On one busy day, three glaucoma drugs approved

In rapid succession the FDA approved Travatan, Lumigan and Alphagan P. Now Pharmacia is suing Allergan and Alcon over patent rights.

WASHINGTON — It is unlikely that the luck of the Irish had anything to do with it, but the day before St. Patrick’s Day the Food and Drug Administration approved three glaucoma medications from Allergan and Alcon.

Alcon’s Travatan and Allergan’s Lumigan were approved on Friday, March 16. Allergan announced March 19 their other new glaucoma medication, Alphagan P, was also approved.

In conjunction with the approvals, Pharmacia has sued the two companies, saying Lumigan and Travatan violate Pharmacia’s patents on latanoprost and prostaglandin derivatives. The companies are contesting these charges.

Travatan approved

The FDA approved Travatan (travoprost ophthalmic solution 0.004%, Alcon) for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are intolerant of other IOP-lowering medications or insufficiently responsive to another IOP-lowering medication.

The phase 3 trials for Travatan ended in March 2000, followed by a presentation to the Food and Drug Administration (FDA) in June 2000.

Travatan was studied in eight controlled clinical trials consisting of more than 1,800 men and women. Patients were dosed with travoprost once a day in the evening for up to 12 months. Travoprost was compared with latanoprost once a day and timolol twice a day.

In these studies, travoprost lowered IOP up to 9 mmHg. When used adjunctively with timolol 0.5%, it produced a 7 mmHg reduction of IOP in patients not controlled by timolol 0.5% alone.

Rick Halprin, Alcon’s senior U.S. product manager for glaucoma, said Travatan is already in the distribution channel. “Travatan was shipped to wholesalers and retail pharmacies on the day of approval. For the large chain outlets, it will be in the stores in the next week or two. Independent pharmacies may take a little longer.”

While Travatan showed excellent results in all patient groups studied, the drug’s efficacy in black patients was especially noted. A breakout of data from the clinical studies showed that the drug had greater effectiveness in black patients.

According to Alcon, studies have shown that black patients are four times more likely to suffer from glaucoma and are much more likely to go blind from the disease than are individuals of other races. Mr. Halprin explained the unique labeling for Travatan.

“The data on black patients were thoroughly reviewed by the clinical reviewers and by statistiticians at the FDA. The package insert states, ‘In subgroup analysis of these studies, mean IOP reduction in black patients was up to 1.8 mmHg greater than in non-black patients. It is not known at this time whether this difference is attributed to race or to heavily pigmented irides.’ Additional prospective studies in the African-American glaucoma population are also underway.”

He was quick to point out, though, that it was not only black patients who responded well to Travatan. “When evaluating the results of the trials and excluding the data on black patients, Travatan worked as well or better than latanaprost and significantly better than timolol,” he said.

“Travatan was as good as or better than latanoprost and timolol across all patient groups but was significantly better than both drugs in black patients. Travatan is the first and only treatment to demonstrate additional efficacy in black patients,” Mr. Halprin said.

Mr. Halprin noted that there were two recent positive events for African-Americans regarding glaucoma: the approval of Travatan and the recent approval of the glaucoma screening benefit for patients who are at risk of developing the disease. The targeted population for the screening benefit includes all seniors age 60 and above with a family history of glaucoma and other populations designated as high-risk, including blacks age 40 and above in the Medicare population.

“African-Americans make up roughly 20% of the treated glaucoma population, but they should be about 40%. This difference is due to under-screening,” he said.

Lumigan approved

Mere hours after Travatan’s approval was announced, Allergan announced the FDA approval of Lumigan (bimatoprost ophthalmic solution 0.03%, Allergan), a synthetic prostamide analog. It is indicated for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension who are intolerant of other IOP-lowering medications or insufficiently responsive to another IOP-lowering medication.

Allergan said Lumigan will be available in the next few weeks.

In phase 3 clinical studies of 715 patients, 64% of patients receiving Lumigan once daily achieved target IOP of 17 mmHg or less. In contrast, 37% of patients receiving timolol twice daily achieved the same target pressure. At 6 months, Lumigan produced a 33% reduction in IOP, compared with 23% for timolol (8.1 mm Hg versus 5.6 mmHg, respectively).

Allergan said the study data suggested that Lumigan lowers IOP by increasing outflow of aqueous through both the trabecular meshwork and uveoscleral routes.

Lumigan has a favorable safety profile and was well tolerated by patients. Minimal systemic side effects were observed during the 12 months of therapy. The most frequently reported adverse events, occurring in approximately 15% to 45% of patients dosed once daily, in descending order of incidence, were conjunctival hyperemia, growth of eyelashes and ocular pruritus.

Conjunctival hyperemia, primarily trace to mild, was reported in 45% of patients, with only 3% discontinuing as a result. The company reported that 5.3% of patients showed a greater-than-mild increase in conjunctival hyperemia from baseline.

Gradual eyelash growth (lengthening, darkening and thickening) and darkening of the eyelid skin were reported after treatment with bimatoprost. Darkening of the iris was reported in 1.5% of patients treated for 12 months. These changes may be permanent.

Bimatoprost is formulated for once-daily dosing. Unlike some other IOP therapies, bimatoprost does not require refrigeration. It is available in 2.5-mL and 5-mL sizes.

Alphagan P approved

The following Monday, Allergan announced that Alphagan P (brimonidine tartrate ophthalmic solution 0.15%, Allergan), preserved with Purite, had also been approved by the FDA for the lowering of IOP in patients with open-angle glaucoma and ocular hypertension.

Alphagan P is a new formulation containing brimonidine tartrate, a selective alpha-2 agonist, the same active ingredient used in Alphagan. Two 12-month clinical studies have shown that Alphagan P is comparable in efficacy to Alphagan with lower rates of certain adverse events. Alphagan P lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow. Alphagan P is expected to be available within the next 6 months.

Alphagan P was developed to offer physicians a new treatment option with comparable efficacy to Alphagan while reducing the risk of some side effects. The Purite in the new Alphagan is the same preservative that can be found in Allergan’s Refresh Tears. It is being used to improve ocular surface compatibility of Alphagan P. One of the side effects of the original Alphagan was ocular allergy.

In clinical trials, the most frequently reported adverse events included allergic conjunctivitis, conjunctival hyperemia, ocular pruritus, burning sensation, conjunctival foliculosis, hypertension, oral dryness and visual disturbance.

Lawsuits traded

All these approvals have not come without some bumps in the road.

In February, Pharmacia sued Alcon over Travatan. Pharmacia claims that the new drug infringes on its patents covering Xalatan and prostaglandin derivatives. Alcon has described Travatan as a prostaglandin analogue.

In an interview with Ocular Surgery News, Mary Dulle, corporate communications director for Alcon, responded that Pharmacia’s lawsuit against Alcon is an unwarranted attempt to force Alcon to stop selling Travatan.

“Pharmacia’s patent cannot validly be read to cover Travatan, and Pharmacia has clearly overreached in an improper attempt to prevent competition from Alcon. Alcon intends to contest Pharmacia’s accusations vigorously and will not allow Pharmacia’s litigation tactics to prevent Alcon from making this promising new treatment available to doctors and glaucoma patients,” Ms. Dulle said.

Allergan filed a declaratory relief lawsuit March 1 against Pharmacia in U.S. District Court for the District of Delaware.

After Pharmacia sued both Alcon for Travatan and Novartis for Rescula, officials at Allergan realized it would likely be the next target for Pharmacia and decided to confront the situation with the declaratory relief lawsuit. Allergan has described Lumigan as “the first synthetic prostamide analog.”

Allergan filed this lawsuit against Pharmacia to seek a ruling that Lumigan does not infringe on certain patents owned or controlled by Pharmacia and that such patents are not valid.

Prior to Lumigan’s approval Pharmacia announced that the company believes that its patent rights covering Xalatan are being violated by the manufacture, use and sale of Lumigan.

A Pharmacia statement said the company reviewed the specific allegations in the lawsuit Allergan filed on March 1, and that based on its analysis of Allergan’s complaint, believes that the chemical structure of Lumigan violates two of Pharmacia’s patents.

Pharmacia said it plans to defend all of its patent rights supporting Xalatan and prostaglandin derivatives.

Allergan contends that Lumigan represents a new class of ocular hypotensive agents that mimic the activity of a newly discovered family of fatty acid amides called prostamides.

For Your Information:

• Mary Dulle, corporate communications director, can be reached at Alcon, 6201 South Freeway, Fort Worth, Texas 76134-2099; (817) 551-8058; e-mail: mary.dulle@alconlabs.com; Web site: www.alconlabs.com.
• Allergan, manufacturer of Lumigan and Alphagan P, can be reached at 2525 DuPont Drive, Irvine, CA 92612; (714) 246-4500; Web site: www.allergan.com.
• Alcon, manufacturer of Travatan, can be reached at 6201 South Freeway, Fort Worth, Texas 76134-2099; (800) 862-5266.
• Pharmacia, manufacturer of Xalatan, can be reached at 100 Route 206 North, Peapack, NJ 07977; (908) 901-8000; Web site: www.pharmacia.com.