Barbara Boughton

November 09, 2009

November 9, 2009 (San Francisco, California) — Oral treatment with the immunosuppressant voclosporin for noninfectious uveitis might be a real advance for treating the eye disease, which can result in complications in up to one third of patients and is implicated in as much as 10% of blinding eye disease, according to several studies presented here at the American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology.

Findings from 2 clinical trials of voclosporin (Luveniq) indicate that treatment resulted in a significant decrease in inflammation, compared with placebo, in active disease and reduced the risk for recurrence in quiescent disease. Patients also experienced fewer adverse effects with voclosporin than with other drugs in the same class, which are current treatments for uveitis.

"This is a historic moment in the field of uveitis and ocular inflammatory diseases, because we have demonstrated success with the first randomized controlled trial with an immunomodulatory agent for the treatment of noninfectious uveitis. It addresses a major unmet medical need," said researcher Quan Dong Nguyen, MD, MSc, associate professor of ophthalmology at the Wilmer Eye Institute of the Johns Hopkins University in Baltimore, Maryland.

Dr. Nguyen noted that most current treatments for uveitis are used off-label, and treatment often involves steroids that have significant adverse effects. The US Food and Drug Administration has granted voclosporin fast-track status, and its manufacturer, Lux Biosciences, plans to file a New Drug Application for marketing approval in the United States by the end of 2009 or early in 2010.

The LUMINATE program, sponsored by Lux Biosciences, involved 3 different clinical trials with different end points. LX211-01 tested the drug in the treatment of active posterior inflammation, LX211-02 was an investigation of maintenance and control of quiescent inflammation, and LX211-03's objective was the treatment of active anterior inflammation in medical centers in North America, Europe, and India. Results of LX211-01 and LX211-02 were presented at the meeting, as were safety data for all 3 studies.

In LX211-01, 217 patients with active posterior segment uveitis received active treatment with voclosporin 0.2 mg/kg, 0.4 mg/kg, or 0.6 mg/kg, all given twice daily, or placebo. At 16 and 24 weeks, the 0.4 and 0.6 mg/kg dosages of voclosporin significantly reduced inflammation, compared with placebo, while preserving visual acuity and reducing corticosteroid use to less than 5 mg daily. The study was designed to detect a mean difference of 1 grade from placebo with 90% power.

In the LX211-02 trial, 232 patients with quiescent uveitis received voclosporin 0.2, 0.4, or 0.6 mg/kg twice a day or placebo. In the trial, corticosteroids were tapered to less than 5 mg daily over 12 weeks.

The LUMINATE investigators told meeting attendees that voclosporin 0.4 mg/kg reduced inflammation by 50% at 26 weeks, compared with placebo, while preserving visual acuity. The estimated mean time to exacerbation based on 26-week data was 10.3 months in the placebo group and 24.1 months in the voclosporin group. "We successfully reduced inflammation in these patients, but it's also important to do longer-term follow-up," said researcher Bahram Bodaghi, MD, PhD, professor of ophthalmology at the Pitié-Salpêtrière University Hospital, Université Pierre et Marie Curie in France.

In interviews with Medscape Ophthalmology, Dr. Bodaghi and Dr. Nguyen both noted that the 0.4 mg/kg dose of voclosporin might eventually prove the most beneficial for patients. Although there were similar improvements in inflammation with both the 0.4 and 0.6 mg/kg doses in all 3 clinical trials, pooled safety data indicated that adverse effects were significantly higher with the 0.6 mg/kg dose.

Although nearly 20% of patients experienced a decrease in renal function with the 0.6 mg/kg dose, this adverse effect was seen in only 8.2% of patients with the 0.4 mg/kg dose and in 4.1% of patients with placebo. Other drugs in the same class result in decreases in renal function impairment in 26% to 38% of cases, Dr. Nguyen said. Hypertension was experienced by 7.5% of patients in the 0.4 mg/kg group and in 10.3% of patients in the 0.6 mg/kg group. However, only 5 patients discontinued the drugs because of hypertension; in other patients, this adverse effect was readily manageable, Dr. Nguyen noted.

"The approval of voclosporin would mean that we would have the first oral agent approved specifically for intraocular inflammation. It has the potential to eradicate inflammation with relatively few side effects. It would be a big step forward," said uveitis and retinal specialist Robert Janigian, MD, clinical assistant professor of surgery at the Warren Alpert School of Medicine at Brown University, Providence, Rhode Island.

However, Dr. Janigian noted that patients with posterior segment uveitis are often difficult to treat and can require more than local therapy. "The disease is often severe and it can be a bilateral condition," he said. Based on his experience with other immunomodulatory therapies, Dr. Janigian hypothesized that voclosporin alone would not be sufficient for these patients.

"But the study on voclosporin was very rigorous; it took a lot of effort and resources, and the investigators left no stone unturned," he said.

Dr. Nguyen reports serving on the steering committee for the LUMINATE studies and his employer, Johns Hopkins University, has received research funding from Lux Biosciences, Inc. Dr. Bodaghi reports receiving research funding from Lux Biosciences and being a consultant for Alcon Laboratories Inc., Bausch & Lomb Surgical, Novartis Pharmaceutical Corp., and Pfizer Ophthalmics. Dr. Janigian has disclosed no relevant financial relationships.

American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology (AAO-PAAO): Abstracts PA026 and PA027. Presented October 26, 2009.

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