CT SPOTLIGHT

An Antibiotic for Dry AMD?

A Virginia ophthalmologist bets on doxycycline.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

What if an effective treatment for dry AMD, one that could halt geographic atrophy and its vision-destroying consequences, has been right in front of us all along? What if the drug that could do this had been invented 50 years ago?

If Paul Yates, MD, PhD, who is assistant professor of ophthalmology at the University of Virginia, is right, then doxycycline is that drug. The tetracycline-class antibiotic, which is also used to prevent malaria and treat acne, has demonstrated anti-inflammatory properties in lower doses that may target the underlying pathophysiology of AMD. Dr. Yates discussed his trial with Retinal Physician.

MULTIPLE TARGETS

“The overall rationale for using tetracycline derivatives,” Dr. Yates explains, “is that they reduce reactive oxygen species, inhibit matrix metalloproteinases (MMPs) that are involved in the breakdown of the barrier between the RPE and Bruch’s membrane, inhibit caspase activation and thereby prevent cell death, prevent complement activation, and inhibit cytokine production through their effects on microglia and T-cell activation.” Dr. Yates says.

All of these pathways are known to be associated with the development of dry AMD. A possible advantage of doxycycline over other candidate drugs for dry AMD is that doxycycline may be able to achieve synergistic effects by inhibiting more than one pathway.

A KNOWN QUANTITY

Another nice thing about doxycycline is that, because it has been around so long, its safety profile is well known. The most serious concern about longterm antibiotic use is the rise of antibiotic-resistant infections, including Clostridium difficile colitis.

However, the 40-mg dosage used in this study, 30-mg immediate release and 10-mg delayed release, has been shown to be subantimicrobial. Dr. Yates says an attractive aspect of doxycycline over other tetracycline derivatives, such as minocycline, is the clear dosing split between its anti-microbial (>100 mg/day) and anti-inflammatory (40 mg/day) effects.

Dr. Yates also notes that long-term subantimicrobial doses of doxycycline for treating chronic periodontitis have shown no alterations in the composition of oral or intestinal microflora.

TOGA PARTY

Galderma Laboratories, LP (Fort Worth, TX) manufactures Oracea (40 mg doxycycline that is FDA-approved to treat active-form skin lesions due to rosacea), and will supply the study drug for this investigator-initiated trial.

The trial has been dubbed TOGA: Treatment with Oracea for Geographic Atrophy. The primary outcome measurement is the ability of Oracea to inhibit progression of geographic atrophy (GA) as measured by standard fundus photography.

Participants will complete a six-month observation period to determine their baseline rate of GA progression and then will be randomly assigned in 1:1 ratio to either Oracea or placebo control once daily for 24 months. The TOGA study will enroll 246 patients at approximately 20 sites in the United States.

INTERESTED IN MORE INFORMATION?

Dr. Yates expects the trial will begin enrolling participants in late summer. Sites interested in participating in this trial should contact Dr. Yates directly. For more information on the TOGA study, go online to http://clinicaltrials.gov/ct2/show/NCT01782989.RP