FDA Requests More Trials of Retinal Disease Treatment

Alimera Sciences, Inc., a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, today announced that it has received a complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) in response to the New Drug Application (NDA) for ILUVIEN® for the treatment of diabetic macular edema (DME) associated with diabetic retinopathy.

A CRL is issued by the FDA's Center for Drug Evaluation and Research when their review of an application is completed and questions remain that precludes the approval of the NDA in its current form.

Alimera is seeking approval for Iluvien as a treatment for diabetic macular edema, a condition that can cause blurred vision and blindness.

The FDA stated that it was unable to approve ILUVIEN because there was no provide sufficient data to support that ILUVIEN is safe and effective in the treatment of patients with DME. The FDA stated that the risks of adverse reactions shown for ILUVIEN in the FAME® Study were significant and were not offset by the benefits demonstrated by ILUVIEN in these clinical trials. The FDA has indicated that Alimera will need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

The company officials will request a meeting with the FDA to clarify its next steps. 

ILUVIEN is Alimera's investigational, sustained drug delivery system that releases sub-microgram levels of fluocinolone acetonide (FAc) for the treatment of DME.

Alimera initially had asked the FDA to approve Iluvien in June 2010. In December, the FDA asked the company to report data from a third year of a clinical trial, and Alimera filed that data in May 2011. It also responded to the agency's concerns about manufacturing, packaging and sterilization of the drug. 

In December 2010, the FDA issued a CRL to Alimera related to its June 2010 NDA for ILUVIEN, which included data through month 24 of the FAME™ Study.

In that first CRL, the FDA asked for, among other things, analyses of the safety and efficacy data through month 36 of the FAME Study. Alimera submitted a response to the FDA on May 12, 2011, addressing the issues raised in the first CRL and including 36-month trial data. The FDA classified Alimera's response as a Class 2 resubmission, resulting in a six-month review period and a Prescription Drug User Fee Act, or PDUFA, date of November 12, 2011.

For Europe, Alimera expects to submit its formal response to the Preliminary Assessment Report to the Medicines and Healthcare products Regulatory Agency (MHRA) later this month. Based on this submission, the MHRA is expected to make a recommendation on the approvability of ILUVIEN to Alimera and the Concerned Member States (Austria, France, Germany, Italy, Portugal and Spain) by the end of this year, with a decision regarding the approval of ILUVIEN expected in the first half of 2012. The market opportunity in Europe is similar in size to the U.S. market opportunity.

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Ocuseva, a drug in clinical trial in Japan for treatment of Retinitis Pigmentosa

R-Tech Ueno Ltd. (Tokyo, Japan) announced it has completed a phase 2 clinical trial of 0.15% UF-021 isopropyl unoprostone (Ocuseva), which is under development as a treatment for retinitis pigmentosa (RP). The trial investigated the possibility of improving visual function in the central part of the retina with UF-021 in patients with RP.

The randomized, multicenter, comparative study examined 112 patients with RP that had progressed to the mid-to late-stage, defined as a visual acuity of less than 6/18 with a narrow visual field. Patients received placebo or Ocuseva, instilled one drop per time or two drops per time (at a 5 minute interval), twice a day in the morning and evening for 24 weeks. The primary efficacy endpoint was the change seen on the visual field analysis as checked by an instrument called the MP-1 microperimeter (Nidek, Gamagori, Japan), Retinal sensitivity was also studies by a regular Humphrey visual field analyzer (10-2), visual acuity, contrast sensitivity, and health-related quality of life, using a questionnaire on visual function (VFQ-25).

After 24 weeks, positive change in the retinal sensitivity of the central 2 degree field of vision from baseline increased the most in the two-drops-per-time group, followed by the one drop- per-time group. The placebo group had the least significant increase in sensitivity.

The change in the retinal sensitivity from the pretreatment level by 4 dB or more was seen as improvement in 15.2% of patients in the placebo group, 7.9% in the one-drop-per-time group, and 18.4% in the two-drops-per-time group, whereas the change was seen as aggravation in 21.2% in the placebo group, 15.8% in the one-drop-per-time group, and 2.6% in the two-drops-per-time group. There were a significantly lower number of aggravated cases in the 2-drops-per-time group, compared with the placebo group. The retinal sensitivity measured with the Humphrey perimeter showed statistically significant improvement at weeks 4 and 8 in the two-drops-per-time group compared with the placebo group.

The main adverse effect of Ocuseva was ocular irritation, which, the company said, disappears several minutes after instillation.

The results show promise, specifically with the advantage that it only requires instillation of drops, rather than a completed surgical intervention. Ocular irritation, which anyway lasts a few minutes, is the only adverse effect. The follow-up in the trial is 6 months (24 weeks), which is considered good enough to consider in any retinal trial. The only thing difficult to understand is the group that was instilled with placebo drops (meaning no medication) still showed improvement in about 17 of the 112 patients in the trial (15.2%).