful in detailing small changes over time.

Another SLO-based device, the Panoramic200 from Optos plc, provides a wider view of the retina, and may prove useful in evaluating patients for glaucoma. This device was primarily developed for detection of retinal diseases such as diabetic retinopathy and macular degeneration. It provides an extended ultra-wide (200°) single color image of the retina, without the need for pupil dilation.

Optical coherence tomography (OCT) -- This device, introduced into the marketplace by Zeiss Humphrey Systems, can depict a dimensional-depth image (rather than a topographical view as with other imaging devices) of the retina's nerve fiber layer and/or the optic nerve, for detecting very small changes from normal baseline. It is, perhaps, even more sensitive than the other devices described above.

As noted at this year's ARVO meeting, several improvements in some of the techniques noted above, such as ultrahigh resolution OCT imaging, and correcting for corneal polarization in SLP, may make them even more useful in more easily detecting the early stages of glaucoma. (For more on these newer developments, see the glaucoma section in the accompanying writeup reviewing this year's ARVO meeting on this website.)

Medical Treatment of Glaucoma and Ocular Hypertension

Historical

For more than two decades, glaucoma treatment protocols have called for first trying drug therapies for lowering IOP, then laser trabeculoplasty, and finally, if nothing else worked, surgical intervention. Over the past several years, some ophthalmologists have advocated using laser therapy first, in conjunction with drugs, but because of the nature of the argon laser trabeculoplasty procedure, causing scarring of the trabecular meshwork and thus limiting re-treatments, that option has had only limited acceptance. Drug therapy alone has always been limited by poor patient compliance of the usual 2-3 times a day medications that sometimes sting and cause irritation upon application.

Current Therapies

First generation drugs included pilocarpine for treatment of ocular hypertension and IOP reduction, followed in the early 1970s by the introduction of the beta blockers, which quickly became the therapy of choice. In 2000, annual sales of the beta blockers alone were approximately $235 million in the United States, led by Betoptic from Alcon Labs; Timoptic and Timoptic XE from Merck; and Betagan from Allergan. Later, in the 1990s, alpha agonists, carbonic anhydrase inhibitors and prostaglandin analogs were introduced, along with combination formulas, leading to worldwide sales in the order of $2 billion worldwide by 2000 (of a total approximately $4 billion eye pharmaceutical market, when retinal and other medications are included).

The major problem with the use of medical therapies has been and continues to be patient compliance in inserting the eyedrops, which can cause stinging, ocular irritations and discomfort.

Today, however, several newer approaches exist. On the pharmaceutical side, three companies, Pharmacia, Alcon and Allergan, have introduced improved once-a-day next-generation drugs -- Xalatan from Pharmacia; Travatan from Alcon; and Lumigan from Allergan. Also, a new laser treatment option has just been introduced by Coherent Medical (recently acquired by ESC Medical, and renamed Lumenis), based on selective targeting of pigment in the trabecular meshwork, which appears to offer long-term success for open-angle glaucoma, and is repeatable unlike argon laser trabeculoplasty.

Angle-closure glaucoma, on the other hand, is primarily treated by surgical intervention, including laser iridotomy, wherein either a YAG or diode laser is used to punch holes in the iris to allow aqueous outflow from the posterior to the anterior chamber of the eye.

A Look to the Future

On the horizon are potential therapies that may slow, stop, and/or reverse ganglion cell death, often initially caused by elevated IOP in the optic nerve. Neuroprotectors are thought to increase blood flow, decrease nitrous oxide production in the optic nerve, and modify cellular communications that may offer substantial benefits to patients suffering from glaucoma. All of the major ophthalmic drug companies are working on compounds that may have this effect.

And, even genetics may play a future role. If scientists can identify the genes that are the root cause of glaucoma (and early work appears fruitful), in the future gene therapy/manipulation might prove useful in identifying hypertensive people susceptible to progressing to glaucoma and by adding/changing genes, might be able to prevent that from happening.

In the March issue of Nature, New England Eye Center researchers reported on identifying a novel stress response pathway in the outflow fluid in the eyes of people with glaucoma, that was not found in eyes of normal people. If further research proves that there is indeed a marker for the disease, it may lead to a simple blood test that could potentially identify patients at risk prior to the clinical findings or loss of vision. The research team is currently recruiting volunteers for a blood test study that may bring us one step closer to predicting the chance of developing glaucoma with the potential genetic marker.

Surgical Alternatives

Despite the primary role of medicines in the management of glaucoma, there are circumstances in which a physician must look to more aggressive means for controlling the disease. In some cases, a patient may present at a stage in which the risk of visual loss warrants immediate aggressive intervention, or side effects with the continued use of drugs may not be tolerable. Furthermore, there are situations where surgical intervention may be more economically feasible when compared to the significant expense associated with using one or more medicines over an extended period of time.

Significant advances have been made in the surgical management of glaucoma over the past few decades, including the development of laser therapy and filtration surgery. Considering the potential impact of new diagnostic techniques and innovative surgical devices, it appears that surgical methods may become the preferred treatment methodology, and improve the outlook for those suffering with glaucoma.

Surgical Methods

In cases where medical or original laser intervention (argon laser trabeculoplasty) is inadequate to lower IOP, surgical procedures may represent a patient's last chance for the prevention of loss of sight.

Trabeculectomy -- "Filtering" surgery is the most common surgical intervention. This procedure creates a new drain in the trabecular meshwork and sclera. It is the primary surgical method for the treatment of open-angle glaucoma, and is performed about 125,000 times annually in the United States. The trabeculectomy procedure takes about 30-45 minutes, but requires significant post-procedure care, upwards of one to two office visits over a period of four to six weeks. Medicare reimbursement averages about $959. Clinical studies have demonstrated that the procedure is successful in about 80% of patients over a period of two to five years. However, the body's natural wound healing response is responsible for many failed procedures. This can be mediated somewhat by using antimetabolites, such as 5-fluorouracil (5 FU) and Mitomycin C to control or reduce the post-operative healing response.

While the use of antimetabolites have improved the success rate of trabeculectomies, there use is also associated with a higher incidence of complications such as over filtration (or abnormally low IOP), and long-term risk of serious ocular infections. Long-term studies indicate that as many as half of treated patients will eventually exhibit some loss of original pressure reduction or further progression of the disease.

Deep sclerectomy -- In order to avoid some of the complications of filtration surgery, some surgeons use "non-penetrating" techniques, such as deep sclerectomies. These are procedures wherein a small flap is created in the sclera, followed by "unroofing" of the outer wall of Schlemm's canal and the exposure of Descemet's membrane, to create a fluid drainage channel. Again, however, the body's natural healing response in closing the pathway has led to a high failure rate. An alternative is the use of the STAAR Surgical AquaFlow "wick", this small implantable, biocompatible collagen device can be used to hold the drainage pathway open. The device is re-adsorbed after about 6 to 9 months, which is long enough to prevent closure of the pathway during the healing process. This device is very close to FDA approval. Two comparable devices are available. One is made of a hydrogel, the T.Flux from IOLTech, while the other is composed of cross-linked hyaluronic acid and is marketed in Europe by Corneal, under the name of SKGel implant.

Tubes/shunts -- Other implantable drainage tubes/shunt devices that are used in trabeculectomy surgeries include the Molteno, Baeveldt, and Ahmed implants. Basically composed of plastics, they are implanted in the anterior chamber and drain to an external reservoir. Success rates of as high as 80% have been reported, but significant complications are possible, and as such, these implants are usually restricted to high-risk patients, or those that have failed trabeculectomies.

Laser Approaches

Laser trabeculoplasty (ALT/SLT) -- Typically using an argon or diode laser, laser trabeculoplasty is the most common laser procedure performed for treating open-angle glaucoma. A series of 50-100 laser coagulative "burns" are placed in the peripheral trabecular meshwork, creating scars that help to improve fluid flow through the shrunken tissue surrounding the scars. An estimated 250,000 to 300,000 procedures are performed annually in the United States, with the effectiveness of the procedure varying from patient to patient. Usually, an average of 7 mmHg IOP reduction occurs. However, long-term studies indicate that pressure is controlled in only 45%-55% of treated patients after 5 years, and the laser treatment cannot be repeated because of the permanent scarring that occurs.

As noted above, a new procedure for performing selective laser trabeculoplasty (SLT) has recently been approved by the FDA, and is being introduced into the marketplace. Using a Q-switched frequency doubled YAG laser, made specifically for the procedure by Coherent Medical, the Selecta 7000, SLT is a non-thermal, repeatable laser procedure that in international clinical trials achieved an 80% success rate in obtaining a 23% IOP reduction that lasted for up to 24 months. Minimum complications were seen and all were easily treated.

The procedure is similar to ALT, with 45-55 laser spots placed along an 180° arc in the trabecular meshwork. The difference, however, is that by selectively targeting the melanin pigment within the trabecular meshwork cells, rather than creating a thermal burn, a cellular reaction occurs that enhances fluid outflow without thermal destruction of the targeted cells. This means that the procedure is repeatable. With the demonstrated efficacy in patients with primarily open-angle glaucoma, even in patients with previously failed ALTs, it is our belief that SLT could conceivably evolve as the ideal primary treatment option for patients who cannot tolerate or are non-compliant with medication.

Laser iridotomy -- Some forms of angle-closure glaucoma can be treated with the laser iridotomy procedure. Iridotomy is preformed using either an argon, diode or YAG laser, to create several holes in the iris, to allow outflow of aqueous humor between the posterior and anterior chambers. Iridotomy can be viewed as a preventative measure, as it minimizes the liklehood of further surgical intervention. Laser iridotomy is also useful in the management of pigmentary glaucoma.

Laser cytophotocoagulation -- The primary objective of laser cytophotocoagulation is to reduce the amount of fluid produced in the eye, through the selective destruction of the ciliary process, the tissue responsible for producing the aqueous. EndOptics and Iridex both produce small diode lasers and the delivery systems for performing this procedure. EndOptics' probe device is inserted into the eye and accesses/targets the ciliary process, which is located beneath the iris, while Iridex's G-Probe does not enter the eye, but rather is a transcleral procedure, performed from the outside of the sclera. The laser cytophotocoagulation procedure is normally done when all other methods have failed, with the real problem being not knowing how much of the ciliary process cells to destroy to effectively control the fluid buildup and elevated IOP.

Market Size

The glaucoma market is made up of several elements; the treatment market (office examination and diagnosis visits, which according to some studies number approximately 7 million per year, surgical procedures, and the administration/dispensation of drugs) and the equipment market, including the sale of diagnostic devices, laser systems, and surgical equipment to doctors, surgical centers and hospitals. In the table below, I have tried to estimate the size of the two markets in the United States for 2000, and a projection for 2002. The market size for the rest of the world is probably some two to three times the U.S. market size. With the recent HCFA announcement about covering examinations for those predisposed to glaucoma, I have significantly increased the forecast for the examination market size in 2002. I have done likewise for the size of the forecasted laser market if, as I believe, laser procedures such as SLT become frontline treatment options.


Treatment Market, MM $ 2000E 2002F
Exams $700 $910
Treatment:
drugs $1800 $2200
surgical $150 $165
laser $240 $480

Total Treatment Market $2890 $3755

Equipment Market, MM$ 2000E 2002F
Diagnostics $150 $195
Surgical $25 $28
Lasers $56 $73
Total Equipment Market $231 $296

Source: Spectrum Consulting Estimates, June 2001.

Acknowledgement -- Several sections of this report were adapted from: "Glaucoma in the 21st Century: New Ideas, Novel Treatments", authored by Dave Therkelsen and William Quirk of Dain Rauscher Wessels, February, 2001.

1 Comments:

At 10:43 AM, Blogger Tom said...

An excellent review of the types of glaucoma, diagnostic modalities, and treatment options.

With your background in lasers, you might find this online video of a LPI laser iridotomy interesting to watch:

laser iridotomy

 

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