Photodynamic therapy is moving toward approval for wet AMD

Three drugs are in the pipeline. The best news: some patients may actually regain lost vision.

Research into age-related macular degeneration has uncovered increasingly less destructive methods to treat choroidal neovascularization (CNV). Some new methods may even be able to restore lost visual acuity.

Retinal photocoagulation is still the only proven surgical technique for CNV. Photodynamic therapy (PDT) is a promising new treatment that uses nonthermal lasers to activate photosensitive drugs for more controlled coagulation of abnormal blood vessels. Unlike photocoagulation, however, PDT spares the overlying layers of retinal tissue.

Since the last time Ocular Surgery News took an in-depth look at AMD (“New treatments show promise where once there was none,” May 15, 1998), PDT has advanced from phase 2 clinical trials to the verge of Food and Drug Administration premarket approval.

Three companies are now developing PDT drugs to treat age-related macular degeneration, as well as cancer, autoimmune disorders and heart disease.

Although the FDA has placed PDT on fast-track review, it is still available only within clinical trials, said Robert P. Murphy, MD, a retinal specialist in practice in Baltimore. In the meantime, clinicians must rely on retinal photocoagulation.

“There are more invasive procedures and less invasive procedures, and the tide is tipping in favor of the less invasive procedures,” Dr. Murphy said.

Focus is on future

The 1999 budget for the National Eye Institute (NEI) is about $395 million. Researchers will spend an estimated $95.5 million of that working on macular degenerative conditions, with an estimated $25.3 million going just to AMD.

The idea is to develop better treatments for the disease before the aging baby boomers experience the condition in droves.

According to Frederick L. Ferris, MD, the director of NEI’s Division of Biometry and Epidemiology, retinal photocoagulation is the only available proven treatment to stop the growth of blinding blood vessels. However, this laser treatment is most effective in patients with abnormal blood vessels growing away from the central retina, especially those who have clearly defined new-vessel membranes.

“Those are a minority,” Dr. Ferris said. “Of all patients with neovascular AMD, there are 15% with new blood vessels that would fit into that group. For the vast majority, we don’t have a lot of options.”

Treatments such as PDT that have come close to proving effectiveness, he added, are all still undergoing clinical trials. Other regimens involve “fantastic surgical feats” to pluck neovascular lesions from beneath the retina. These techniques more often succeed in younger patients with healthier retinas.

“The disappointment may result from the fact that these are diseased eyes to start with,” Dr. Ferris said. “Taking the new vessels out doesn’t change the fact that they have serious macular degeneration.”

PDT is useful in the 10% of AMD patients who have subfoveal lesions associated with “wet” macular degeneration, that is, the exudative/neovascular form. Although only about 10% of AMD patients have the wet form, this accounts for 90% of those who lose vision from AMD. The NEI estimates that of the 34 million Americans over age 65, about 1.7 million have already been affected by some AMD-related visual impairment.

Where the NEI predicts an epidemic of AMD as the baby boomers age, private industry sees a potentially lucrative market as better treatments are introduced.

PDT delivers an inactive and nontoxic compound to diseased tissues via the bloodstream. Once activated, the drug forms singlet oxygen, which disrupts the surrounding tissue and essentially cauterizes the blood vessels. The compound collects in sluggish, abnormal capillaries, such as areas of CNV, while passing more quickly from normal, healthier blood vessels. This allows surgeons to apply laser light to a wide area but activate the drug only in those areas where tissue should be coagulated.

Visudyne

QLT PhotoTherapeutics Inc. and CIBA Vision have been working in partnership to develop Visudyne (verteporfin) therapy for wet AMD. They submitted a new drug application to the FDA on August 16 seeking marketing clearance.

The companies filed a specific indication request for the treatment of AMD in patients with predominantly classic subfoveal CNV. The FDA granted priority review within a 6-month period, citing the fact that there is no current satisfactory treatment for the majority of patients with wet AMD.

The submission is based on 12-month data from two 24-month randomized, double-masked, placebo-controlled phase 3 trials known as the TAP (Treatment of AMD with Photodynamic therapy) Investigation. The trials are taking place at 22 centers in North America and Europe and have enrolled a total of 609 patients.

At the 12-month follow-up visit, among the 243 patients in the trial with predominantly classic lesions, those treated with Visudyne therapy exhibited a large treatment benefit.

The companies also filed for approval of Visudyne with the European Medicines Evaluation Agency (EMEA) for marketing clearance in the European Union (EU), as well as the Swiss regulatory agency, Interkantonale Kontrollstelle für Heilmittel (IKS).

Visudyne is carried by low-density lipoproteins and selectively accumulates in endothelial cells of CNV lesions. The laser-activated Visudyne creates free radicals that damage the neovascular endothelium. This triggers platelets and occludes the leaky CNV vessels.

According to the drug’s developers, Visudyne’s liposomal formula makes the drug highly selective for neovascular tissues and spares the normal tissues outside the CNV.

A corporate spokesperson for QLT and CIBA told Ocular Surgery News that a complete analysis of the data will be made public in abstracts or peer-reviewed articles. However, researchers have presented some phase 3 study data at several ophthalmology conferences, and press releases based on that data have been issued.

According to these reports, 609 patients with subfoveal CNV were enrolled in the study and randomized to receive verteporfin or placebo. Patients had to have evidence of AMD, lesions smaller than 5,400 µm and best-corrected visual acuity between 20/40 and 20/200.

Treatment consists of first reconstituting Visudyne with sterile water to create 7.5 mL of liquid containing 2 mg/mL of drug. A calculation is performed to determine the patient’s body surface area based upon height and weight. Clinicians refer to a chart specifying the dose required to achieve a concentration of 6 mg/m².

The physician then draws the appropriate amount of drug and dilutes it with 5% dextrose solution to obtain a total volume of 30 mL. This amount is administered intravenously at a rate of 3 mL per minute over a 10-minute period.

Fifteen minutes after the start of the infusion, 689-nm laser light is applied to the retina for 83 seconds at 50 J/cm² and an intensity of 600 mW/cm². One laser used in the study is built by Zeiss and the other is by Coherent. Patients are warned to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 24 hours after treatment.

Patients underwent retreatment up to every 3 months if leaking of CNV lesions was found by fluorescein angiography.

The phase 3 trials showed for the overall study population that vision was stable or improved in 61% of patients treated with verteporfin compared to 46% of patients in the placebo group. The treatment benefit in patients with predominantly classic subfoveal lesions showed stable or improved vision in 67% of patients treated with Visudyne therapy compared with 39% of patients receiving placebo.

Fewer than 2% of patients withdrew because of adverse reactions, and withdrawals were comparable in drug and placebo groups. Adverse events included reactions at the injection site, transient vision disturbances and self-re -solving photosensitivity reactions.

Peter Kaiser, MD, of the Cole Eye Institute, Cleveland Clinic Foundation, is an investigator in the study. He has been using Visudyne in AMD patients for almost 2 years and said that the treatment is easy to administer and is well tolerated by his patients. While the 1-year data appear very promising, he cautioned that the treatment is not meant for all patients with AMD. Because there are several other experimental treatments for CNV, including surgery, radiation, medication and laser, patients need to be carefully evaluated to determine if they would benefit from PDT or some other treatment.

Dr. Kaiser also deferred detailed comment on the efficacy of the drug until after the data analysis is published later this year.

PhotoPoint-SnET2

Miravant and Pharmacia & Upjohn are developing PhotoPoint, their brand name for PDT using the compound tin ethyl etiopurpurin (SnET2). This treatment is also directed at wet AMD, which includes some 400,000 new cases per year in the U.S. and Europe, according to Miravant.

Researchers have treated 40 patients in phase 1 and 2 trials, and patients are being enrolled in the phase 3 trial.

According to Edgar Thomas, MD, one of the clinical researchers, treatment with SnET2 has improved vision in patients who underwent therapy, while most other PDT research shows stability or some loss of vision over time.

“The natural course of this disease is to get worse,” he said. “The longer you live, the worse it gets.”

Patients in the phase 1 and 2 trials were followed for 12 weeks to establish optimum dosing of drugs and light.

In the trials, researchers tested three drug doses and three light durations to establish the most effective regimen. Drug doses ranged from 0.25 mg/kg to 1 mg/kg and light doses from 35 J/cm² to 126 J/cm².

The 664-nm laser light is delivered by a solid-state diode laser made by Iris Medical Instruments. Patients who received between 0.5 and 0.75 mg/kg with a light dose of 35 J/cm² showed an average gain in visual acuity of 2.7 lines at 12 weeks, with patients treated with 0.75 mg/kg showing an average gain of 3 lines. Researchers confirmed the benefits of treatment using retinal diagnostic imaging.

Dr. Thomas and other researchers used fluorescein angiography to detect CNV lesions and optical coherence tomography (OCT) to examine retinal tissue after PDT.

Dr. Thomas reported that OCT revealed that the remaining tissue had thinned and the overlying retina re turned to a normal configuration.

“The presence of some abnormal tissue alone does not preclude recovery of vision,” Dr. Thomas said. “In the Macular Photocoagulation Study, when you lasered all that tissue, you produced a laser scar that caused loss of vision. We’ve got evidence that the PhotoPoint treatment is a biologically different process.”

Early trends positive

A follow-up study conducted by Drs. Thomas and Murphy followed a subgroup of 14 patients from the SnET2 phase 1 and 2 trials for 6 months. Each patient received a single PhotoPoint treatment, but a variety of drug and light doses were used.

The data showed good trends, but was unmasked and of short duration.

At 6 months, half the eyes had retained their increase in visual acuity, although the average change for all eyes in this study of various doses was a loss of 1.1 lines.

“Even though it’s fairly selective and not a randomized, prospective study, we saw a significant number of patients have a beneficial effect at 6 months,” Dr. Thomas said.

“This single PhotoPoint treatment actually alters the biology of the disease,” he added. “It really makes it a less aggressive and more indolent process. Visual loss is less. The tissue shrinks and starts to work again. By looking at this 6-month data, there is a long-term beneficial effect with a single Photo Point- SnET2 treatment.”

The researchers are now enrolling patients for phase 3, which will involve hundreds of patients who will receive one of two medium levels of drug (0.5 or 0.75 mg/kg) and 1 minute of laser light. Researchers are selecting patients with subfoveal CNV and visual acuity between 20/63 and 20/500. When randomization is finished, researchers will follow each patient for up to a year.

The company was placed on the fast-track approval course by the FDA, so as soon as researchers find a beneficial effect in phase 3 the company can apply for approval, Dr. Murphy said.

“All of the exciting experimental protocols address stages of macular degeneration in which there has not been too much irreversible loss,” Dr. Murphy said.

Optrin

Michel Sickenberg, MD, of the Hôpital Ophtalmique Jules Gonin, University of Lausanne, Switzerland, announced interim phase 1 and 2 clinical results with the PDT drug Optrin (motexafin lutetium injection) at the European Society of Ophthalmology meeting in Stockholm. The drug developer, Pharmacyclics, has granted Alcon a license to investigate and potentially market ophthalmic uses of the drug.

According to Richard A. Miller, MD, an oncologist and the president and chief executive officer of Pharmacyclics, the active ingredient in Optrin — motexafin lutetium — is one of a group of patented synthetic expanded porphyrin molecules called texaphyrins. In motexafin lutetium, the rare-earth metal lutetium is bound in the center of a bio - chemical ring.

The ophthalmic formulation, Optrin, is water-soluble and clears relatively quickly from the bloodstream. Like other PDT drugs, it selectively accumulates in diseased tissue where it can be activated by light, in this case by a 732-nm laser made by Zeiss.

Preclinical studies have shown that following activation by light, Optrin can selectively destroy CNV.

“We think that we will have certain advantages over the QLT compound,” Dr. Miller said. “We can formulate ours in a simple aqueous solution. It’s totally synthetic and water-soluble. Verteporfin needs to be formulated in liposomes.”

Optrin has a half life of a few hours. Because of the more rapid clearance, it avoids one of the principal limitations in this field, which is cutaneous photosensitivity. (The severe phototoxicity that was seen with early PDT drugs has been greatly reduced in the drugs now being investigated for ophthalmic uses, according to the manufacturers.)

The drug also fluoresces.

“Optrin’s fluorescence following activation with light may provide additional potential advantages for PDT of AMD by allowing for the imaging of the diseased tissue in order to determine the optimum time for treatment following injection of the drug,” Dr. Miller said.

Dr. Sickenberg reported results from 58 patients with the wet form of AMD treated with increasing doses of drug and light and also varying time intervals between drug administration and light delivery.

Depending on the doses of drug and light and the interval between them, Optrin PDT resulted in complete or partial closure of diseased vessels.

The best results presented were seen with patients who received 4 mg/kg of drug. In this group, 20 of 26 patients had complete or partial closure.

Light dose was also an important parameter. At a dose of 100 J/cm², 19 of 31 patients had complete or partial CNV closure. In the combined group receiving light doses of 125 or 150 J/cm², eight of nine patients had complete or partial closure.

Dr. Miller said that the study defined drug delivery boundaries, and additional research will reveal the best drug and light doses and interval between administering them.

Patients receiving higher doses of Optrin reported transient tingling of their fingertips. One patient developed facial phototoxicity following sun exposure. No other systemic toxicity was observed.

Five patients experienced damage to collateral normal retina. These patients either received the highest dose of drug (4 mg/kg) or received light within a short interval following drug administration. Dr. Sickenberg did not find retinal damage in patients who received high doses of light.

Phase 2 studies were scheduled to begin in September at the Massachusetts Eye and Ear Infirmary under the direction of Joan Miller, MD, at Stanford University under Mark Blumenkrantz, MD, and at Vitreous, Retina, Macula Consultants of New York under David Guyer, MD, according to Pharmacyclics.

Clinicians’ frustration

Researchers obviously have found much hope for future treatments, but clinicians are frustrated over what to do for patients today.

“We don’t have the armamentarium available to use on patients outside of clinical trials,” Dr. Thomas said. “The real push ought to be to get as many clinical trials completed and get good data on multiple drugs and modalities.”

In addition to PDT, submacular surgery and subthreshold laser treatment (see accompanying article) could help patients who fall outside the recommended indications for PDT.

“We have to rely on the previous trials,” Dr. Thomas said. “We look at the Macular Photocoagulation Study and we continue to use it. It’s a good study. It’s been 17 years since it was published and we still treat patients every day.”

Other studies have proved some experimental therapies to be ineffective, Dr. Ferris said.

Alpha interferon was considered a promising new treatment because it slowed the spread of new blood vessels. However, further research found that patients generally did well without the treatment.

A few studies are looking at radiation therapy of abnormal blood vessels. Radiation attacks actively replicating cells, which is when DNA is vulnerable to harm, but results have been mixed.

If a message of hope exists for patients, then it is the fact that one does not go completely blind from AMD. According to Dr. Ferris, who oversees the NEI’s collection of epidemiology data, AMD progresses slowly. Once the wet form sets in, however, visual loss can occur rapidly.

Patients with large drusen in both eyes have about a 20% chance of progressing to new blood vessel growth in 5 years. The highest risk group is patients who have developed new blood vessels in one eye but not yet in the other. Even in that group, far less than half will go blind in their fellow eye in 5 years. The chance of bilateral blindness is very low.

“Almost no one goes blind to the point that they can’t take care of themselves,” Dr. Ferris said, “but losing central vision is a devastating loss. If we could prevent that it would make a big difference in people’s lives.”

For Your Information:

• Frederick L. Ferris, MD, is director of the Division of Biometry and Epidemiology of the National Eye Institute, 31 Center Drive, MSC2510, Bldg. 31, Room 6A52, Bethesda, MD 20892; (301) 496-6583; fax: (301) 496-2297. Dr. Ferris does not have a direct financial interest in any products nor is he a paid consultant for any companies mentioned in this article.
• Robert P. Murphy, MD, practices at the Glaser Murphy Retina Treatment Center, 901 Dulaney Valley Road, Towson, MD 21204; (410) 337-4500; fax: (410) 339-7326. Dr. Murphy does not have a direct financial interest in any products nor is he a paid consultant for any companies mentioned in this article.
• Edgar Thomas, MD, practices at Retina Vitreous Associates, 1127 Wilshire Blvd., Los Angeles, CA 90017; (213) 483-8810; fax: (213) 481-1503. Dr. Thomas does not have a direct financial interest in any products mentioned in this article. He is a paid consultant for Miravant.
• Peter Kaiser, MD, practices at the Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., A-31, Cleveland OH 44195; (216) 444-6702; fax: (216) 445-3598. Dr. Kaiser does not have a direct financial interest in any products nor is he a paid consultant for any companies mentioned in this article.
• Richard A. Miller, MD, is president and CEO of Pharmacyclics, 995 E. Arques Ave., Sunnyvale, CA 94086-4521; (408) 774-0330; fax: (408) 774-0340.

• CIBA Vision Ophthalmics is located at 11460 Johns Creek Parkway, Duluth, GA 30136; (770) 418-3014; fax: (770) 418-4256.
• Pharmacia & Upjohn is located at 100 Route 206 North, Peapack, NJ 07977; (908) 901-8000; fax: (908) 306-4433.
• QLT PhotoTherapeutics is located at 520 W. Sixth Ave., Vancouver, British Columbia, V5Z 4H5, Canada; (604) 872-7881; fax: (604) 873-0816.
• Miravant is located at 336 Bollay Drive, Santa Barbara, CA 93117; (805) 685-9880; fax: (805) 685-2959; Web site: www.miravant.com.
• Pharmacyclics is located at 995 E. Arques Ave., Sunnyvale, CA 94086-4521; (408) 774-0330; fax: (408) 774-0340; Web site: www.pcyc.com.