CLINICAL TRIAL SPOTLIGHT

TargeGen Targets Wet AMD With Eyedrop

Phase 2a trial to test enzyme inhibitor for safety and efficacy.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

TargeGen (San Diego) has announced its intention to enroll patients in a phase 2 trial for its age-related macular degeneration (AMD) drug TG100801, perhaps as early as this month. Initial phase 1 results, discussed in a press release of Feb. 27, 2007, indicated that the small-molecule drug was well tolerated in healthy subjects when administered twice daily. Phase 2a will enroll treatment-naïve patients suffering from subfoveal choroidal neovascularization due to exudative AMD. Peter K. Kaiser, MD, a retinal specialist at the Cleveland Clinic Foundation Cole Eye Institute and an investigator on the study, spoke with Retinal Physician about the upcoming trial.

"TG100801 is actually a prodrug," Dr. Kaiser says. "The active form is TG100572. It's in the class of tyrosine kinase inhibitors, working on kinases that are involved in the vascular endothelial growth factor (VEGF)-signaling pathway. So, it inhibits downstream VEGF activation of endothelial cells and blocks the effect of VEGF on the receptors by blocking the enzyme."

It is the very small size of TG100801 that has, in part, made it the subject of interest by research ophthalmologists. Dr. Kaiser says, "It's been shown in multiple animal models to inhibit VEGF and CNV growth, including the VEGF induced vascular permeability model and the Ryan laser-induced CNV model with similar efficacy as pegaptanib sodium (Macugen, OSI/Pfizer), bevacizumab (Avastin, Genentech), VEGF Trap (Regeneron), and other drugs that have been tested in these models, but this is a topical drug."

The ability of TG100801 to permeate the eye has also been shown, Dr. Kaiser says. "What is very exciting about this drug is that there are indeed very high levels at the choroid. With topical administration, it appears to enter via a trans-scleral entry route. The fact that it's a prodrug allows even better penetration and greater VEGF inhibition than the actual drug itself."

Another obvious attractive feature of TG100801 is that, because it is topically administered, patients will not have to undergo intravitreal injections. "This will be easier on the patients," Dr. Kaiser says, "and so we hope to enroll this trial quickly." The current enrollment goal is 40 patients. Dr. Kaiser stresses that the enrollment criteria are broad. "We are accepting patients with subfoveal CNV due to exudative AMD with any lesion composition and with sizes as large as 12 disc areas."

Discussing the primary endpoint for the phase 2a trial, Dr. Kaiser says that retinal-thickness measurement will be done with optical coherence tomography (OCT). "What we're trying to determine is the effect of this drug taken topically twice a day for 30 days on OCT retinal thickness." In addition, other safety and efficacy parameters will be explored including visual acuity.

The Feb. 27 press release hinted at possible indications for TG100801 other than AMD, including diabetic macular edema (DME) and diabetic retinopathy. "As we get more and more information from the AMD studies, DME studies will certainly be in the pipeline," Dr. Kaiser says. "Really, any macular edema caused by VEGF could benefit from this drug including macular edema from retinal vein occlusions." Furthermore, while TG100801 has only been shown to work on VEGF-initiated angiogenesis, Dr. Kaiser says, "It's not out of the question for this drug to work on other growth factor pathways that work via the tyrosine kinase cascade."

Finally, there is a rescue criterion for the phase 2a study, which will likely make it even more attractive to potential enrollees — follow-up treatment with ranibizumab (Lucentis, Genentech). "If, after a month, a patient's OCT gets worse or their visual acuity deteriorates," Dr. Kaiser says, "they'll receive rescue treatment with Lucentis."

Dr. Kaiser indicates that the investigators on the phase 2a trial will be meeting this month and that enrollment will begin following that meeting. According to the TargeGen Web site, phase 2b studies of TG100801 will begin shortly after the phase 2a studies have begun. RP