At two years, Avastin (bevacizumab) and Lucentis (ranibizumab injection), two widely used drugs to treat age-related macular degeneration, improve vision when administered monthly or on an as-needed basis, although greater improvements in vision were seen with monthly administration, according to researchers involved in the Comparison of AMD Treatments Trials (CATT), a two-year clinical trial. Second year results were published in May in Ophthalmology. First year results were published in the May 19, 2011 issue of the New England Journal of Medicine

Most clinicians use these drugs on an as-needed basis when there is evidence of active disease, such as fluid leakage. However, in the original clinical trials for AMD, Lucentis was administered monthly. It was unknown if as-needed dosing would produce the same long-term visual improvements achieved with monthly administration.

Thus, CATT was designed to compare Avastin and Lucentis with monthly and as-needed treatment schedules. At enrollment, patients were assigned to four treatment groups defined by drug (Avastin or Lucentis) and dosing regimen (monthly or as-needed). After year one, patients initially assigned to monthly treatment were randomly reassigned to monthly or as-needed treatment without changing their drug assignment. 

At two years, visual acuity with monthly treatment was slightly better than with as-needed dosing, regardless of the drug. As measured on an eye chart, monthly treatment resulted in a mean improvement of about half a line better than as-needed dosing. Switching to as-needed treatment after one year of monthly treatment yielded outcomes nearly equal to those obtained with as-needed treatment for the full two years. Changes in retinal anatomy differed by drug and frequency of treatment, but did not have an impact on vision through two years. 

“Both drugs were highly effective regardless of the approach to dosing,” said Daniel F. Martin, MD, study chair for CATT and chairman of the Cole Eye Institute at the Cleveland Clinic. “There was slightly less vision gain with as-needed treatment. Patients seeking the small extra advantage of monthly treatment need to be mindful of the additional burden, risks and costs of monthly injections. Since as-needed dosing required 10 fewer eye injections over the course of two years and yielded similar visual results, many patients may choose this option.”

The median age of patients in CATT was over 80 years, and a high rate of hospitalizations would be anticipated as a result of chronic or acute medical conditions more common to older populations. Serious adverse events (SAEs) occurred at a 40-percent rate for patients receiving Avastin and a 32-percent rate for patients receiving Lucentis. Although Avastin had a higher rate of SAEs, they were distributed across many different conditions, most of which were not associated with Avastin when evaluated in cancer clinical trials, in which the drug was administered at 500 times the dose used for AMD. Fewer doses were associated with a higher rate of SAEs, which is not a typical dose-response relationship. The number of deaths, heart attacks and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. Additional data from other clinical trials may provide information on long-term safety profiles of these drugs when used to treat AMD. 

“The dramatic and lasting improvement in vision with these two drugs is extraordinary. At two-years, two-thirds of patients had driving vision (20/40 vision or better). With previous treatments, only 15 percent of patients retained similar visual acuity,” said Maureen Maguire, PhD, principal investigator, CATT Coordinating Center at the University of Pennsylvania. 

Also presented last month were the one-year results of the Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN) study, which also found the two drugs to be equally effective in treating neovascular AMD. The IVAN findings will also appear online shortly in Ophthalmology.

IVAN, conducted at 23 hospitals and universities in the UK, included 610 patients with wet AMD. The one-year results show there was no functional difference in the effects of both drugs and that the effects of Lucentis and Avastin on preventing vision loss were similar.

Patients received injections of the drug into the affected eye every month for the first three. Groups were then subdivided to receive either injections at every visit thereafter or only if the specialist decided there was persistent disease.

The study also investigated whether treatment as needed is as effective as monthly treatment, and revealed that giving the drugs as needed, compared to regularly every month, resulted in almost identical levels of vision. The as-needed group received on average seven injections over the first year compared to 12 for the monthly treatment group. 

In addition, patients in IVAN had their ability to read small print and their reading speed tested, and these tests also showed no difference between drugs or methods of treatment. 

IVAN had a slightly higher rate of arteriothromboembolic events (mainly heart attacks and strokes) or heart failure among people treated with Lucentis compared with Avastin, which was not observed in CATT. When the results of the two trials were combined no difference in heart attacks or strokes was observed between the two drugs. 

Both IVAN and CATT have consistently shown no difference in mortality between the groups receiving different drugs, but both found a slightly higher rate of other serious adverse events in those who received Avastin. This evidence became stronger when the results were combined. 

The researchers state that the findings in relation to adverse events may not be attributed to Avastin directly due to a number of reasons, including that events were more common in patients treated less frequently and that they arose mainly from hospitalizations for a wide variety of causes not previously associated with either drug.

IVAN is continuing to follow participants to two years. A more detailed analysis will be presented when the two-year time point is reached.

Research Breakthrough In Dry AMD
University of Kentucky researchers, led by Jayakrishna Ambati, MD, report a major breakthrough in dry AMD or geographic atrophy. Their study was published in the April 26 online edition of Cell.

Previous research from Dr. Ambati’s laboratory showed that in human eyes with geographic atrophy there is a deficiency of the enzyme DICER1, leading to accumulation of toxic Alu RNA molecules in the retinal pigmented epithelium. The Cell paper shows that when these RNAs build up in the eye they trigger activation of an immune complex known as the NLRP3 inflammasome. In turn, this leads to the production of a molecule known as IL-18, which causes death of RPE cells and vision loss by activating a critical protein known as MyD88.

Dr. Ambati and colleagues found evidence that activity of the inflammasome, IL-18 and MyD88 were all increased in human eyes with GA. They then showed that blocking any of these components could prevent retinal degeneration in multiple disease models. The researchers are excited that blocking these pathways could herald a new potential therapy for GA, for which there is no approved treatment.

Diabetes Drug Metformin Blocks Uveitis in Rats
University of Texas Medical Branch at Galveston researchers have discovered that a drug already prescribed to millions of people with diabetes could also have another important use: treating uveitis. 

In lab rat and cell-culture experiments, metformin, which is commonly used to control blood sugar levels in type 2 diabetes, also substantially reduced the effects of uveitis. Uveitis causes 10 to 15 percent of all cases of blindness in the United States. The only treatment now available  is steroid therapy, which has serious side effects and cannot be used long-term.

“Uveitis has various causes—the most common are infectious diseases and autoimmune disorders—but they all produce inflammation within the eye,” said UTMB professor Kota V. Ramana, PhD, senior author of the study now online in Investigative Ophthalmology & Visual Science. “Metformin inhibits the process that causes that inflammation.” 

The scientists discovered metformin’s efficacy when they tested it in rats given an endotoxin that mimicked the inflammatory effects of bacterial infection. The results showed clearly that metformin was a very effective anti-uveitis agent.

“We found that the drug is therapeutic as well as preventive—if we gave our rats the drug beforehand, they didn’t develop uveitis, and if we gave it after uveitis had developed, it was therapeutic,” said UTMB professor Satish Srivastava, PhD, also an author of the IOVS paper. “Metformin’s strong anti-inflammatory properties make this possible.”

Metformin works by activating an enzyme called AMPK, which in turn damps down the activity of the protein NF-kappa B. The inhibition of NF-kappa B suppresses the production of inflammatory signaling molecules—cytokines and chemokines—needed to initiate and sustain uveitis. 

Because metformin is already used so widely as a therapy for diabetes, the UTMB scientists believe that it has a good chance of being rapidly adopted as an anti-uveitis drug. 

“I think after a few more pre-clinical studies are done, we can get this drug to patients in a shorter time than usual,” Dr. Ramana said. “Its safety is already known, so all that we need to see is its efficacy in humans.”

Oraya Trial Meets Primary Endpoint
Oraya Therapeutics announced that the INTREPID trial of radiation therapy has met its primary endpoint of reduction in anti-VEGF injections for patients with wet AMD. INTREPID is the first sham-controlled, double-masked trial to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. Preliminary result analyses found no indication of radiation-related adverse events at the one-year trial endpoint.

Enrollment in the INTREPID trial was completed on April 15, 2011. All 230 patients had previously received at least three anti-VEGF injections in the prior year and required further anti-VEGF treatment. Within two weeks following injection, one-third of the subjects received a sham exposure and the remainder received a radiation dose of either 16 or 24 Gray (Gy). They were then followed monthly and treated with anti-VEGF (Lucentis) as-needed according to specified reinjection criteria. The multinational study included sites in Austria, Czech Republic, Germany, Italy and the United Kingdom. 

“We are excited about the opportunity to bring this important technology and its benefits to physicians, patients and their families to help ease the burden and cost associated with the treatment of [AMD],” said Jim Taylor, CEO of Oraya. “Our intent is to focus our early commercial efforts in the countries that were part of the trial, and we expect that the first participating sites will initiate treatments within the next few months.”  REVIEW