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Combination drugs: establishing additivity is a top priority
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Combination drugs for treating glaucoma offer obvious advantages in terms of convenience and patient compliance. However, the Food and Drug Administration’s stringent criteria for these drugs hold them to a higher standard for demonstrating “contribution of elements.” Companies must establish that the use of their combination drug is much more effective than either of the individual components dosed separately.
“The powers in control at the FDA have set fairly high hurdles for combination drugs,” said Jimmy D. Bartlett, OD, FAAO, a lecturer and author who practices in Birmingham, Ala. “In general, philosophically, the FDA is opposed to combination agents. You really need to show some additivity — that the combination in the bottle is actually better than the separate bottles.”
Xalcom: awaiting U.S. approval
A combination of latanoprost 0.005% and timolol 0.5%, Xalcom (Pfizer Inc., New York,) was approved by the European Union in August 2001. Currently, Xalcom is still awaiting FDA approval.
“My understanding is that Pfizer Ophthalmics had to conduct several clinical trials to show that their drug does, indeed, meet that additivity requirement,” Dr. Bartlett told Primary Care Optometry News. “The first time around, they were showing about a millimeter of advantage with that combination, and the FDA would like to see more.”
A spokesperson from Pfizer stated that because Xalcom is pending FDA approval, the company is unable to discuss the drug at this time.
According to EyeNet Magazine Online, May 2001, a German trial of Xalcom found once-a-day dosing for 6 months resulted in IOP reductions that were greater than those seen with concomitant therapy. Study results showed a mean 1.2-mm Hg diurnal difference in IOP between the combination treatment and latanoprost alone and a 1.9 mm Hg difference between the combination and timolol alone.
A phase 3 study presented at the American Academy of Ophthalmology meeting in 2000 found a 2.9-mm Hg difference between Xalcom and timolol alone and a 1.1-mm Hg difference between Xalcom and latanoprost alone.
Dr. Bartlett said Xalcom appears to be an efficacious combination drug for glaucoma. “It has shown itself to be a reasonably good combination agent,” he said. “With Xalcom, you can get the pressure down at least as well as with concomitant separate latanoprost plus timolol.”
Alcon’s new combination drug
Alcon (Fort Worth, Texas) also has filed a New Drug Application for a new combination drug for treating glaucoma.
Data on this drug, currently identified as travoprost 0.004% plus timolol 0.5% fixed combination (TTFC), was presented at the Royal Hawaiian Eye Meeting. The data from one of these studies showed that TTFC reduced IOP by up to 12 mm Hg. TTFC reduced IOP 2 mm Hg more than travoprost 0.004% alone at the 8 a.m. time point. At the 10 a.m. and 4 p.m. time points, TTFC reduced IOP between 1 and 2 mm Hg more than travoprost 0.004% alone.
Alcon also presented preliminary data from two other phase 3 clinical trials. These trials compared the IOP-lowering effect of TTFC to concomitant therapy of travoprost 0.004% and timolol 0.5%. In the concomitant therapy, the travoprost was dosed in the evening, and the timolol was dosed in the morning. TTFC was found not to be statistically different from concomitant therapy at all the 8 a.m. time points and at most of the other measured time points.
The safety profile of TTFC when measured against concomitant therapy was found to be comparable, the study found.
“We believe the results of our clinical studies are compelling in that they demonstrate that TTFC may be able to achieve at least the same IOP reduction as travoprost and timolol used concomitantly, without a medically significant increase in side effects,” Stella Robertson, PhD, vice president of Alcon pharmaceutical products, research and development, told Primary Care Optometry News. “We hear regularly from physicians that they would welcome a combination product like this to reduce the frequency of the dosing schedule and to potentially improve compliance with the therapeutic regimen they prescribe.”
However, Dr. Bartlett reiterated the fact that companies must establish more than convenience and compliance to satisfy FDA requirements. “When TTFC and concomitant therapy were compared head to head, there was no statistical difference,” he said. “That tells me there may be some delay in getting this approved.”
Another possible approach to lowering IOP is the use of serotonergic 5-HT2 agonists, which Alcon scientists are currently studying in animals.
According to an abstract of a 2003 Alcon study on monkeys, “compounds [that] function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in man.” (May JA, McLaughlin MA, Sharif N, Hellberg M, Dean T. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys, Journal of Pharmacology and Experimental Therapeutics Fast Forward, 2003;April.)
Also in the pipeline
Recently approved in Canada as a combination drug, Combigan 5 mL (brimonidine tartrate 0.2%, timolol maleate 0.5%, Allergan, Irvine, Calif.) continues to await FDA approval in the United States. The company received an approvable letter, but the FDA required that an additional clinical trial be conducted.
“They may be facing the same hurdles with the FDA here in the United States in trying to show additivity,” Dr. Bartlett said.
A spokesperson from Allergan stated that because Combigan is pending FDA approval, the company is unable to discuss the drug at this time.
Cosopt: efficacy and convenience
Cosopt (dorzolamide HCl-timolol maleate, Merck & Co., Whitehouse Station, N.J.) gained FDA approval in April 1998 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Specifically, Cosopt is indicated for those patients who do not respond adequately to beta-blockers alone.
Dr. Bartlett said he finds Cosopt to be a “convenience drug” that is very useful in situations where patients have trouble with other types of medication.
“Typically, I put patients on prostaglandins first, then a topical carbonic anhydrase inhibitor second. If the patient has trouble with the prostaglandin, I may take him or her off of that and go to a beta-blocker,” he said. “In that case, if the patient is going to be on a separate bottle of carbonic anhydrase inhibitor, then another bottle of beta-blocker, I would switch to Cosopt for convenience.”
According to Dr. Bartlett, Cosopt is very effective in this type of situation. He said he might also reach for Cosopt in a situation in which a prostaglandin is unable to achieve target pressures.
“So instead of adding just one medication to the prostaglandin, I add Cosopt. This way, I have three drugs on board with the second bottle rather than two,” he said. “And I have found that I usually get a better pressure reduction when I use that particular combination vs. the beta-blocker added to the prostaglandin or the carbonic anhydrase inhibitor added to the prostaglandin.”
Dr. Bartlett said studies have yielded positive data about Cosopt. “When Cosopt first came out, there were several studies that looked at the advantages and disadvantages of having the two drugs in a single bottle,” he said. “They found that, in quite a number of cases, you can get better pressure reduction using the combination Cosopt rather than the concomitant individual bottles.
For Your Information:
- Jimmy D. Bartlett, OD, FAAO, is a lecturer and author who practices in Birmingham, Ala. He can be reached at the School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294-0010; (205) 934-3036; fax: (205) 934-6758; e-mail: Jbartlett@icare.opt.uab.edu. Dr. Bartlett has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Stella Robertson, PhD, is vice president of pharmaceutical products, research and development for Alcon. She can be reached at Alcon Laboratories, 6201 South Freeway, Fort Worth, TX 76134-2099; (817) 293-0450; fax: (817) 551-8893; e-mail: Stella.Robertson@AlconLabs.com.