New Alcon Initiatives in Retinal Arena
Two Research Deals Are Signed.
JERRY HELZNER, SENIOR EDITOR
■ Alcon has signaled its intention to again be a major player in the race to develop innovative drugs for retinal diseases. The initiative comes three years after the company experienced a significant disappointment when its anecortave acetate (Retaane) treatment for wet AMD failed in a pivotal phase 3 trial. The failure was surprising after Retaane raised hopes with an encouraging phase 2 trial and being granted fast-track status by the FDA.
The new initiative largely centers on two recently-announced research agreements, one with AstraZeneca and the other with PhiloGene.
In the more extensive AstraZeneca deal, Alcon has entered into a five-year collaborative research agreement with AstraZeneca for the exclusive ophthalmic discovery and potential development rights to AstraZeneca's compound library.
The agreement covers multiple classes of small molecules with lead compounds targeting development of drugs to treat sight-threatening conditions such as glaucoma, wet and dry AMD, and other retinal diseases, as well as ocular allergy, dry eye and other inflammatory eye conditions.
In addition, Alcon has entered into a research and licensing agreement with PhiloGene, Inc. for rights to a VEGF protein. The company plans to develop this protein for the treatment of wet AMD and diabetic macular edema.
“Our agreement with AstraZeneca stems from our strategy of enhanced access to sources of technologies and compounds through partnership with leading biomedical research organizations,” said Sabri Markabi, MD, Alcon's senior vice president of research and development, and the company's chief medical officer. “The combination of AstraZeneca's broad capabilities in discovery and Alcon's scientific expertise in eye disease provides potential for therapies that fulfill unmet medical needs in ophthalmology.”
Under the terms of the agreement, Alcon obtains immediate access to thousands of AstraZeneca compounds in a variety of drug classes. AstraZeneca will hand over development and regulatory documentation associated with each compound as relevant to ophthalmology. Alcon will perform and fund all research and development activities to move selected compounds forward.
The agreement provides for individual license agreements to be negotiated on a case-by-case basis for any compound that moves into clinical development, including regulatory milestone payments and royalties on product sales. The agreement does not preclude Alcon from pursuing compounds it develops itself or licenses from other companies prior to the initiation of phase 3 confirmatory clinical studies.
“This strategic partnership represents an extraordinary opportunity to bring Alcon's global leadership in the field of ophthalmology together with AstraZeneca's world-class basic research capability to advance treatments in eye care,” said Kevin Buehler, Alcon's president and CEO.
At ASCs, a Retinal Reprieve
Same-day scheduling OK for Emergencies.
RENÉ LUTHE, SENIOR ASSOCIATE EDITOR
■ Retinal specialists at ASCs dodged a regulatory bullet recently when CMS announced a compromise with ASC advocacy organizations on the issue of same-day scheduling. The original ruling had decreed that no patients could undergo a procedure on the same day the procedure was scheduled, in order to allow sufficient time for patients to be notified of, and consider, their rights.
The ruling would have been particularly intrusive for retinal surgeons and their patients, as many retina procedures are emergencies: endophthalmitis, trauma, and patients who have a maculal or retinal detachment and who will have good visual potential provided the retina is repaired in a timely manner.
“Retina is not the only specialty affected, but it's probably the specialty that's most affected,” says Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona in Phoenix and founding partner of Spectra Eye Institute in Sun City, AZ.
The response from retinal surgeons at ASCs to the initial CMS ruling was swift.
“I think that this issue has probably raised more concern and ire than anything in a couple of years,” says Mike Romansky, Washington Counsel and vice president of Cor por ate Development for the Outpatient Ophthalmic Surgery Society.
ASC advocacy organizations presented a compelling case to CMS on behalf of emergency procedures. The agency reversed its original ruling and will now permit same-day scheduling of ASC procedures if the referring physician files documentation that the procedure is medically necessary and that an ASC is the appropriate setting for the procedure. However, CMS will also monitor the number of same-day cases to check ASC compliance.
Dr. Dugel says that he is gratified that CMS recognized its ruling's potentially detrimental effects on emergency eye care and moved quickly to reverse the decision. Still, he anticipates that surgeons will not appreciate the extra bureaucratic hurdle they will encounter in filing the new documentation for emergency procedures.
“Is it something we can live with? If we have to,” he says. “But on the other hand, I would think that regulatory agencies would look at the situation and say, �The one thing we want to do when people need care, in order to save their eye, is to make things easier, not more difficult.’”
Patients who need non-emergency care are still prohibited from same-day scheduling, a burden to the often-elderly patients who may have to travel significant distances and may require someone to transport them to and from the ASC.
“Patient inconvenience, unfortunately, cannot be a factor in your decision to do surgery; that's what the government has said,” explains Mr. Romansky.
Dr. Ambati Cautions on 21-NT siRNAs
… And Identifies a Wet AMD Marker.
JERRY HELZNER, SENIOR EDITOR
■ Some “gene-silencing” siRNA drugs (specifically those classified as 21-NT small-interfering RNA) being studied as potential treatments for retinal disease could have side effects even more broad-based than previously reported, says Jayakrishna Ambati, MD, PhD, a University of Kentucky researcher who has been cautioning about the use of these siRNAs as wet AMD treatments for more than a year.
The new findings were published in a recent online issue of Proceedings of the National Academy of Sciences (www.pnas.org), the official journal of the US National Academy of Sciences.
In related news, the Ambati team also announced that it has discovered a biological marker for wet AMD.
With regard to the siRNAs, three have recently been investigated as potential wet AMD treatments. Two of these studies were recently terminated due to inadequate efficacy, with the drugs deemed to be safe by their sponsors. The third siRNA studied for wet AMD, PF-04523655, being developed by Quark and Pfizer, is not a 21-NT and is currently in clinical trials. Dr. Ambati, an ophthalmologist, has been involved in safety testing for the Quark/Pfizer siRNA.
Dr. Ambati and his colleagues now assert that 21-NT siRNAs can be toxic to both blood endothelial cells, which line blood vessels, and also to the cells lining the lymphatic channels. The findings on the lymphatic cells are the result of new research.
Dr. Ambati says the new findings reinforce a note of caution sounded by his team's previous study. In the earlier study, the Ambati laboratory discovered previously unrecognized immune side effects of 21-NT siRNAs.
Specifically, they showed that in two different established animal models of new blood vessel growth, a siRNA killed these cells by activating an immune receptor called toll-like receptor 3 (TLR3). This was a critical finding, says Dr. Ambati, as immune and blood vessel toxicities were not believed to occur with this pharmacologic technique. He says that much of his research regarding 21-nucleotide siRNAs and TLR3 has recently been confirmed by other researchers.
Dr. Ambati's lab also reported last year in the New England Journal of Medicine that 21-NT siRNA can be deleterious to other cell types involved in AMD, such as the retinal pigment epithelium.
“This may be a broadly imprinted response in the mammalian immune system that is activated by siRNA,” Dr. Ambati says. “In terms of benefit, siRNA may be utilized in the treatment of diseases of the lymphatic system, including lymphangiomas for which there is currently no effective targeted pharmacologic intervention.”
The wet AMD marker identified by the Ambati team is a receptor known as CCR3, a molecule also implicated in inflammatory processes that is expressed on the surface of choroidal neovascular vessels in humans but is absent from normal vascular tissue.
Dr. Ambati says the receptor shows strong potential as a means for both the early detection of the disease and for preventive treatment. The findings were reported in the online site of the journal Nature.
“This is a major paradigm shift in macular degeneration research,” says Dr. Ambati. “With CCR3, we have for the first time found a unique molecular signature for the disease. This brings us closer than we have ever been to developing a clinical diagnostic tool to discover and treat the disease early, before vision is lost.”
■ Lucentis for RVO and CRVO. Genentech announced that its phase 3 BRAVO trial of Lucentis for macular edema associated with branch retinal vein occlusion and CRUISE trial for macular edema due to central retinal vein occlusion met their primary end-point of improvement in BCVA at six months. Specific study results will be presented on October 4th during the Retina Congress in New York.
■ Drug studied for PCV. Oxigene, a clinical-stage biopharmaceutical company developing treatments for cancer and eye diseases, said it has initiated a phase 2 study of its vascular disrupting agent drug candidate Zybrestat in patients with polypoidal choroidal vasculopathy (PCV), which is similar to wet AMD. Oxigene says that current therapies active against wet AMD appear to have limited benefits in patients with PCV.
The study will examine effects of Zybrestat on PCV assessed as a change from baseline in the number of polypoid lesions as measured by imaging with indocyanine green angiography as well as changes to the vascular network, edema and retinal thickness. The company expects to announce top-line data from the phase 2 trial in the first half of 2010.
■ VEGF Trap-Eye trials move ahead. Regeneron Pharmaceuticals said that the first patient has been enrolled in the phase 3 program of VEGF Trap-Eye to treat central retinal vein occlusion. Regeneron also announced that enrollment in the phase 2 DA VINCI study of VEGF Trap-Eye in diabetic macular edema has been completed and data are expected during the first half of 2010.
The CRVO program consists of two multinational, one-year clinical studies. The COPERNICUS (COntrolled Phase 3 Evaluation of Repeated iNtravitreal administration of VEGF Trap-Eye In Central retinal vein occlusion: Utility and Safety) study is being led by Regeneron and the GALILEO (General Assessment Limiting InfiLtration of Exudates in central retinal vein Occlusion with VEGF Trap-Eye) study is being led by partner Bayer HealthCare.
Patients in both studies will receive six monthly intravitreal injections of either VEGF Trap-Eye at a dose of 2 mg or sham control injections. The primary endpoint of both studies is improvement in visual acuity versus baseline after six months of treatment. At the end of the initial six months, patients will be dosed on a PRN basis for another six months. All patients will be eligible for rescue laser treatment. Results from both CRVO studies are expected in 2011.
■ Retinal implant for RP. Second Sight Medical Products, Inc., a developer of retinal prostheses for the blind, is currently conducting a 32-patient study of its Argus II Retinal Implant for patients who are blind or have severely impaired vision due to retinitis pigmentosa.
Mark Humayun, MD, of Doheny Eye Institute at the University of Southern California, said six-month study results for the first 17 individuals are encouraging.
“The results demonstrate preliminary safety and the potential to achieve spatial localization, motion detection,orientation, mobility, and other skills using a retinal implant for people who are blind or whose vision is severely compromised,” said Dr. Humayun. RP