Two major drug trials conclude there was little risk from the AMD drug Lucentis (ranibizumab). Yet a Mayo Clinic ophthalmologist began to note something concerning in some of her patients: an increase in pressure inside the eye. It led to a retrospective study and findings that was presented at last month’s American Academy of Ophthalmology meeting.

Sophie Bakri, MD, had been treating patients in her clinic with FDA-approved ranibizumab, when she began noticing a change in some patients. “I was treating patients and measuring pressures, and I was surprised to see that in some of these people, their intraocular pressure was higher, and they didn’t have a diagnosis of glaucoma,” Dr. Bakri says. “So, why did the pressure go up? Was it from the drug itself, or the actual injection? Is this real? You don’t know if it’s a fluke unless you go back and look at the clinical trials. I took a closer look at the pooled data.” 

Data from the two clinical trials in many ways held the answers to Dr. Bakri’s questions, but she found that knowing what to look for helps. 

MARINA and ANCHOR evaluated drugs, including Lucentis, for treatment of age-related and other forms of macular degeneration. Both were two-year studies with monthly injections of Lucentis, compared to a control group who did not receive the injection. Pooling the two studies, which followed the treatment of 1,125 eyes, Dr. Bakri was able to perform a more robust evaluation of IOP changes. Some patients received Lucentis and others unknowingly received sham injections, or verteporfin photodynamic therapy.

Dr. Bakri found what she suspected: a subset of patients had increased IOP.

“We still don’t know if it goes up because of the drug or the pressure of the repeated monthly injections, or both,” she says. The take-home finding: Intraocular pressure should be monitored in eyes receiving ranibizumab. 

“A greater proportion of eyes in the ranibizumab groups had IOP increases regardless of the presence or absence of pre-existing risk factors, such as history of glaucoma, suspicion of glaucoma, ocular hypertension or use of a glaucoma medication,” Dr. Bakri says. 

A small portion, 8 percent, of all eyes across treatment groups received glaucoma medications in the study. Importantly, none of the patients needed glaucoma surgery.

“Our analysis was surprising because the increase was so prevalent and highly statistically significant,” Dr. Bakri says. “Lucentis is an excellent drug that works very well, but if we use a drug, we gain long-term experience, and that’s where side effects start showing up.”

Two new studies add to the growing body of evidence that femtosecond laser cataract surgery may be safer and more efficient than today’s standard procedure. The new approach is FDA-approved, but not yet widely available in the United States. Research reported at the American Academy of Ophthalmology meeting by William W. Culbertson, MD, of the Bascom Palmer Eye Institute at the University of Miami School of Medicine, and by Mark Packer, MD, of Oregon Health and Sciences University, confirms several advantages of laser cataract surgery. 

Dr. Culbertson’s team studied how pre-treating cataracts with the femtosecond laser affected the level of ultrasound energy. In Dr. Culbertson’s prospective, randomized study, 29 patients had laser cataract surgery with a femtosecond laser in one eye and standard phacoemulsification in the other. Laser surgery included a laser capsulotomy, followed by laser lens fragmentation, then ultrasound emulsification and aspiration. Lens fragmentation involved using the laser to split the lens. Standard surgery included a manual incision, followed by ultrasound emulsification and aspiration. After cataract removal by either method, intraocular lenses were inserted.

The use of ultrasound energy was reduced by 45 percent in the laser pre-treated eyes compared with the eyes that received the standard cataract surgery procedure. Also, surgical manipulation of the eye was reduced by 45 percent in eyes that received laser pre-treatment as compared to manual standard surgery. This study involved the most common types of cataracts, those graded 1 to 4. Dr. Culbertson notes that these findings may not apply to higher grade cataracts.

“In clinical practice, surgeons would expect safer, faster cataract surgery when laser pre-treatment is performed before cataract removal,” said Dr. Culbertson. “The combination of precision and simplification that is possible with the femtosecond laser represents a major advance for this surgery.”

Dr. Packer’s team at the Oregon Health & Sciences University in Portland, Ore., assessed the safety of laser cataract surgery in terms of loss of corneal endothelial cells as measured after cataract surgery. Dr. Packer’s study found that when laser lens fragmentation was used in 225 eyes, there was no loss of endothelial cells, while the 63 eyes that received standard treatment had cell loss of 1 to 7 percent. 

“Our finding, that laser lens fragmentation appears to protect corneal endothelial cells, represents a significant benefit of this new surgery,” said Dr. Packer. “This procedure is safer than standard cataract treatment and is likely to mean better vision and fewer eye-health concerns for cataract patients over the long term.”

Earlier studies of femtosecond laser cataract surgery found other benefits. The laser allows the surgeon to make smaller, more precise incisions and to perform improved capsulotomies. This reduces the chance that an IOL will later become displaced. Also, laser cataract surgery appears to improve results in patients who opt for advanced technology IOLs, plus corrective corneal incisions, to achieve good all-distance vision.

A recent study gives hope to those suffering from severe cases of bacterial corneal ulcers, which can lead to blindness if left untreated. The use of topical corticosteroids in a randomized controlled trial was found to be neither beneficial nor harmful in the overall patient population in the study. However, it helped patients who had more serious forms of bacterial corneal ulcers, according to University of California, San Francisco researchers.

In a paper published in October’s Archives of Ophthalmology, researchers found significant vision improvement—one and a half to two lines of improvement—by using steroid therapy on patients with severe ulcers.

“We consider this finding very significant; it’s a clinically meaningful difference,” said the paper’s co-author Nisha Acharya, MD, MS, associate professor and director of the Uveitis Service in the UCSF Department of Ophthalmology. Although secondary to the study’s original purpose, Dr. Acharya said the results in severe cases were identified early on, so “we didn’t start doing all of these analyses after the fact. It was of interest. So I think there is something there.”

The use of topical corticosteroids is somewhat controversial within the ophthalmology community, with no specific evidence pointing one way or the other. Concerns include corneal perforation and worsening vision.

“It’s important to note that in the worst ulcer group, not only do we not find a safety problem, we actually found that steroids resulted in a benefit in vision,” Dr. Acharya said. “So I think that is really reassuring because those were the people with whom we were most scared to use steroids.”

UCSF researchers collaborated with colleagues at the Aravind Eye Care System, in Madurai, India. They studied 500 participants from the United States and India between September 2006 and February 2010 in the Steroids for Corneal Ulcers Trial (SCUT). Half of the patients received corticosteroid treatment and the other half received placebos.

Complications from contact lens use are the most common culprit in corneal ulcers in the United States, while agriculture-related injuries are the most common in India. Researchers checked participants three months after the start of the trial, testing for visual acuity and corneal perforations. Patients showed no significant improvement in their vision for participants in the corticosteroid treatment group versus those in the control group.

The study also reinforced the use of steroids in treatment of the ulcers because it found that they were not harmful.

“There was no increase in cornea perforations in our patient population,” Dr. Acharya said. “I’m reassured to know that it’s not associated with harm.”

Building on their findings, Dr. Acharya and her colleagues intend to continue their work, studying patients with even more severe corneal ulcers.

   

“It makes us feel like we’re moving towards an evidence-based paradigm of care for corneal ulcers rather than a trial-and-error sort of approach,” Dr. Acharya said. “We have a good collaboration and now that we’ve had some success with this, we hope to be able to continue with it to answer other questions related to this field.”

ISTA: Phase III Results for Two Drugs

Ista Pharmaceuticals announced statistically significant results from the company’s Phase III clinical program for Prolensa (bromfenac ophthalmic solution), a low concentration of bromfenac in a modified ophthalmic solution developed to treat pain and inflammation associated with cataract surgery. In both Phase III studies, Prolensa was statistically significantly better than placebo and met the primary efficacy endpoint of absence of ocular inflammation 14 days following surgery and the secondary efficacy endpoint of elimination of ocular pain one day post-surgery. There were no serious drug-related ocular or systemic adverse events, and Prolensa’s safety profile was found to be consistent with Ista’s currently marketed topical non-steroidal anti-inflammatory compound, Bromday (bromfenac ophthalmic solution) 0.09%.

“Our goal with the bromfenac franchise has been to deliver a safe and highly effective treatment for pain and inflammation post-cataract surgery, with the most convenient dosing schedule,” said Timothy R. McNamara, PharmD, vice president of Clinical Research and Medical Affairs at Ista. “The new, optimized formulation used for Prolensa enhances the penetration of the drug into ocular tissues, allowing us to lower the concentration of the active ingredient, bromfenac, while maintaining the convenience of once-daily use currently prescribed with Bromday. This study had the lowest number of adverse events (greater than 2 percent) than any of our bromfenac clinical trials for cataract surgery to date. And, to the best of our knowledge, Prolensa contains the lowest concentration of bromfenac currently under investigation in any clinical trials for inflammation and pain associated with cataract surgery. We are very pleased with the strong clinical results for Prolensa, as they represent an important step in extending the commercial success of our bromfenac product line. Based upon the results … we plan to file a New Drug Application with the FDA for Prolensa in the first quarter of 2012, with a commercial launch planned for late 2012 or early 2013.”

Ista also announced top-line results from the second of its two Phase III studies to evaluate the short-term safety and efficacy of two concentrations of Remura (bromfenac ophthalmic solution for dry eye) in alleviating the signs and symptoms of dry-eye disease.

In the EAST study, Remura was highly effective in treating a sign and symptom of dry eye but was not statistically significantly better than placebo in the entire patient cohort, a common outcome reported in studies testing other dry eye therapies. In both Phase III studies, safety data demonstrated Remura was well-tolerated, with an adverse event profile similar to placebo and consistent with those observed previously with Remura in a Phase II study and with other prescription dry-eye drops. All three formulations were rated by patients as very comfortable.

“For the EAST study, we amended the statistical plan to focus on the subpopulation identified in the WEST study as responders,” said Dr. McNamara. “In the previously announced WEST study, the results showed a statistically significant improvement over placebo in the sign of conjunctival staining, as measured using the lissamine green staining test, among female patients 51 to 70 years of age with moderate dry-eye disease. However, the EAST study did not show a significant difference from placebo in this subpopulation, which we believe is partly due to the fact that the EAST study enrolled far fewer patients with mild to moderate dry-eye disease. We will complete a full analysis of the data, but focus our efforts on the potential use of the vehicle as an over-the-counter artificial tear product.”