intravitreal, VEGF Therapy, macula

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Article Date: 7/1/2013

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SUBSPECIALTY NEWS

Regeneron Sets Future Direction

Provides broad overview of strategic path.

BY JERRY HELZNER, SENIOR EDITOR

■ Speaking at the recent Goldman Sachs Annual Global Healthcare Conference, Michael Aberman, MD, Regeneron vice president of Strategy and Investor Relations, provided a carefully stated but informative outline of how the company intends to build upon its initial major success with its Eylea (aflibercept) anti-VEGF treatment for retinal diseases. One piece of new information he offered was that the company has been working with the FDA to obtain approval for a pre-filled syringe version of Eylea, rather than the vials that are currently used for all anti-VEGF eye drugs.

Dr. Aberman said the FDA has set “a high hurdle” for pre-filled syringe packaging to ensure sterility at every step of the process from manufacturer to the time the physician opens the blister pack and performs the injection.

He also hinted that the positive results from a “competitor’s” recent combination anti-PDGF and anti-VEGF phase 2 trial for wet AMD may have spurred Regeneron into moving quickly to begin two of its own combination studies. The trial Dr. Aberman was most likely referring to was conducted by Ophthotech.

Dr. Aberman said that although combination therapies for retinal disease appeared to be quite promising, he believes that drug combinations need to be “co-formulated” so as to minimize the number of injections that patients would need to receive.

The possibility of sustained-release implants for delivering anti-VEGF drugs has become a hot topic, but Dr. Aberman expressed rather broad reservations about the feasibility and safety of this type of delivery system. He said studies to date of implant devices “have not been that convincing that you’re really going to get much of a benefit in terms of duration with these devices.”

Dr. Aberman said Regeneron is looking forward to FDA approval of Eylea for DME as the company believes the opportunity could be as great as that for wet AMD therapies. He noted that patients with DME tend to be younger than those with wet AMD and would need drug therapy for a longer duration.

Finally, Dr. Aberman pointed to strong launches of Eylea in Australia and Japan, where Eylea has quickly taken about half of the branded anti-VEGF market it shares with Lucentis (ranibizumab). He said Eylea has achieved about equal market share with Lucentis in the overall branded marketplace and was being used more widely in “difficult” cases where it has demonstrated an ability to eliminate fluid more effectively than other anti-VEGF therapies. He said the development of Eylea had thus far cost Regeneron and international partner Baxter Healthcare approximately $1 billion.

IN BRIEF

■ Eylea success shared with rival. A little-mentioned January 2012 agreement between the two major rivals in anti-VEGF therapies for retinal diseases – Regeneron and Genentech – gave Regeneron a nonexclusive license to use the important Smith-Davis patents relating to VEGF receptor proteins. In return, Regeneron agreed to pay unspecified royalties to Genentech (now a subsidiary of Roche) once cumulative sales of Regeneron’s retinal disease drug Eylea reached $400 million.

Under the terms of the agreement, Regeneron will make payments to Genentech based on US sales of Eylea through May 7, 2016, starting with $60 million upon cumulative US sales of Eylea reaching $400 million. Thanks to the stunning and early success of Eylea, US sales of the drug are already well over $1 billion and climbing, providing Genentech with a significant return for licensing the key patents.

At the time the agreement was reached, Regeneron contended it had not infringed on any Genentech patents but said it made the financial agreement to avoid the uncertainty and risk of further litigation.

Heidelberg offers angiography module. Heidelberg Engineering is now delivering the new Non-Contact Ultra-Widefield Angiography Module for the Spectralis and Heidelberg Retina Angiograph (HRA 2) product family to customers. The Module consists of a dedicated lens and software. Heidelberg says the lens attaches easily to the camera head and is interchangeable with the existing high resolution 30° and 55° widefield lenses.

Ophthotech Funded for Pivotal Fovista Trial

Management aligned for development phase.

■ Ophthotech Corp. has raised $175 million to finance a global phase 3 clinical program of its lead compound Fovista, an anti-platelet-derived growth factor (PDGF), in combination with anti-VEGF therapy for the treatment of wet AMD. The multi-national phase 3 trial is expected to begin in the third quarter of 2013 and enroll nearly 1,900 patients in more than 200 centers worldwide.

The financing consists of $125 million from Novo A/S, in exchange for royalties on Fovista sales. The remaining $50 million is in the form of a Series C preferred stock financing from Novo A/S and current venture investors in Ophthotech.

To accelerate the clinical development of Fovista, Ophthotech also announced the expansion of its management team. David R. Guyer, MD, the company’s chairman since its inception, has accepted the position of CEO, and Samir Patel, MD, co-founder and current president of Ophthotech, has been appointed to the additional role of vice chairman. Under the new management structure, Dr. Guyer will direct the company’s corporate and financial strategy, while Dr. Patel will focus fully on clinical development.

“We are grateful to our investors for their profound confidence in Ophthotech and Fovista as a potential game-changing therapy that we hope will improve outcomes for millions of people with wet AMD,” noted Dr. Guyer.

In a large, randomized, controlled phase 2b study reported last year, Fovista in combination with Lucentis (ranibizumab injection) demonstrated superior efficacy over Lucentis monotherapy in patients with wet AMD. Patients receiving the combination of Fovista (1.5 mg) and Lucentis gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared to 6.5 letters for patients receiving Lucentis monotherapy, representing a 62% additional benefit. No significant safety issues were observed for either treatment group in the trial.

IN BRIEF

Iluvien gets positive UK review. Alimera Sciences, developer of the Iluvien implant for the treatment of DME, said the Appraisal Committee of the UK National Institute for Health and Care Excellence (NICE) has issued a positive Appraisal Consultation Document (ACD) on Iluvien for the treatment of pseudophakic patients with chronic DME considered insufficiently responsive to available therapies.

The ACD recommends a change to the published guidance issued by NICE in January and notes that a simple patient access scheme (PAS) was submitted by Alimera for rapid review. NICE had initially ruled that Iluvien was not a cost-effective therapy. However, the ACD takes into account the fact that pseudophakic patients who receive Iluvien will not be subject to side effects that could require cataract surgery.

In the ACD, The NICE Appraisal Committee reconfirmed Iluvien’s clinical effectiveness in treating chronic DME considered insufficiently responsive to available therapies. Additionally, the committee noted that, based on the PAS, the cost-effectiveness threshold has been met for a subgroup of chronic DME patients who are pseudophakic.

Jetrea gets preliminary OK in UK. ThromboGenics NV announced that NICE in the UK has provisionally recommended Jetrea (ocriplasmin) for reimbursement within the National Health Service (NHS).

Jetrea gets preliminary OK in UK. ThromboGenics NV announced that NICE in the UK has provisionally recommended Jetrea (ocriplasmin) for reimbursement within the National Health Service (NHS).

The NICE Appraisal Consultation Document initially recommends Jetrea as an option for treating vitreomacular traction (VMT) in adults, including when associated with a macular hole of less than or equal to 400 μm, when patients have severe symptoms and an epiretinal membrane is not present.

Jetrea is the first pharmacological treatment indicated for use in patients diagnosed with VMT and macular hole of diameter less than or equal to 400 μm and was approved in the European Union by the European Commission in March 2013.

■ Ohr shares listed on NASDAQ. Ohr Pharmaceuticals, which has recently begun a phase 2 trial for squalamine eyedrops for the treatment of wet AMD, announced that its common stock has been listed on NASDAQ under the symbol OHRP.

Squalamine, an antiangiogenic aminosterol, was originally studied by now-defunct Genaera as an intravenously administered therapy for wet AMD but the trial was halted when IV squalamine proved to be less efficacious than ranibizumab.

More Genetic Markers Linked to AMD

Seven new loci could lead to better predictive models.

BY RICH KIRKNER, EXECUTIVE EDITOR

■ The AMD Gene Consortium has identified seven new genetic loci that play a role in the pathogenesis of AMD and, with further research, may help to identify individuals at risk of developing more severe disease, according to a presentation before the Genetics Group at ARVO 2013.1

Sudha K. Iyengar, PhD, of Case Western Reserve University School of Medicine, reported the discovery brings to 19 the total number of loci implicated in AMD. “The exact sizes of the seven new loci are smaller and some of them play a role on the same pathways that are involved with the 12 previously known loci,” Dr. Iyengar said. “Some on the other hand are completely new pathways that we know nothing about.”

The next step to applying these findings in the clinic is to identify how these loci function to cause the protein changes that set off the physiological cascade that leads to AMD. “From that we will be able to understand why some people perhaps get more severe disease, which has quite a bit of clinical application,” she said. When physicians and patients know of these markers, they will be better equipped to intervene earlier, with steps such as diet changes or smoking cessation, to avoid or prevent the onset of more serious disease, she added.

In an interview, Dr. Iyengar cited the 23andme DNA Spit Kit (23andme Inc., Mountain View, CA), the $99 home test that can identify up to 240 health conditions, as evidence that genetic testing is becoming more affordable and accessible. One of the challenges in using the genome to predict AMD, along with other eye diseases such as glaucoma and diabetic retinopathy, has been the weakness of their predictive models. “The new experiments that we are doing are going to give us better predictive models,” she said.

The AMD Gene Consortium, a network of international investigators representing 18 research groups, will continue to pursue that research. The report of the seven newly discovered loci was originally published online in the journal Nature Genetics.2

REFERENCES

1. Iyengar SK. Advances in the genetics of age-related macular degeneration. Presented at ARVO, Seattle, WA: May 5, 2013.

2. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nature Genetics. 2013;45:433-439.

IN BRIEF

■ Oral therapy for AMD in trial. Ampio Pharmaceuticals of Greenwood Village, CO, recently updated its clinical progress on its oral therapy for DME, the low-dose steroid Optina (danazol). Optina is being tested in a 505(b)(2) trial, which is a more rapid pathway to commercialization for previously approved drugs. Danazol was originally approved by the FDA in the 1970s under the name Danocrine as a treatment for endometriosis.

Ampio says its in vitro data suggest that danazol has a biphasic effect on endothelial cells: At low doses, danazol decreases vascular leakage, while at higher concentrations an increase in vascular permeability is observed. The company says that low-dose danazol has been proven to be safe with no evidence serious of adverse events.

The randomized, placebo-controlled, double-masked, multicenter United States trial is expected to enroll approximately 450 patients. The primary endpoint is improvement in BCVA compared to placebo. Secondary endpoints are: 1) categorical changes in visual acuity in treated patients compared to placebo; 2) reduction in central macular thickness in treated patients compared to placebo; and, 3) safety and tolerability of the two Optina doses.

Interim four-week masked data of approximately 360 patients will be announced in the fourth quarter of 2013. Full twelve-week top-line preliminary data will be announced in the first quarter of 2014.

Versa VIT boosts Synergetics’ sales. Increased sales of its Versa VIT vitrectomy system helped Synergetics grow its third-quarter sales to $16.3 million, an increase of 11.6% year-over-year and 15.7% on a sequential quarterly basis.

“We posted solid top-line growth driven by normalized ordering patterns from our OEM partners and improving sales contributions from our VersaVIT vitrectomy systems,” said David M. Hable, company president and CEO. “While still early in our commercialization of the VersaVIT system, we have made considerable progress since receiving FDA approval less than a year ago.”

Eylea Promising in New Indication

Positive data from myopic CNV study.

■ Regeneron Pharmaceuticals and Bayer HealthCare have announced positive top-line results for Eylea (aflibercept) Injection from the phase 3 MYRROR study in myopic choroidal neovascularization (mCNV).

In myopic CNV, abnormal blood vessels grow into the retina in severe myopes with refractive error in excess of -6.00 D. The disease is characterized by an abnormally elongated eye with a physical stretching of the sclera, choroid, and retina, resulting in degenerative and progressive changes. These changes can incite the development of choroidal neovascularization.

Myopic CNV has a poor prognosis and, if left untreated, can within approximately 10 years progress to legal blindness in a majority of patients. Most prevalent in east Asia, mCNV is the second most common cause of blindness in Japan.

In this trial, patients receiving Eylea at an initial dose of 2 mg, followed by treatment on an as-needed basis, had a mean improvement in best-corrected visual acuity (BCVA) from baseline at week 24 of 12.1 letters, compared to a loss of 2.0 letters in patients receiving sham injections.

“Effective treatment options are urgently needed for patients with myopic choroidal neovascularization (mCNV),” said Kemal Malik, MD, Bayer head of Global Development. “We are pleased that the results of this study demonstrate that Eylea may provide a treatment option for these patients.”

Data from this study will be presented at an upcoming medical conference. Bayer HealthCare expects to submit the first application for regulatory approval for this indication in Asia in the second half of 2013.

MYRROR was a double-masked, sham-controlled trial that randomized 122 patients to receive either Eylea 2 mg or sham. Patients in the active treatment arm received one initial 2 mg dose of Eylea. Patients were evaluated every four weeks and were eligible to receive additional Eylea 2 mg intravitreal injections on an as-needed basis, determined by visual and anatomic criteria, through 20 weeks.

Patients in the sham arm received monthly sham injections through week 20. Starting at week 24, patients in both arms were eligible to receive Eylea 2 mg on an as-needed basis through week 44. The primary endpoint of the study was the mean change at week 24 from baseline in BCVA as measured on the Early Treatment Diabetic Retinopathy Scale (ETDRS) eye chart, a standard chart used in research to measure visual acuity. RP

IN BRIEF

■ Rao retinal fellowship established. The American Academy of Ophthalmology announced the establishment of the Sunil K. Rao, MD, Memorial Retina Fellowship Award, which provides funding for two retina fellows to attend the 117th Annual Meeting of the Academy in November in New Orleans. The application process is under way.

The fellowship honors Dr. Rao, a retina specialist, who his colleagues say of him that he “taught and practiced ophthalmology with extraordinary expertise and enthusiasm and was renowned for his generosity.” Dr. Rao trained at Brown University and completed his medical and surgical vitreoretinal fellowship at The New York Eye and Ear Infirmary. He passed away suddenly in 2012 at the age of 34.

“Dr. Rao set an example for all of us through his extremely high level of knowledge, skill and compassion for patients,” said Daniel Brocks, MD, one of the fund’s founders. “This award will ensure that Dr. Rao’s legacy of promoting patient care, education and enthusiasm for the profession continues on and enables a bright future for the next generation of retina specialists.”

ERRATUM

In the article “Vitrectomy for DME Without Macular Traction” by Takao Hirano, MD, and Toshinori Murata, MD, PhD, in the June 2013 issue of Retinal Physician, Figure 1 on page 62 was incorrect. The correct figure appears below. Retinal Physician regrets the error.

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Retinal Physician, Volume: 10 , Issue: July 2013, page(s): 8 - 12

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