rx perspective
The Case for Combination Drugs
Mixed results from clinical trials may underestimate the value of this glaucoma treatment option.
By Christopher Kent, Senior Associate Editor

Today, an estimated 50% of glaucoma patients in the United States use two or more medications to lower their IOP. Given that fact, pharmaceutical companies are eager to market combination drugs.

Cosopt -- a combination of dorzolamide and timolol -- was the first modern combination drug to be approved, and remains the only one available in the United States. Currently, however, three new combination drugs are under investigation: Extravan (travoprost plus timolol) from Alcon; Xalcom (latanoprost plus timolol) from Pfizer; and Combigan (brimonidine tartrate plus timolol) from Allergan. Combigan has received an approvable letter from the FDA; the FDA response requires that an additional clinical trial be conducted. (Allergan declined to comment.)

Getting approval may not be easy. For the most part, clinical data so far has indicated that the combination drugs are only as effective -- or slightly less effective -- than the drugs used concomitantly.

Evaluation Pitfalls

To get a better perspective, we interviewed two doctors well-acquainted with the situation.

Paul F. Palmberg, M.D., Ph.D., who practices at the Bascom Palmer Eye Institute in Miami and is professor of ophthalmology at the University of Miami School of Medicine, has consulted with Pfizer on the clinical trials of Xalcom. "Evaluating a combination drug is extremely complex," he notes. "Strategies used to evaluate the first drug often don't work well when you add a second drug. Also, some patients may actually be non-responders to one of the drugs.

"Pharmacia/Pfizer conducted studies that compared switching from timolol to Xalatan with switching from timolol to Xalcom; they only found a difference of 1.0 or 1.2 mmHg. However, to get into the study you had to be on timolol monotherapy with a pressure of 25 mmHg or more. So, many patients who were switched to Xalcom had already failed to respond to one of Xalcom's two ingredients.

"I conducted a subgroup analysis just looking at subjects whose pressure dropped at least 6 mmHg on timolol. This time, switching to Xalcom was 1.89 mmHg more effective than switching to Xalatan -- a noticeably better result.

"Also, many of these studies include both ocular hypertensives and glaucoma patients. When I separated these subgroups in studies that Pfizer conducted, the results were noticeably better in glaucoma patients than in ocular hypertensives, whose measured high pressure may have been the result of thick corneas. So there's reason to believe that many of these studies underestimate what this class of drugs is capable of doing."

Working in the Real World

Joel S. Schuman, M.D., professor and chairman of ophthalmology at the University of Pittsburgh School of Medicine, and director of the University's Eye Center, has participated in trials of Alcon's combination drug Extravan. He notes that similar issues arose when Cosopt was being developed. "Concomitant therapy was slightly more effective than Cosopt in the phase III studies. Nevertheless, Cosopt has found heavy usage worldwide.

"In clinical trials you often have more compliance from patients than you have in practice," he notes. "For instance, most patients using multiple drops don't wait between drops as instructed, which can cause washout of the first drop.

"Extravan lowers pressure significantly -- at least a 27% reduction at all time points in all visits studied. That's better than any other single drop that's currently available. Also, it hasn't been found to cause any more adverse events than the two drugs used concomitantly.

"I think combination drops will turn out to have clinical utility, even though the efficacy isn't perhaps all that we had originally hoped."

Dr. Palmberg agrees. "I have a lot of friends in other countries that have access to the combination drugs. They feel these drugs have been a big help to them, and their patients are very happy about the convenience. I'd like to be able to prescribe them for my patients!"