Anti-VEGF DARPin Shows Promise
Study suggests a durable response.
■ Molecular Partners said recent progress with its anti-VEGF drug DARPin, currently being developed in partnership with Allergan for the treatment of retinal disease, has been highly promising, leading to a more advanced clinical trial.
Allergan recently announced that DARPin has successfully completed phase 2a development and was shown to be safe and well tolerated, with no dose-limiting toxicity, after a single administration. Furthermore, preliminary efficacy results from this study suggest a dosing interval of up to three months. Based on these results, Allergan has initiated a double-masked phase 2b study comparing two high doses of DARPin with Lucentis, the current standard of care.
“We are very pleased with the rapid progress of the studies performed by Allergan and the safety profile of the anti-VEGF DARPin,” said Michael Stumpp, PhD, chief science officer of Molecular Partners. “The fact that no dose-limiting adverse effects were observed, even at the highest doses, underlines the potential of the product. The observed treatment effects on macular edema were potentially meaningful due to the fact that the study was conducted in anti-VEGF refractory patients, where other treatments provide little, if any, therapeutic benefit.”
Molecular Partners said that DARPin (designed ankyrin repeat proteins), a small therapeutic protein, is potent, stable and soluble with favorable pharmacokinetics. The company said the possibility for achieving a sustained therapeutic effect without the need for initial loading doses would be a meaningful benefit for patients, physicians and payers.
Allergan has purchased exclusive global rights for DARPin for ophthalmic indications. Allergan and Molecular Partners will work together during phase 2b development and Allergan will be responsible for phase 3 development and commercialization activities. Molecular Partners received an upfront payment of $45 million and is further entitled to receive additional payments of up to an aggregate of $375 million upon meeting certain development, regulatory and sales milestones. In addition, Molecular Partners will receive tiered double-digit royalties on any future sales of DARPin.
Repeated Ozurdex Safe and Effective
Even up to 10 implants.
■ A study conducted by David G. Dodwell, MD, Medical Director at the Illinois Retina Center, demonstrates that patients being treated for macular edema secondary to RVO can receive regular and repeated injections of the Ozurdex dexamethasone implant (Allergan) and that any implant-related increases in IOP can be well-controlled.
Dr. Dodwell set out to evaluate the IOP in patients receiving serial intravitreal Ozurdex therapy for macular edema secondary to BRVO or CRVO.
In this single-center, retrospective, consecutive case study of all patients receiving two or more Ozurdex implants for macular edema secondary to RVO (with at least 3 months follow-up after last implant), patients were monitored every three to six weeks with Cirrus HD-OCT. Ozurdex was given in a treat-andextend method with retreatment after recurrent macular edema was observed on OCT. Visual acuity, IOP and OCT data were acquired at all visits.
Overall, 37 eyes of 37 patients with macular edema secondary to RVO (8 CRVO, 29 BRVO) received a total of 165 Ozurdex implants, with a mean of 4.5 implants per patient and a range of two-to-10 implants in any individual patient.
Dr. Dodwell found that Ozurdex consistently decreased macular edema on OCT, with retreatment occurring at a mean of 17.4 weeks after prior Ozurdex treatment. At the initial implant, mean IOP was 14.8 mm Hg and 10 eyes were on topical glaucoma therapy. Of these, two eyes had open-angle glaucoma and eight had steroid-induced glaucoma from prior therapy.
During follow-up of all 37 eyes, the mean highest IOP change from baseline was +7.46. Post-Ozurdex IOP increased ≥10 mm Hg in 10 eyes. The mean highest IOP change from baseline in these 10 eyes was +15.5 mm Hg. Of the 10 eyes with ≥10 mm Hg elevation in IOP, four eyes increased after the initial implant and three, one and two eyes increased ≥10 mm Hg after the second, third and fourth implant, respectively. Two of the 10 eyes on topical glaucoma therapy prior to initial implant and eight of 27 eyes not on glaucoma therapy prior to the initial implant had an IOP increase of >10 mm Hg.
Topical glaucoma therapy at initial implant was not shown to be a risk factor for subsequent IOP elevation post-implant. Three eyes had glaucoma valves implanted: one had no history of glaucoma or prior steroid therapy and two had been on 3 to 4 glaucoma drops for steroid-induced glaucoma before starting Ozurdex therapy. No patient developed rubeosis iridis.
Presenting at the recent ARVO meeting, the researcher concluded that topical glaucoma therapy prior to Ozurdex treatment was not a risk factor for IOP elevation and did not prevent successful serial implants. Multiple Ozurdex implants for macular edema secondary to RVO, given an average of every four months, was safe and effective. Any increase in IOP was well controlled and did not prevent continued Ozurdex treatment. The researcher noted that further study regarding the frequency of Ozurdex for macular edema secondary to RVO may be of benefit.
CATT Two-year Study Results
Little difference found between Lucentis and Avastin.
■ Two-year data from the CATT study for wet AMD was released just before Retinal Physician went to press. The CATT Research Group, led by Daniel F. Martin, MD, concluded in an Ophthalmology paper that “ranibizumab and bevacizumab had similar effects on visual acuity (VA) over a two-year period.”
As-needed treatment resulted in less gain in VA than monthly treatment. This difference was demonstrated whether as-needed treatment was instituted at enrollment or after one year of monthly treatment.
The second year of the CATT study encompassed 1,030 patients who were available for follow-up out of 1,185 who were originally enrolled. At year two, a total of 68 patients had died. Missed visits accounted for most of the other patients who did not complete year two follow up.
The researchers noted that, over two years, “the rates of death, myocardial infarction and stroke did not differ” between the two drugs. The higher rate of serious adverse events for bevacizumab-treated patients reported in year one continued in year two. Also, as reported for year one, the risk of serious adverse events was not higher with monthly treatment relative to as-needed treatment. Among all organ systems, the greatest imbalance in adverse events was in gastrointestinal disorders. Although the number of these events was small, the researchers noted that this has been an area of concern in previous studies of systemically administered bevacizumab. When all known VEGF-related events were excluded, most of the imbalance remained, leaving it uncertain whether the higher rate of gastrointestinal adverse events reported with bevacizumab “was the result of chance, imbalances at baseline not captured in multivariate modeling, or truly higher risk.”
The researchers commented that results from other ongoing clinical trials worldwide may provide additional, independent information about comparative risk between the two drugs.
The CATT research group noted that “in 2010, ranibizumab accounted for nearly 10% of the Medicare Part B drug budget, its single largest expenditure. As treatment of patients continues indefinitely, the cumulative financial burden will only increase. The choice of drug and dosing regimen must balance the comparable effects on vision, the possibility of true differences in adverse events, and the 40-fold difference in cost per dose.”
|■ HHS sanctions ophthalmic stem cell researcher. Peter J. Francis, MD, PhD, formerly an ophthalmologist at the Casey Eye Institute, Oregon Health & Sciences University (OHSU), has voluntarily agreed to two years of supervised research after the Office of Research Integrity (ORI) of HHS found that he had “fabricated results of a pilot experiment” on two grant applications submitted to the National Eye Institute.|
The research involved the injection of RPE embryonic stem cells from rhesus monkeys into a strain of rats that develop what the ORI termed “retinal degeneration.”
Dr. Francis has been in the forefront of ophthalmic stem cell research.
In a statement, OHSU said it “takes research integrity matters very seriously. When questions were raised about one of Dr. Francis's research projects, he was immediately placed on leave. An investigation took place by our Scientific Integrity Committee and the results were reported to the Office of Research Integrity of the National Institutes of Health. At the conclusion of the investigation, Dr. Francis decided to leave the university.”
Further details regarding the sanctions appeared in a “Findings of Research Misconduct” release that appeared in The Federal Register on April 13.
Supervision is considered the milder of the two sanctions that the ORI can impose on a researcher.
■ Dry AMD drug moves to phase 3 trial. MacuClear, Inc., a clinical-stage specialty pharmaceutical company focused on discovering and developing novel solutions for vascular disorders of the eye, is beginning phase 3 studies for its lead compound, MC-1101, for dry AMD. MC-1101 is a proprietary, topically administered eye drop for treating and stopping the progression from dry AMD to wet AMD by increasing ocular blood flow in the choroidal vessels.
The first stage of MacuClear's double-blinded phase 3 study will examine 60 patients, using improvements in visual function as the trial's primary endpoint.
■ Thrombogenics gets funding for ocriplasmin launch. ThromboGenics NV announced that it has recently raised $103.6 million from investors through a private placement. The funds will be used by ThromboGenics to execute the US launch and commercialization of ocriplasmin, potentially the first pharmacological treatment for symptomatic vitreomacular adhesion, including macular hole.
The money will also help fund the clinical development of ocriplasmin for additional indications on a 50/50 basis with Alcon, its commercialization partner for non-US markets, strengthen its core ophthalmology franchise by in-licensing development-stage product candidates, and for general corporate purposes.
■ Visudyne receives orphan drug status for CSC. QLT said the FDA has granted orphan drug designation to its Visudyne therapy for the potential treatment of chronic or recurrent central serous chorioretinopathy (CSC). The company is currently working with external advisors on potential clinical study options for the assessment of the safety and efficacy of Visudyne in the treatment of chronic CSC that will allow QLT to evaluate possible development plans.
■ Eylea sales soar; beats all estimates. In an announcement that stunned investors and industry analysts alike, Regeneron reported that first-quarter sales of its newly approved wet AMD drug Eylea reached $124 million, enabling the company to achieve profitability for the first time in its more than 20-year history. Regeneron earned 37 cents per share on a non-GAAP basis and predicted that the company would be profitable for the full year.
In addition, Regeneron now estimates that 2012 sales of Eylea will be in the $500 to $550 million range, far above its previous estimates of $250 to $300 million.
The announcement on April 26 initially pushed the price of Regeneron shares above $140, capping off a year of huge gains for the stock.
■ Denmark study hails anti-VEGF. The risk of severe visual impairment and blindness from wet AMD has been cut in half within the past five years in Denmark. The findings parallel the introduction of new drug therapy for wet AMD in that country.
A report from the University of Copenhagen and the Glostrup Hospital in Denmark published in the American Journal of Ophthalmology shows that the number of new cases of blindness and severe visual loss in Denmark has been halved during the recent decade. The study examined the records of 11,848 new cases of legal blindness. The rate of blindness from AMD fell from 522 cases per million inhabitants aged 50 years or older in 2000 to 257 cases per million in 2010, a reduction by 50.8%.
The bulk of this decrease occurred after 2006, following the introduction of new effective drug treatments for wet AMD in the form of Lucentis and Avastin. RP