A Guide to Research in Dry AMD

PHARMACEUTICAL

Acucela

On June 4, 2008, Acucela Inc. announced that it had dosed the first subject in a Phase I trial for its lead compound ACU-4429 (formerly ACU-02), an orally available small molecule being developed for the treatment of dry AMD. ACU-4429 modulates the visual cycle by significantly reducing the accumulation of the retinal related toxic by-product A2E, believed to damage retinal cells.

Dr. Ryo Kubota, Acucela's chairman and chief executive officer, says that, because the drug is a non-retinoid (not derived from vitamin A), it has the potential to be safe for a wide range of people, including young patients and women of child-bearing age. Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness, says ACU-4429 may also be a beneficial treatment for people with Stargardt disease.

In January 2010, following the success of the Phase I clinical trial, Acucela began recruiting participants with dry AMD for Phase II

Known as the ENVISION Clarity Trial, the 90-day dose-escalation safety study offered 56 subjects with geographic atrophy either ACU-4429 or placebo once per day. Approximately four hours after subjects were given either ACU-4429 or placebo, and following pupil dilation and dark adaptation, electroretinogram (ERG) measurements were recorded at multiple time points after three minutes of exposure to a bright, bleaching light. The interim data was reported at the annual ARVO meeting in May 2012. It showed that subjects receiving ACU-4429 had a dose-dependent response and that rod visual cycle was modulated, as measured by ERG, for doses up to 10mg.

The results of Acucela's Phase 2 trial were announced at the ARVO meeting in 2013. This proof of concept study demonstrated a dose-dependent biologic effect and ACU-4429's ability to modulate the visual cycle. Systemic adverse events were minimal. Results suggest that ACU-4429 (now called emixustat HCl) may be a useful agent in the treatment of geographic atrophy. A long-term Phase 2b/3 study is now underway to evaluate the drug. For more information about the trial, contact Covance Clinical Research Unit in Dallas, Laura Lonsdale at (214) 920-9053, Covance Clinical Research Unit in Austin, David Carter at (512) 302-6519, or visit www.clinicaltrials.gov and search for "Acucela."

More about Acucela.

Tandospirone (AL-8309B)

AL-8309B, a selective serotonin 1A agonist, is under evaluation by Alcon for dry AMD. Applied as an eyedrop, it is expected to slow atrophic lesion growth and improve visual acuity. Results are expected in 2012. ARC1905

Ophthotec's ARC1905 works selectively, blocking the complement factor (C5) that seems to contribute to dry AMD, while allowing other immuno-protective complement factors in the body to work. A Phase I clinical trial on patients with wet AMD showed the treatment to be safe, with almost 50% of participants gaining vision. An additional Phase I study is now underway in patients with dry AMD.More about ARC1905.

Aspirin

Aspirin appears to be beneficial as a preventer of AMD. More about aspirin and AMD.

Brimonidine Tartrate Implant

Allergan is testing the effectiveness of injecting an implant into the vitreous of the eye containing brimonidine tartrate. Brimonidine is approved by the FDA for the treatment of glaucoma, but it shows potential for slowing vision loss from AMD. The trial ended in 2011, and patients are being followed through 2013.

Carbon dioxide

AMD patients are benefitting from a new drug therapy involving a combination of medicines which includes carbon dioxide. More about carbon dioxide therapy.

Copaxone

Copaxone (glatiramer acetate) injections are given in Alzheimer's disease to decrease destructive beta-amyloid deposits. These deposits are similar to the proteins seen in drusen found in dry AMD, so researchers are trying copaxone for treatment of dry AMD. In week 12 of a small preliminary study, 4 eyes (3 patients) treated with copaxone showed a total reduction of drusen area from baseline of 66%. Two eyes receiving sham injection had essentially no significant change in drusen area.

Ref: www.medscape.com/viewarticle/564015_2

Eculizumab for Geographic Atrophy

Alexion Pharmaceuticals concluded The COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study in June 2012. It was designed to prospectively evaluate the effect of eculizumab, a systemic inhibitor of complement component 5 (C5), on the development of geographic atrophy. Eculizumab was well tolerated through the first 6 months of the trial. The 6-month outcome data are currently being analyzed and will be presented.

FCFD45145

Genentech/Roche has developed this drug to be injected into the eye to block a rate-limiting enzyme called complement factor D. Factor D is thought to be associated with dry AMD by genetic association. Trials are underway.

Encapsulated Cell Technology (ECT

ECT is a means of delivering drugs into the retina on a time release basis. It is achieved by a device called Renexus (formerly NT-501) implanted into the vitreous of the patient's eye. Renexus continuously produces and releases a drug called ciliary neurotrophic factor (CNTF) over a period of two years to preserve the health of the retinal photoreceptor cells. In May 2011, results from Phase 3 clinical trials showed continued promise. More about ECT.

Fenretinide

Fenretinide (RT-101), a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt's patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE's ability to nourish the photoreceptors. News of the drug was worth following, but the developer, Sirion Therapeutics, announced in February 2012 that the trials had been suspended. The FDA ruled that the Phase 2 results were flawed, and, for now, the high cost of continuing the trials has halted further research. More about fenretinide.

GSK933776 for Geographic Atrophy

This is a Phase 2a proof of concept study conducted by GlaxoSmithKline to evaluate the safety and efficacy of GSK933776 via intravenous infusion for the treatment of geographic atrophy. Estimated trial completion date is March 2014. Iluvian (fluocinolone acetonide)

Iluvian is a corticosteroid that has shown signs of preventing macular degeneration in animals. PSivida Ltd. has begun an early-stage clinical trial for testing a tiny implanted insert called Medidur for delivery of the drug to the retinas of patients with bilateral geographic atrophy (dry AMD). Iluvien is being evaluated in the MAP-GA trial, funded by Alimera Sciences, the developers of the delivery system. The trial is designed to assess whether low dose, sustained-release Iluvian can slow the progression of geographic atrophy in patients with dry AMD.

MC-1101

MC-1101 is a proprietary, topically administered eye drop drug for treating and stopping the progression of AMD from the early-stage (Dry AMD) to the late-stage (Wet AMD) by increasing ocular blood flow in the choroidal vessels. It was developed by MacuCLEAR, Inc. (Plano, Texas) under the leadership of George Chiou, Ph.D.

MacuCLEAR has completed a successful Phase Ib/proof of concept human clinical trial for MC-1101 which showed that the drug is safe and well tolerated by study subjects.

The first stage of MacuCLEAR's double-blinded Phase III study will examine 60 patients, using improvements in visual function as the trial's primary endpoint. In addition to the data from this Phase III trial, MacuCLEAR will submit results from non-clinical studies to the FDA before filing for a new drug application.

Ref: www.macuclear.com

RN6G

A study by Pfizer beginning in June 2012 and ending in June 2014 to test the safety and efficacy of intravenous RN6G on development of geographic atrophy.

OT-551

On February 26, 2007, Othera Pharmaceuticals presented new preclinical data demonstrating the safety and effectiveness of OT-551, an experimental drug in eye drop form for treatment of geographic atrophy (end stage dry AMD). Results from the Phase I trials demonstrated that when the compound is added to either Lucentis or Avastin treatment there is a synergistic effect versus either treatment alone. According to Dr. Len Parver, Othera's Medical Director, "OT-551 could potentially improve the outcome of patients already on Lucentis by treating the underlying macular degeneration and decreasing the need for frequent Lucentis injections."

On April 8, 2009, Othera announced positive interim data results from its Phase 2 trial of OT-551. The 12-month findings from the 2-year trial suggest an emerging trend for reducing moderate vision loss (i.e. 15 letters or more on the ETDRS chart) in treated patients compared to the placebo group.