FDA: Arxxant Requires Another Trial
Lilly Intends to Appeal the Decision.
Eli Lilly and Company said it has decided to appeal a request by the FDA for an additional, 3-year, phase 3 clinical trial for ruboxistaurin mesylate (Arxxant). Arxxant has been considered a highly promising drug because, if approved, it would be the first oral treatment for moderate-to-severe nonproliferative diabetic retinopathy (DR).
The FDA said it wants additional efficacy data before it will consider approving Arxxant for DR. Lilly believes that such a trial would require up to 5 years to complete. The new request from the FDA follows Lilly's August announcement that it had received an "approvable" letter from the FDA.
At the time Lilly received the approvable letter, the company was hopeful that it could avoid a new trial by providing the additional clinical data from 2 ongoing phase 3 clinical trials. Lilly has already signed a long-term agreement to co-promote Arxxant with Alcon. However, the agreement is contingent upon FDA approval of the drug.
"We are certainly disappointed with this communication from the FDA. Diabetic retinopathy is a significant unmet medical need to which we have devoted more than a decade of clinical research with no guarantee of approval," said John Lechleiter, PhD, president and chief operating officer of Eli Lilly and Company. "We still believe that ruboxistaurin has potential as a treatment for diabetic eye disease and are exploring the feasibility of further development of this molecule," he added.
Ongoing clinical trials for Arxxant will continue while Lilly evaluates its options for further development of the drug.
Arxxant is a specific protein kinase C beta (PKC) inhibitor and is the first of a new class of compounds being investigated for the treatment of DR, diabetic peripheral neuropathy, and diabetic nephropathy. PKC is a signaling enzyme in the body and overactivation has been linked to the underlying process of microvascular damage caused by diabetes. While tight blood sugar control lowers the risk of diabetic microvascular damage, there are currently no oral medications approved in the United States to treat DR. According to the World Health Organization and the American Diabetes Association, DR is the leading cause of vision loss in adults 20 to 74 years old in industrialized countries.
Lilly had previously said that pooled data from 2, 3-year phase 3 trials involving 813 patients showed that 32 mg of Arxxant daily reduced the risk of sustained moderate vision loss by 41% when compared to placebo in patients with moderate-to-severe nonproliferative DR. Vision loss occurred in only 6.1% of patients treated with Arxxant compared to 10.2% of patients treated with a placebo. Vision loss was defined as a 3-line loss on the eye chart that was sustained for at least 6 months.
Investigators found that Arxxant was generally well tolerated and had an overall adverse event profile, as well as a serious adverse event profile, similar to placebo.
Arxxant was submitted to the FDA in February 2006 and subsequently was granted priority review. The August approvable letter from the FDA requested additional efficacy data to support the clinical evidence presented by Lilly in its New Drug Application (NDA). The latest announcement results from ongoing communication between Lilly and the FDA to determine if the additional evidence could come from ongoing trials or if a new trial would be required.
At this time, Lilly does not intend to withdraw the NDA, because withdrawal would require restarting the review process, should Lilly ultimately move forward with development of Arxxant.
Avastin vs Lucentis
Study Gets OK
NIH Will Fund 2-Year Trial.
A head-to-head study comparing the efficacy and safety of 2 Genentech drugs, Lucentis and Avastin, as treatments for wet AMD now has the financial support of the National Institutes of Health (NIH). There have been many calls for such a study due to the fact that Lucentis costs approximately $1,950 an injection and Avastin can be given for less than $100 an injection.
The National Eye Institute, part of the NIH, will finance the study. The trial is expected to cost approximately $16 million and involve up to to 1200 patients, who are expected to be divided into 4 groups.
NIH sources said 1 group would be given Lucentis injections every 4 weeks. A second group would receive Avastin every 4 weeks. The other 2 groups would get either Lucentis or Avastin on an as-needed basis, with retreatements determined by OCT measurements. In the recently completed PrONTO study, the use of OCT measurements to determine retreatment resulted in most patients requiring approximately 5 to 6 injections per year. Patients will be followed for 2 years.
Before Lucentis won US regulatory approval in June, numerous retina specialists began using Avastin to treat wet AMD because it has a similar molecular structure to Lucentis and could be used off-label as an intravitreal injection. Avastin is an FDA-approved systemic colorectal cancer treatment. Since Lucentis was approved, many doctors have switched to that drug, particularly for patients with good insurance coverage.
In related news, Genentech said that Lucentis sales in the quarter ended Sep. 30 far exceeded analysts' forecasts. Lucentis, which is rapidly being adopted as a first-line treatment for wet AMD, had sales of $153 million, while Wall Street was looking for $35 to $45 million.
Bayer Will Share in Development Costs.
Bayer HealthCare and Regeneron Pharmaceuticals, Inc. announced that the companies have entered into a collaboration agreement for the global development, and commercialization outside the United States, of VEGF Trap for the treatment of eye disease by local administration, specifically intravitreal injection. VEGF Trap, currently in phase 1 and 2 clinical trials, is a protein that binds to or "traps" vascular endothelial growth factor (VEGF) and blocks its activity. VEGF is thought to play a critical role in certain eye diseases, particularly the wet form of AMD.
Regeneron, which has been developing the drug, will retain all rights to the commercialization of VEGF Trap within the United States.
Retinal Physician reported in its September/October issue that Regeneron was in active talks with potential partners for VEGF Trap. This interest intensified following the report of highly promising phase 1 trial results for VEGF Trap and positive comments from leading retina specialists.
Under the agreement, Bayer and Regeneron will collaborate on the development of VEGF Trap through an integrated global plan that encompasses wet AMD, diabetic eye diseases, and other eye diseases and disorders. The companies will jointly commercialize VEGF Trap-Eye outside the United States and will share equally in profits from ex-US sales. Regeneron will retain 100% of all profits from U.S. sales.
Bayer will make an upfront payment of $75 million to Regeneron and the 2 companies will share the global development costs, expected to total more than $250 million over the next several years.
Phase 2 Data on AMD Drug
Safety and Duration of Response Are Encouraging.
Acuity Pharmaceuticals, a clinical stage ophthalmic pharmaceutical company, has announced positive results from its phase 2 CARE trial for bevasiranib sodium (formerly Cand5), Acuity's lead compound for the treatment of wet AMD. Bevasiranib is a first-in-class small interfering RNA (siRNA) therapeutic designed to silence the genes that produce vascular endothelial growth factor (VEGF).
The CARE study was a randomized, double-masked trial that included 3 dose levels of bevasiranib tested in 129 patients with wet AMD at 28 sites nationwide. The study focused on patients with serious disease, classic or active minimally classic AMD, including those patients who had failed previous treatments.
Acuity reports that all doses were well tolerated and most adverse events mild and related to the administration (intravitreal injection) procedure. There were no systemic adverse events observed. In 2 separate bevasiranib clinical trials, there was no systemic bevasiranib exposure in patients.
"Bevasiranib is a promising new agent that has now demonstrated encouraging potential in this first large-scale study in wet AMD patients with aggressive disease," said Lawrence Singerman, MD, founder and executive secretary of the Macula Society, clinical professor of ophthalmology at Case University, and a principal investigator for the study at its Cleveland site. "Bevasiranib's excellent safety profile, its demonstrated ability to inhibit the growth of choroidal neovascular lesions, and its potential for prolonged duration of effect warrant proceeding to phase 3."
■ Visudyne sales drop. Global sales of QLT's Visudyne therapy for wet AMD totaled $75.1 million for the quarter ended Sept. 30. This represents a decrease of 39.3% over sales in the third quarter of 2005 and a 21.2% decline compared to the second quarter of 2006. Visudyne sales in the United States for the quarter were approximately $11.0 million, compared to $18.9 million for the June quarter.
"The decline in Visudyne sales has been more rapid than anticipated and as a result we are lowering our 2006 annual Visudyne sales range from the previous range of $370 million to $385 million, to a new range of $340 million to $355 million," said Bob Butchofsky, president and CEO of QLT Inc. "Forecasting product sales in a market undergoing the kind of significant transformation that we see in age-related macular degeneration is very difficult and we are disappointed at having to reduce our annual guidance. However, we continue to believe that Visudyne will remain an important part of treatment regimen for AMD and that combination therapy with Visudyne is the future for AMD treatment."
■ PASCAL data. Julia Haller, MD, professor of ophthalmology at Wilmer Eye Institute of Johns Hopkins Medical Center, has presented new data demonstrating that the Pascal photocoagulator from OptiMedica, Inc., offers substantial advantages compared to conventional photocoagulation. These advantages include increased speed, precision, and patient tolerance.
In a presentation titled, "Initial Clinical Experience with a Patterned Scanning Laser (PASCAL) for the Treatment of Retinal Diseases," Dr. Haller reported on a pilot study of 10 eyes comparing Pascal photocoagulation to conventional photocoagulation. Patients were treated for proliferative diabetic retinopathy and diabetic macular edema at Wilmer Eye Institute. The study demonstrated increased uniformity and precision of spot placement, substantially reduced treatment time, and considerably improved patient tolerance in the treatment of proliferative diabetic retinopathy with Pascal photocoagulation.
Dr. Haller also discussed the collective experience of Pascal laser photocoagulation treatments conducted at 5 leading research institutions. "We have now treated more than 1,200 patients and our experience has shown that the Pascal system performs as well as conventional single-spot delivery lasers in terms of efficacy and lack of complications, but far better in terms of physician and patient acceptance" she said.