Lilly weighing options after FDA requests additional trial for Arxxant

Ophthalmologists and market analysts look beyond ruboxistaurin to the future of diabetic retinopathy treatment.

Issue: November 15, 2006

ByAndy Moskowitz

Eli Lilly and Co. has appealed the U.S. Food and Drug Administration’s request for an additional 3-year, phase 3 clinical trial of its treatment for nonproliferative diabetic retinopathy, but the fate of the drug remains uncertain.

Carl D. Regillo

Before the FDA’s request, a Banc of America Securities report estimated that ruboxistaurin mesylate, proposed trade name Arxxant, “could capture 30% of the 1 million moderate-to-severe diabetic retinopathy patient population in the U.S.” and predicted 2007 Arxxant sales of $145 million, increasing to roughly $550 million by 2010. Subsequent to the FDA’s request, however, Banc of America rescinded those sales estimates and said it believes that “Lilly may decide to discontinue ongoing development.”

The prospect of the drug’s disappearance dims the hope for expansion of the limited diabetic retinopathy (DR) treatment market. Whereas current treatments are indicated for complications of DR, such as proliferative retinopathy and diabetic macular edema (DME), Arxxant was the only treatment being tested for nonproliferative DR, the underlying form of the disease that is largely untreatable.

“[Arxxant] tried to do everything. [Lilly was] trying to prevent progression of nonproliferative changes, prevention of vision loss in diabetic macular edema and prevention of progression from DME to proliferative disease,” Scott W. Cousins, MD, director of the Duke Center for Macular Disease at the Duke Eye Center, told Ocular Surgery News.

Carl D. Regillo, MD, director of the Wills Eye Hospital Retina Clinical Research Unit, likened ruboxistaurin to a popular cholesterol-lowing drug.

“[Arxxant] was a risk reduction-like treatment, sort of like giving Lipitor for high cholesterol where you’re doing that over time to reduce the risk of having problems such as heart attack or stroke,” said Dr. Regillo, Ocular Surgery News Retina/Vitreous Section Member.

Looking to the future

After the FDA’s request for additional study, Lilly announced that it is “weighing options for further development” of Arxxant. The ophthalmic community is now confronted with the question of what’s next for the treatment of DR.

“I don’t know of anything in the preclinical stage of treating the biology of hyperglycemia causing retinopathy, which was the beauty of Arxxant,” Dr. Cousins said. “I think the future’s going to be focused on what subset of diabetes we are actually going to treat.”

Dr. Regillo agreed, highlighting the importance of treatments for DME, a DR complication that is the primary cause of vision loss in diabetic patients.

“So instead of preventing [diabetic retinopathy] from occurring or decreasing the risk of it progressing, which is what Arxxant was thought to be doing, you have a variety of treatments that we already have at our disposal or perhaps some new ones that we’re using or will be using to actually treat edema development,” he said.

Ruboxistaurin is currently in trials for DME, but results are not expected until 2010, according to a Lilly representative.

Anti-VEGF possibility

Alfred Louis Renna, managing director of World Trans Med, a division of Phonic Corp., said, “I believe Lilly should continue trials of ruboxistaurin but pursue other developing techniques and competitive market opportunities.”

“Novartis supported QLT and did very well,” he said, referring to the companies’ partnership on the development of Visudyne (verteporfin for injection), a proactive drug used in photodynamic therapy. “But at the same time, as soon as [a VEGF-inhibitor] hit the market, Novartis did not waste any time to partner with Genentech. It is apparent the major ophthalmic pharmaceutical players like Novartis are not waiting for something to happen — they’re making it happen.”

One such possibility, according to Mr. Renna, is vascular endothelial growth factor inhibition, “one of the most important, cutting-edge technologies” in today’s highly competitive global arena. Dr. Cousins said he sees a significant role for anti-VEGF drugs in DR treatment. “For [proliferative diabetic retinopathy], I think this is where the future is. It turns out that that stage of retinopathy is exquisitely sensitive to VEGF inhibition,” he said. “And whether it’s Avastin or Macugen, proliferative retinopathy goes away quickly after you treat the eye with an anti-VEGF inhibitor.”

“Another approach is, instead of using an anti-VEGF instead of laser, why not use it as an adjunct to laser? So you can come in with a standard laser plus an anti-VEGF and improve the effectiveness and durability over either one alone. And that would now alter the way we do proliferative patients,” Dr. Cousins said.

Dr. Regillo, who reports anecdotal success using off-label intravitreal Avastin (bevacizumab, Genentech) to treat proliferative retinopathy and macular edema, compared anti-VEGF use to off-label steroid injections for the treatment of DME.

“Using Avastin has an advantage over steroids in the eye, in that it … does not cause cataracts and does not cause any rise in IOP. A significant rise in IOP occurred with intravitreal steroid use about 30% to 40% of the time. Cataract progression is likely to be accelerated with steroid use, especially with multiple injections. The downside to Avastin use or any anti-VEGF agent … is that it doesn’t seem to last as long. It may only give you a couple of months’ duration of effect,” he said.

Steroid delivery devices

Another DME treatment possibility with clinical and business potential is sustained drug delivery systems, a “very hot area,” according to Mr. Renna. These devices are implanted intravitreally and gradually release a calculated dosage of steroids over a predetermined period, minimizing trauma and the need for repeat injections. “Two major ophthalmic pharmaceutical players in this market thus far have secured their competitive futures in drug delivery systems with the right acquisitions,” he said.

“While most key players in this market are seeking competitive alternatives, not all are golden opportunities, especially injectables inserted or implanted into the eye. Risks are high and demand unique skills,” Mr. Renna said.

Dr. Cousins noted, “It’s clear that steroids reduce diabetic edema in the majority of cases,” but he questioned the benefit of a delivery device over intravitreal injection.

“The unanswered questions in the trials are: Can one of these sustained steroid delivery systems achieve improved vision or anatomical drying of the retina in an eye that failed an injection? … Or does it produce a better visual recovery over the injection?” he said.

Dr. Cousins added: “I don’t think that particular question is being addressed. But I think it’s exciting that at least we’ll have an alternative to intravitreal Kenalog (triamcinolone acetate, Bristol-Myers Squibb). Whether the expense is going to be worth it depends on the questions I just raised.”

For more information:

Scott W. Cousins, MD, can be reached at Duke University Eye Center, DUMC Box 3802, Durham, NC 27710; 919-684-3090; fax: 919-681-6474; e-mail: scott.cousins@duke.edu.

Carl D. Regillo, MD, can be reached at Retina Service, Wills Eye Hospital, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; 215-264-3159; fax: 610-856-7787; e-mail: cregillo@aol.com.

Alfred Louis Renna can be reached at 718-631-7367; e-mail: alr@worldtransmed.com.

Andy Moskowitz is an OSN Staff Writer who covers all aspects of ophthalmology. He also writes daily news updates for OSNSuperSite.com.