- Professor Paul Sternberg, Jr. discusses the Phase II trial results of OT551, an antioxidant eye drop under development by
Othera Pharmaceuticals for the treatment of non-exudative age-related macular degeneration. He considers how new treatment
targets are being explored, what other promising agents are on the horizon and how these will change the lives of dry AMD
While the treatment for the more rapidly progressive stage of age-related macular degeneration (AMD) — neovascular, or wet,
AMD — has evolved rapidly in recent years, currently there is no medical therapy or surgical intervention available to slow
the development of or prevent progression from the more insidious, non-exudative, stage of the disease. Failing to develop
effective treatments for the non-exudative form of the disease means that the macula will continue to deteriorate, ultimately
suffering permanent, irreversible, damage. Treatments for wet AMD are expensive as well as invasive, but have been highly
successful because they do not merely limit or arrest further disease progression, but they frequently lead to improvements
in visual function.
It is clear that this situation must be remedied. In light of new understanding about the pathogenesis of the condition, several
pharmaceutical companies are currently developing therapies for dry AMD. Complement inhibitors have shown some promise; likewise,
interest in antioxidants and neuroprotective factors is gaining momentum. Following the discovery of the first genes known
to be implicated in the development of the disease, however, recent research1 suggests that short interfering RNA therapies may be counter-productive in the treatment of dry AMD.
Dr Paul Sternberg, the study chairman of Othera Pharmaceutical's OMEGA (Multicenter Evaluation of Geographic Atrophy) trial
of OT551, a topical antioxidant designed to treat geographic atrophy in dry AMD, explains the compound's mechanism of action,
and discusses why eye drops may be the safest and most efficacious therapeutic approach.
Could an eye drop really be the key?
OT551 is a small lipophilic molecule that has been shown to penetrate the cornea easily and to achieve therapeutic levels
in animal models. Once inside the eye, the compound is converted to Tempol-H (tempol hydroxylamine), an agent developed to
treat cataracts. The drop is then distributed rapidly within the eye: it is detectable in the retina within 15 minutes of
topical administration and for up to 16 hours thereafter.
"In the trial, the efficacy of the eye drop, at doses of 0.45% and 0.3%, is being compared with placebo to determine the effect
on reducing the area of progression of geographic atrophy," explained Dr Sternberg.
For the two-year duration of the trial, patients self-administer the drug four times daily; to establish efficacy and safety,
the trial investigators will evaluate changes in the extent of geographic atrophy and best-corrected visual acuity, as well
as monitoring adverse events. The first patients to be treated in the trial were selected in June 2007 and randomly assigned
to drug or placebo, with the final patients recruited in March 2008.
"We're currently in a Phase II trial: we hope to be able to review the 12-month data sometime this spring and report the results
later in the year," Dr Sternberg commented. "We presented some early data at the AAO meeting last year, just to let people
know that the trial was ongoing: that we had recruited patients, and that demonstrating efficacy was the goal of this trial.
Hopefully, we'll be able to initiate a Phase III trial once we have some promising results."
According to Dr Sternberg, the trial is progressing well and providing insights that might be beneficial in developing a medical,
therapeutic treatment for dry AMD.
What's in the pipeline?
"The first thing that's exciting about the OMEGA trial is that there is actually a trial to begin with — the idea that we
could treat dry AMD with nothing more than an eye drop is incredible. And Othera isn't the only company exploring such possibilities:
OT551 is one of a half dozen new compounds for dry AMD being explored by various companies," clarified Dr Sternberg.
Other compounds currently in development for dry AMD include ACU-02 (Acucela, Inc), an oral compound that reduces the accumulation
of A2E, thereby preserving retinal cells; NT-501 (Neurotech Pharmaceuticals), an intraocular, cell-containing polymer implant
that provides continuous, long-term release of the therapeutic protein Ciliary Neurotrophic Factor (CNTF) directly into the
back of the eye; POT-4 (Potentia Pharmaceuticals), designed to reduce inflammation and modify the upregulation of factors
influencing angiogenesis by binding to complement component C3; ARC1905 (Ophthotec Corp), an anti-C5 complement aptamer that
incorporates anti-VEGF properties; and MC-1101 (MacuCLEAR), an eye drop targeting geographic atrophy.
"As someone who's been researching dry AMD for 20 years and trying to get the attention of the pharmaceutical industry, it's
wonderful that now they recognise the condition as a major cause of vision loss that needs to be approached aggressively with
new drug treatments," Dr Sternberg enthused.
The future of dry AMD treatment
Unlike the currently approved therapies for wet AMD (but in common with many of the treatments in development for dry AMD),
OT551 is neither an injection nor a sustained release system, but an eye drop.
"This approach is very advantageous. It's certainly easier for the patients: they don't have to come in regularly for treatments
or go to the operating room. In addition, eye drops are a standard approach: drops have been used for many years to treat,
for example, glaucoma and infections, so patients are familiar with how to use them," Dr Sternberg continued. "If OT551 turns
out to be efficacious, it will certainly have good applicability towards our patients."
Eye drops offer significant benefits over other treatment methods, in terms of cost, convenience, and patient adherence; the
fact that this approach is being explored by multiple companies is encouraging, and bodes well for the future of dry AMD treatment,
as it has now become conceivable that patients diagnosed with the condition will not be forced to accept developing wet AMD
as an inevitable consequence.
"Patients with dry AMD should be optimistic that there are new treatments on the horizon. We hope within the next couple of
years to have eye drops for dry AMD clinically available, and then we'll be able to start to make some inroads into the treatment
of dry AMD, just like we've been able to do for wet AMD," Dr Sternberg concluded.
Paul Sternberg, Jr., MD is the G. W. Hale Professor and Chairman of the Vanderbilt Eye Institute, Nashville, Tennessee, US. He may be reached by