Positive phase 3 uveitis trial results for voclosporin

Mar 29 2009

Isotechnika Inc. has announced that their partner, Lux Biosciences, Inc., reported the results from the three Phase 3 LUMINATE trials investigating voclosporin oral capsule (LUVENIQ or LX211) for the treatment of uveitis.

Voclosporin is a next generation calcineurin inhibitor that Isotechnika has licensed to Lux for ophthalmic indications. The data show a positive effect on ocular inflammation and a safety profile consistent with the expected use in uveitis. Following full analysis of the data, the results of the LUMINATE clinical trials will be submitted for publication and presented at upcoming conferences. In parallel, Lux Biosciences will be preparing submissions for approval. "The available results from the LUMINATE program demonstrate that LUVENIQ, if approved, can play a significant role in the treatment of inflammation in certain forms of sight-threatening uveitis," said Eddy Anglade, M.D., Lux Biosciences' Chief Medical Officer. "A significant unmet therapeutic need exists for an approved agent which is not a corticosteroid and allows sparing of those drugs to reduce their associated, serious side effects." "These results further demonstrate the ability of voclosporin to impact a wide range of autoimmune conditions and highlight its broad commercial potential," said Dr. Robert Foster, President and Chief Executive Officer of Isotechnika. "We are committed to support Lux as they move forward with their LUVENIQ filings." The three randomized, double-masked, dose-ranging and placebo-controlled trials comprising the LUMINATE Program, the largest clinical program ever conducted in uveitis, enrolled 558 patients in 7 countries (United States, Canada, United Kingdom, France, Germany, Austria and India). The key results in the LUMINATE trials were:

• Overall, of the 3 doses studied, the 0.4 mg/kg BID dose had the most acceptable safety profile relative to effect on the disease. Isotechnika, Inc. previously reported that 0.4 mg/kg BID demonstrated both efficacy and an acceptable safety profile in their clinical trial of voclosporin in plaque psoriasis, which is in the range of the maintenance dose of voclosporin anticipated for use in kidney transplantation.
• Study LX211-01 enrolled 218 patients with active non-infectious uveitis with posterior manifestation of the disease. The 0.4 mg/kg BID dose fully met the primary endpoint of superiority to placebo at both weeks 16 (p=0.008) and week 24 (p=0.04) for mean change from baseline in vitreous haze, a validated measure of inflammation of the posterior segment of the eye. The magnitude of the effect was (greater than)1 step change, demonstrating a clinically relevant benefit.
• Study LX211-02 enrolled 232 patients with clinically quiescent disease. The 0.4 mg/kg BID dose showed a reduction by 50% vs. placebo in rate of recurrence of inflammation at 6 months. The study did not meet the primary analysis endpoint of all-cause therapeutic failure at 6 months as the drug effect on inflammation was diluted by discontinuations that were unrelated to inflammation. This was due to a pre-specified analysis that accounted for data censoring due to non-efficacy-related discontinuations. However, the reduction in inflammation vs. placebo by 50% was statistically significant (p=0.046), thus confirming the positive results from LX211-01.
• Study LX211-03 enrolled a narrow sub-set of 108 patients with active uveitis with anterior manifestation of the disease. The efficacy of the voclosporin dose groups and placebo did not separate during the steroid taper; all showed an improvement by (greater than)1 step mean reduction from baseline in anterior chamber cells, a validated measure of inflammation in the anterior segment of the eye. This study, which is not critical for approval and was added to encompass a sub-set of patients affected by anterior chamber disease, turned out to be underpowered owing to greater than expected variability.

The integrated safety profile of 0.4 mg/kg BID voclosporin in the LUMINATE trials suggests that it would be suitable for chronic use in this high medical need indication. Of particular interest were the relatively small effects of voclosporin 0.4 mg/kg BID on renal function, an area of concern for first generation calcineurin inhibitors. The proportion of subjects experiencing a confirmed rate of decrease in estimated glomerular filtration rate (eGFR) by (greater than or equal to)30% was 8.2% in the 0.4 mg/kg BID dose group vs. 2.7% in the placebo group. Patients experienced a mean increase in systolic blood pressure by study-end over baseline of 6 mm Hg. However, most of these patients were successfully controlled with medication and only 1.3% discontinued therapy due to hypertension. Other adverse events typical of the calcineurin inhibitor class, in particular diabetes, elevation of lipids, hypomagnesemia, and tremor, were not observed in the LUMINATE studies. Other more frequently observed adverse events included headache, diarrhea and infections, which were similar in incidence to placebo. In terms of ocular safety there was no apparent effect on intraocular pressure, cataract formation or endothelial cell density. Ulrich Grau, Ph.D., Lux Biosciences' President and Chief Executive Officer, said, "Based on the available data from the LUMINATE pivotal trial program, we plan to engage in discussions with several regulatory agencies and plan regulatory filings of LUVENIQ in the near future. We are gratified by what appears to be a robust clinical effect of LUVENIQ coupled with an acceptable side effect profile." Voclosporin is designed for use as an oral immune-modulatory agent to treat the forms of non-infectious uveitis that require systemic treatment, including posterior, intermediate and panuveitis, allowing for tapering of systemic corticosteroids to 5 mg or less per day. The mean age of these patients is approximately 40 years and uveitis is the 4th leading cause of blindness; hence, the burden of disease is relatively higher than for age-related ophthalmic diseases, and the medical need for effective treatments is striking. If approved for commercialization by regulatory agencies, voclosporin would be the first corticosteroid-sparing agent available in the United States and most other markets for the treatment of uveitis.

Uveitis is an autoimmune disease characterized by chronic inflammation of the eye. Uveitis is an under-diagnosed and under-recognized medical condition that causes vision impairment, ocular pain, and loss of vision. Experts estimate that 10% of new cases of blindness in the United States result from this disease. Approximately 300,000 people suffer from uveitis in the United States alone. The only therapeutic class approved by the FDA for treatment of uveitis is corticosteroids, which are burdened with multiple side effects, such as osteoporosis, hyperglycemia, hypercholesterolemia, hypertension, mood disturbances, and if applied chronically to the eye, cataract formation and glaucoma.