FDA Approves Lucentis for DME
Panel recommends ocriplasmin for VMA.
Jerry Helzner, Senior Editor
■ The FDA has approved Lucentis for the treatment of diabetic macular edema (DME). Meanwhile, the FDA Advisory Committee that reviews ophthalmic drugs has recommended that ocriplasmin be approved for symptomatic vitreomacular adhesion (VMA). The panel, which voted 10-0 to recommend ocriplasmin, typically carries some weight with the FDA but does not assure final approval.
The FDA approved both the 0.3-mg and 0.5-mg formulations of Lucentis. In a pivotal clinical trial, a slightly higher mortality rate with the 0.5-mm dose was reported. Retina specialists have commonly used Lucentis off-label for years as a treatment for DME.
Ocriplasmin has been granted priority review status by the FDA. The drug is administered by intravitreal injection and if it gains final approval in October it will be the first pharmacologic treatment for VMA, which encompasses such conditions as macular hole. Until now, VMA has been treated only with vitrectomy or observed through what is termed “watchful waiting.”
An article published in August in the New England Journal of Medicine highlights two multicenter, randomized, double-blind phase 3 trials with ocriplasmin that were conducted in the United States and Europe and involved 652 patients with VMA.
Both studies met the primary endpoint of pharmacological resolution of VMA at day 28. Secondary endpoints included nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy and improvement in visual acuity. The phase 3 program found that 26.5% of patients treated with ocriplasmin saw resolution of VMA, compared with 10.1% of patients receiving placebo. Nonsurgical closure of macular holes occurred in 40.6% of ocriplasmin-treated patients, compared with 10.6% of patients on placebo. Patients given ocriplasmin were more likely to achieve a vision gain of at least 3 lines compared with placebo. Treatment with ocriplasmin was associated with some, mainly transient, ocular adverse events.
ThromboGenics developed ocriplasmin after combining its intellectual property with that of NuVue Technologies in 2004. NuVue was formed by Drs. Michael T. Trese and George A. Williams of the Beaumont Eye Institute in Royal Oak, Mich., who had conducted successful human studies of their own plasmin formulation. Alcon is now an international partner with ThromboGenics, having purchased the non-US rights to the therapy.
ThromboGenics recently received more than $100 million in new venture capital money to fund the US launch of ocriplasmin once it receives FDA approval.
This month's Innovation in Retina column on page 16 features an interview with Drs. Trese and Williams highlighting the lengthy development process for ocriplasmin.
|■ Regeneron raises Eylea forecast. After reporting a huge 57% quarter-over-quarter jump in sales to $194 million for its Eylea therapy for wet AMD, Regeneron increased the full-year sales forecast for the drug from $500-$550 million to $700-$750 million and projected that the company would be solidly profitable for 2012.|
“The Eylea launch continues to progress extremely well and is driving strong sales and earnings growth,” said Leonard S. Schleifer, MD, PhD, president and CEO of Regeneron. “Based on the results to date, we now forecast 2012 US Eylea net product sales of $700 to $750 million and expect to be profitable for the full year. We look forward to marketing approvals and launch of Eylea outside the US by our collaborator, Bayer HealthCare, during the second half of the year.
“We also await the September 2012 PDUFA date for an FDA decision on our application to market Eylea in the US for the treatment of central retinal vein occlusion. ”
■ Stem cell trial for dry AMD. Stem Cells, Inc., has initiated a phase 1/2 clinical trial of the company's proprietary HuCNS-SC product candidate (purified human neural stem cells) for treatment of dry AMD. There are no approved treatments for dry AMD. The trial is being conducted at the Retina Foundation of the Southwest's Anderson Vision Research Center in Dallas.
Could an Eyedrop Treat Wet AMD?
Two small companies study the possibilities.
■ Opko Health, a Miami-based diversified healthcare company headed by billionaire investor Philip Frost, MD, said it has signed a research and license agreement with a “prominent” Mexican professor of ophthalmology for a topically active formulation of the anti-VEGF antibody ranibizumab, utilizing Opko's proprietary drug delivery technology. The technology will initially target the development of the ranibizumab product to treat DME but the delivery system will also be studied with other pharmaceutical products to treat DME and other eye diseases.
“Presently, ranibizumab is only approved for delivery by intravitreal injection,” noted Dr. Frost. “We believe the development of a topical VEGF antibody formulation would result in substantial benefits to patients.”
A spokesperson for Genentech, the subsidiary of Roche that holds the patent rights to ranibizumab, said Genentech has no agreement with Opko and no knowledge of the Opko drug-delivery system. Genentech has been working with ForSight Vision to develop a sustained-release format for ranibizumab.
Previously, smallish Ohr Pharmaceutical of Brooklyn, NY, said it was developing a topical version of squalamine for the treatment of wet AMD. Squalamine (also called Evizon) was formerly owned by Genaera, which terminated clinical trials for the drug due to lack of funding and the widespread adoption of ranibizumab and avastin.
The new version of aqualamine recently received fast-track status from the FDA. Two prominent retina specialists, Lawrence J. Singerman, MD, and David S. Boyer, MD, recently joined Ohr's Scientific Advisory Board.
There has been debate in the retinal community as whether a topical therapy can deliver enough medication to the back-of-the-eye to achieve efficacy. Until now, no topical therapy has been approved for the treatment of retinal disease.
|■ Oral treatment for DME studied. Ampio Pharmaceuticals is preparing to begin a large clinical trial for Optina, an orally administered low dose of danazol, for the treatment of DME. Ampio said its chief scientific officer discovered an unexpected activity in his investigation of the mechanism of action of danazol: Very low doses reversed inflammation induced increases in the permeability of blood vessels, thus reducing vascular leakage. Subsequent in vitro studies suggested this effect may reduce the vasogenic edema produced from multiple diseases, including DME.|
Danazol, a derivative of the synthetic steroid ethisterone, was approved by the FDA in the 1970s for endometriosis and, more recently, for other chronic indications, including hereditary angioedema. Ampio said extensive clinical experience with the drug has allowed the FDA to permit Ampio to use the 505(b)2 path for drug registration. The 505(b)2 is a shorter and less expensive path than those of new chemical entities.
■ pSivida implant in uveitis trial. pSivida Corp., which develops sustained-release, drug-delivery implants for retinal disease, has enrolled the first patient in an investigator-sponsored clinical trial of its injectable sustained-release device in posterior uveitis.
These inserts are also being used in the Alimera Sciences' sustained-release DME therapy Iluvien and have been proven effective in largescale clinical trials. pSivida is now independently developing the same devices for use in posterior uveitis.
The insert is a tiny tube about the size of an eyelash containing the steroid fluocinolone acetonide that is released at a consistent rate over a period of approximately 36 months. The micro-insert is placed in the back of the eye during an office visit through the use of a fine-gauge needle.
■ Oertli launches Katalyst brand of retina instruments. Oertli has just introduced its new OertliKatalyst brand of precision retina instruments. The range of micro instruments includes forceps, scissors, polishers and retinal picks. Noteworthy innovations include a new handpiece concept, new tip geometries, an innovative choice of material and improved implementation of ergonomic basic principles. Oertli says the Katalyst line incorporates a number of patentable new designs.
LCA-causing Gene is Isolated
Another step toward a cure.
■ Researchers from three institutions have isolated an elusive human gene that causes a common form of Leber congenital amaurosis (LCA). The newly found LCA gene is called NMNAT1. Finding the specific gene mutated in patients with LCA is the first step toward developing sight-saving gene therapy, the Massachusetts Eye and Ear Infirmary asserted in a news release.
“The immediate benefit of this discovery is that affected patients with mutations in this new LCA gene now know the cause of their condition,” said Eric Pierce, co-senior author and Harvard Medical School associate professor of ophthalmology at Massachusetts Eye and Ear. “Scientists now have another piece to the puzzle as to why some children are born with LCA and decreased vision. The longterm goal of our research is to develop therapies to limit or prevent vision loss from these disorders.”
Collaborators also included researchers from the Children's Hospital of Philadelphia and Loyola University Chicago Health Sciences Division. The findings were published recently online in Nature Genetics.
NMNAT1 is the 18th identified LCA gene. The gene resides in a region that has been known to harbor an LCA gene since 2003, but the specific disease gene was undiscovered until now.
To identify NMNAT1, scientists sequenced the protein-coding regions of the genome (a technique called exome sequencing) of the family of two siblings who initially presented for evaluation of LCA but who had no mutations in any of the known LCA genes.
Having found a mutation in NMNAT1 in this one family, the investigators next asked if mutations in NMNAT1 also cause disease in other patients with LCA. Screening of 284 unrelated patients with LCA allowed them to identify 13 other patients with mutations in NMNAT1 as the cause of their disease.
“Whereas most of the known LCA genes involve dysfunction of retinal ciliary proteins necessary for light detection in the eye, NMNAT1 is uniquely distinguished by being the first metabolic enzyme linked to LCA,” said Dr. Marni J. Falk, co-first author and clinical geneticist at the Children's Hospital of Philadelphia.
|■ Lux drug in uveitis study. Lux Biosciences has completed enrollment in its phase 3 clinical study using voclosporin (branded as Luveniq by Lux) for the treatment of nonin-fectious uveitis. Lux anticipates that data from the study will be available early in the first quarter of 2013.|
The study is a six-month, randomized, multicenter, double-masked, controlled trial to evaluate safety and efficacy of treatment involving the intermediate or posterior segments of the eye. The study includes 155 patients and is taking place at 56 sites across North America, Europe and Brazil. The primary endpoint of the trial is the change from baseline in vitreous haze at 12 weeks or at the time of treatment failure, if earlier.
■ Two types of ETDRS charts and visual acuity. In an interesting small study led by researchers from Wills Eye Institute and presented at the recent ARVO meeting, the researchers first noted the critical importance of obtaining accurate measures of visual acuity (VA) from patients with retinal disease.
The researchers then set out to compare the VA data from 39 eyes with various retinal diseases using two types of ETDRS charts — one a standard back-illuminated ETDRS chart and the other a handheld, internally illuminated ETDRS chart. Results from both charts ranged from 20/20 to 20/200.
The total number of letters seen was 1626 for the standard ETDRS chart and 1629 for the handheld ETDRS chart, with mean difference per eye between the standard ETDRS and handheld ETDRS chart found to be 2.6 letters. Correlation coefficient of 0.963 demonstrated a strong positive linear correlation between standard ETDRS chart and handheld EDTRS chart acuities.
The researchers said they observed “a strong positive correlation between visual acuity obtained by the standard ETDRS chart and the handheld ETDRS chart in patients with retinal pathology.”
They further noted that measurement of VA with the handheld ETDRS chart may come to serve as a useful tool in future clinical studies of retinal disease.
Endophthalmitis and the Baerveldt Shunt
Tube exposure a key risk factor.
■ Though the incidence of endophthalmitis is quite uncommon with the Baerveldt tube shunt, researchers from Bascom Palmer Eye Institute identified nine such cases over a more than 11-year period.
The average time elapsed from tube shunt implantation to endophthalmitis was 20 months with a range of one week to four years. Overall, seven different types of microbes were implicated in the range of infections, with some patients growing one microbe and some growing two. All patients were injected with intravitreal vancomycin and ceftazidime at the time of infection.
Five of nine patients had tube exposure. Two patients underwent evisceration. Three patients underwent tube removal. Median pre-infection visual acuity was 20/100 with a range of 20/50 to hand motion. Median postinfection visual acuity was 20/400 with a range of 20/60 to no light perception. Average loss of vision was 3.4 lines with one patient progressing to light perception and two patients to no light perception.
The researchers concluded that endophthalmitis associated with the Baerveldt shunt is quite uncommon. In the current study, tube exposure was a common risk factor for endophthalmitis. Infections were caused by a broad spectrum of microbes. The researchers said visual outcomes following Baerveldt-related endophthalmitis were generally poor.
Five-Year Follow-up: Lucentis for RVO
Retinal nonperfusion worsens progressively.
■ A study conducted by ophthalmologists representing the Wilmer Eye Institute at Johns Hopkins University sought to determine the long-term effects of intermittent treatment with Lucentis to control macular edema and retinal nonperfusion (RNP) in patients with retinal vein occlusion.
The study, presented at the recent ARVO meeting, involved 20 patients with BRVO and 20 patients with CRVO who were initially treated with three monthly Lucentis injections and then seen every two months. Subsequent Lucentis injections were performed on an as-needed basis. In addition, fluorescein angiograms were done at several time points throughout the five years of follow-up and retinal nonperfusion was graded.
Of the 11 patients with BRVO who completed the full five years of follow-up, the amount of RNP at baseline was none in one, mild in one, moderate in three, severe in three and ungradeable in three. Two patients showed improvement in RNP at three months and none showed worsening.
However, between month three and the five-year follow-up, six BRVO patients showed worsening of RNP, causing severe loss of BCVA in three individuals, while five patients showed no change. Peak mean visual improvement was 22.1 letters, dropping to 13 letters at year 5, due primarily to RNP-related loss of BCVA.
The 10 CRVO patients who completed the full five years of follow-up showed a similar course of mean early improvement in RNP and BCVA followed by progressive worsening. At year 5, four patients showed worsening of RNP, causing severe loss of BCVA in two individuals.
The researchers concluded that in patients with RVO, intermittent treatment with Lucentis to control edema may not be enough to prevent worsening of RNP and loss of BCVA in some patients.
|■ Implants restoring some vision in RP patients. Retina Implant AG, a developer of subretinal implants for patients blinded by retinitis pigmentosa (RP), said the first two UK patients participating in the company's multicenter trial have been successfully implanted and are experiencing some vision restoration. The UK trial is set to include 12 patients in total. RP|