SUBSPECIALTY NEWS
Sustained-release Delivery of Lucentis Studied
Goal is to reduce burden of frequent injections.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Genentech (South San Francisco, CA) has initiated a phase 2 clinical trial investigating the Ranibizumab Port Delivery System (RPDS) implant in patients with wet AMD. The aim of the 316-patient study, called LADDER (Long-Acting Delivery of Ranibizumab), is to assess the efficacy and safety of a refillable implant for the sustained delivery of Lucentis for the treatment of wet AMD.
Genentech researchers have long believed that ranibizumab could be successful in a sustained-release format, due to the fact that the drug has the stability to remain effective when placed in an implant.
In a previous phase 1 study, the RPDS implant was well tolerated and showed an improvement in BCVA comparable to monthly injections, establishing proof of concept for the system. Genentech’s RPDS implant also recently received fast track designation from the FDA. Fast track is a process designed to facilitate the development, and expedite the review, of drugs to treat serious conditions and fill an unmet medical need.
“With the investigation of the RPDS implant, we hope to provide patients with the maximum benefits of treatment with Lucentis while reducing the number of office visits and injections they require,” said Jill Hopkins, MD, medical director, Genentech Ophthalmology.
“Inconsistency in treatment adherence can sometimes result in vision loss,” said Richard F. Dreyer, MD, LADDER clinical investigator. “If successful, the RPDS implant could become a useful tool to better manage wet AMD by providing a consistent level of treatment and potentially result in better long-term visual outcomes.”
LADDER is an interventional, randomized, double-blind, active comparator, multicenter study. The RPDS implant, which is inserted into the eye using standard surgical techniques and requires no sutures, is refillable using a special needle in a minimally invasive office-based procedure.
IN BRIEF
■ Lucentis superior to laser in PDR. Two-year results from the NIH-funded Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S study, published in the Journal of the American Medical Association, compared the efficacy and safety of Lucentis (ranibizumab, Genentech) to standard laser (PRP) therapy in advanced proliferative diabetic retinopathy. The data showed that people treated with Lucentis had an average improvement in visual acuity of +2.8 letters compared to a +0.2 letter improvement in the laser group. The publication also discussed other important outcomes from the 305-patient study, including peripheral visual field impact, visual acuity over two years, and rates of surgery in both treatment groups.
Prespecified secondary outcomes found little change in peripheral vision with Lucentis but a substantial loss of side vision with laser. Subjects on average gained half a line of vision with Lucentis compared to no change with laser. Vitrectomy rates were also lower in the Lucentis group. Injection-related endophthalmitis occurred in one person, which is consistent with known adverse events for Lucentis.
“Proliferative diabetic retinopathy remains a major unmet medical need in ophthalmology. We congratulate the DRCR for designing and executing this landmark study,” said Anthony P. Adamis, MD, vice president, Global Head of Ophthalmology, Immunology and Infectious Diseases at Genentech.
■ Gene therapy gains maintained at three years. Spark Therapeutics (Philadelphia) reported that an eight-patient cohort with inherited retinal dystrophies who had earlier participated in a small phase 1 trial had maintained their vision gains at three years. The patients had undergone a gene replacement procedure using the Spark adeno-associated virus platform and the company’s SPK-RPE65 investigational therapy.
The company had also recently announced that a larger, phase 3 trial of SPK-RPE65 with a similar patient cohort had also been successful based on one year of data. However, the three-year results from the phase 1 study show durability that has been lacking in gene therapy trials conducted by other companies and institutions.
First Three Injections Indicate Response to an Anti-VEGF
DME patients who did well early continued to benefit.
■ A large-scale study in which all 691 patients received the same FDA-approved anti-VEGF therapy for DME indicates that the patients’ response to the first three injections essentially determines how they will respond to the same therapy over the longer term. The data are based on the Protocol I phase 3 study conducted by the Diabetic Retinopathy Clinical Research Network (DRCRnet). Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona and Clinical Professor, USC Eye Institute, Keck School of Medicine, presented the data at the 2015 AAO annual meeting.
Though Allergan does not have an FDA-approved anti-VEGF therapy for DME, the company conducted the post-hoc analysis of the Protocol I study that led to these new data being reported. Allergan said its goal in this endeavor was to support patient care in the management of DME.
“This ‘EARLY Analysis’ study has relevance for retinal physicians looking to assess how patients will respond to anti-VEGF treatment long-term,” said Dr. Dugel. “This data suggests that if treatment goals are not achieved after three injections, further expected improvement may be minimal and physicians may want to consider other treatment strategies.”
This analysis of Protocol I assessed outcomes in three cohorts based on observed BCVA response, which was defined by letters gained on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at week 12. The cohorts were defined as a gain of less than five letters, a gain between five and nine letters, and a gain of greater than or equal to 10 letters. The unadjusted differences in mean BCVA change from baseline was -0.3, +6.9, and +15.2 at 12 weeks, respectively, and +3.0, +8.2, and +13.8 at three years, respectively. After multivariate adjustment, significant correlation remained between BCVA gain at week 12 and years 1 and 3.
“DME is difficult to manage and it requires a customized patient approach,” said David Nicholson, PhD, executive vice president, Global Brands R&D, Allergan. “The EARLY Analysis underscores Allergan’s commitment to broadening our knowledge of the current landscape of DME treatment patterns.”
Though additional studies are needed to confirm these findings, the EARLY Analysis study provides new information that may help to shape more effective treatment patterns for patients with DME.
IN BRIEF
■ Iluvien slows PDR progression. A new analysis of the pivotal FAME study that led to the approval of the Iluvien (Alimera Sciences) sustained-release implant for DME demonstrates that Iluvien also slows the progression of proliferative diabetic retinopathy (PDR). In this new analysis, presented by Charles C. Wykoff, MD, PhD, at the 2015 AAO Subspecialty Day, only 17% of the patients treated with Iluvien had PDR progression at 36 months, while 31% of those treated with placebo have PDR progression over the same time period.
In related news, Iluvien has now received a specific J Code, which Alimera says will streamline the reimbursement process for customers and potential customers.
■ Dr. Pelaez named “Emerging Vision Scientist.” Bascom Palmer Eye Institute’s Daniel Pelaez, PhD, was named as a 2015 Emerging Vision Scientist by the National Alliance for Eye and Vision Research for his novel work on stem cells and retinal regeneration.
Dr. Pelaez was one of 21 scientists selected from across the United States for the inaugural class of emerging vision researchers. During the two-day Decade of Vision 2010-2020 event held in Washington, DC, Dr. Pelaez and other scientists presented their innovative work to members of Congress.
An expert in stem cell biology, tissue engineering, biomaterials, and translational studies, Dr. Pelaez’s research focuses on the use of stem cells in regenerative ophthalmology, neuroregenerative therapies in the optic nerve and retina, molecular biology of ocular tumors, and bioengineered organs for transplantation. During his career, he has applied bioengineering principles to the field of stem cells and regenerative medicine in hopes of translating basic science research observations to clinical practice.
Bascom Palmer Begins Gene Therapy Trial
First patient treated for choroideremia.
■ A research team led by Byron L. Lam, MD, at the Bascom Palmer Eye Institute of the University of Miami Leonard M. Miller School of Medicine has performed gene therapy on a 47-year-old man as part of a phase 2 clinical trial to treat choroideremia (CHM), a rare inherited cause of blindness. The FDA-approved clinical trial will ultimately treat six patients with CHM to help to determine the safety and efficacy of this novel treatment. A promising treatment for CHM had been elusive until the recent advent of gene therapy, which is now being studied by a number of companies and institutions. These researchers believe the transfer of new genes into the dysfunctional cells has the potential to restore the health and function of these cells.
CHM is a progressive degenerative disorder of the retina and the choroid layers that line the inside of the back portion of the eye and is caused by a genetic defect of the X chromosome that results in a faulty protein in the retina. Symptoms of CHM begin with a gradual loss of night and peripheral vision. Over time, CHM leads to complete loss of central sight. CHM affects one in 50,000 people, the vast majority of whom are young men.
The approach used in this clinical trial was to use a large number of harmless viruses (AAV2-REP1) modified to carry copies of the normal gene into the eye to correct the genetic defect in CHM. The gene therapy was delivered to the space under the retina through an injection technique approved by the FDA for research purposes for this clinical trial. The injection provides controlled delivery of the gene therapy. The modified viruses infect retinal cells and carry copies of the normal gene into the cells where the normal gene continues to work to maintain the function and integrity of the cells. The goal of the treatment is to maintain or even improve visual function in CHM patients.
“We are extremely excited and optimistic about the success of this gene therapy trial,” says Dr. Lam. “We are continuing to treat more patients with CHM, and we hope the knowledge gained will help patients with other retinal diseases.” Dr. Lam added that this clinical trial was self-funded by Bascom Palmer and donors interested in retinal research.
IN BRIEF
■ AGTC files for second clinical trial. AGTC (Alachua, FL), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)–based gene therapies for the treatment of rare eye diseases, said it has filed an Investigational New Drug (IND) application with the FDA to conduct a four-site, phase 1/2 clinical trial of the company’s gene therapy product candidate for the treatment of achromatopsia caused by mutations in the CNGB3 gene. The FDA also recently granted AGTC preferred “orphan drug” status for the company’s program in achromatopsia caused by mutations in the CNGA3 gene. Achromatopsia, which occurs in approximately one in every 30,000 people, causes extreme light sensitivity, day blindness, and loss of color discrimination. Current treatments only deal with easing the discomfort caused by the disease. AGTC also recently began an initial human clinical trial using its gene therapy platform to combat the orphan retinal disease XLRS.
“This is another significant milestone for AGTC during what has been a transformative year for the company,” said Sue Washer, president and CEO. “In addition to finalizing our collaboration agreement with Biogen, initiating our phase 1/2 clinical trial for XLRS, and expanding our product pipeline, we remain on track to have a second product candidate in clinic shortly, pending FDA acceptance of the IND application and approval from the sites’ Institutional Review Boards.”
■ Eylea sales continue rapid growth. Regeneron (Tarrytown, NY) reported that US sales of Eylea (aflibercept) grew at a 65% year-over-year pace in the third quarter of 2015, reaching $774 million as compared to $445 million in the year-ago quarter. Worldwide sales of Eylea also grew sharply in the quarter, reaching $1.10 billion, a 53% increase from the year-ago quarter.
The company said it now expects full-year 2015 US Eylea sales to grow at 50% to 55% versus 2014 full-year sales. Previous guidance indicated growth of 45% to 50%.
Ophthotech Fovista Trial Is Fully Enrolled
Second large phase 3 study for combination therapy
■ Ophthotech Corporation (New York, NY) has announced the completion of patient recruitment for its second large-scale phase 3 trial of Fovista (pegpleranib) in combination with Lucentis (ranibizumab, Genentech) for the treatment of wet AMD. The company expects to announce initial, topline data from both phase 3 trials of Fovista in combination with Lucentis in the fourth quarter of 2016. The two trials encompass a total of more than 1,200 patients.
“Completion of patient recruitment in these two large phase 3 clinical trials of Fovista anti-PDGF therapy in combination with Lucentis is a significant milestone in the Fovista phase 3 pivotal program,” said David R. Guyer, MD, CEO and chairman of the board of Ophthotech. “We believe that Fovista administered in combination with anti-VEGF therapy may represent a significant advancement in the treatment of wet AMD, and we look forward to obtaining data from both of these studies.”
The two phase 3 trials investigating the superiority of Fovista in combination with Lucentis compared to Lucentis monotherapy are identical with respect to the trial design in the first year. Therefore, the database from both trials will be locked and analyzed together to optimize pooled analysis of certain relevant endpoints in accordance with the statistical analysis plan. A third large phase 3 trial of more than 600 patients, which is investigating Fovista in combination with either Eylea (aflibercept, Regeneron) or Avastin (bevacizumab, Genentech), continues to enroll patients with recruitment on track.
Ophthotech continues to explore and consider various regulatory filing options with the goal of providing Fovista to physicians for their patients with wet AMD as quickly as possible, assuming favorable trial results from the phase 3 program. The company believes that the most likely strategy is to initially submit a New Drug Application (NDA) to the FDA for Fovista in combination with Lucentis based on data from the two phase 3 trials of Fovista in combination with Lucentis and to subsequently submit an amendment to the NDA with data from the phase 3 trial of Fovista in combination with Eylea or Avastin. Alternatively, the company may elect to file a supplemental NDA for Fovista in combination with Eylea or Avastin following FDA review of the NDA for Fovista in combination with Lucentis.
The FDA granted fast track status for Fovista for the treatment of wet AMD in September 2013. The company believes Fovista is the most advanced anti-PDGF agent in development for the treatment of wet AMD and, if approved, is expected to be first to market in this class of novel therapies for wet AMD.
IN BRIEF
■ PanOptica AMD eyedrop shows biologic activity. PanOptica (Bernardsville, NJ) said its small molecule, anti-VEGF eyedrop showed early signs of biologic activity and safety in a phase 1/2 study involving 50 patients with wet AMD. The company said very preliminary data showed that PAN-90806 “warrants continued investigation.”
“PAN-90806 is a potent, selective, small-molecule VEGF receptor blocker with unusually favorable characteristics for topical back-of-the-eye delivery,” said PanOptica President and CEO Paul G. Chaney. “Reproducible pharmacokinetic findings demonstrate excellent target tissue distribution to the central choroid and central retina, with concentrations sustained at 17 hours post-dose. Moreover, topical dosing results in extremely low systemic exposure, and animal studies suggest that PAN-90806 performs as well as anti-VEGF antibodies administered by intravitreal injection.
“PAN-90806 may have utility in other chronic neovascular eye diseases, including diabetic retinopathy and retinal vein occlusion. Researchers have also expressed interest in studying PAN-90806 as a potential strategy for preventing the progression to wet AMD in patients with high-risk dry AMD,” Mr. Chaney continued. He noted that PanOptica has initiated a phase 1 trial of PAN-90806 in patients with proliferative diabetic retinopathy and that full-results from the AMD trial, including patients in the ongoing stage 2 of the trial treated with a single injection of anti-VEGF therapy followed by PAN-90806 maintenance therapy for up to three months, will be presented in 2016.
Avastin Use Drops With Ohio Requirement
Patient-specific prescriptions add new burdens.
■ Researchers led by Steven Holfinger, MD, of Riverside Methodist Hospital in Columbus, Ohio, sought to evaluate the change in bevacizumab use after a regulatory requirement for patient-specific prescriptions (PSPs) for off-label medications went into effect in Ohio in 2012. Prior to the change in the law, retina practices in Ohio could order bevacizumab from compounding pharmacies in bulk and use the medication for any patient who required it, with no need to fill out individual prescriptions for individual patients.
This study, reported online on November 5 in JAMA Ophthalmology, retrospectively reviewed the aggregate data from the billing records of patients receiving 1.25-mg injections of bevacizumab (Avastin, Genentech), 0.3- or 0.5-mg injections of ranibizumab (Lucentis, Genentech), or 2.0-mg injections of aflibercept (Eylea, Regeneron) for wet AMD or DME in a nine-member retinal specialty private practice.
The review assessed 4,488 intravitreal injections in the three-month period before and 5,253 injections in the three-month period after the Ohio Board of Pharmacy’s requirement of PSPs for bevacizumab. A Likert scale survey was conducted among the nine physicians to identify reasons for any change in the prescription of bevacizumab. The survey inquired about (1) the burden of PSPs, (2) concern about differences in efficacy, and (3) concern about differences in safety.
Bevacizumab use decreased from 2,752 of 4,488 pre-PSP injections (61.3%) to 1,503 of 5,253 post-PSP injections (28.6%), a change of −32.7%. The sharp decline in bevacizumab injections was made up for by a significant increase in ranibizumab and aflibercept injections. In the survey of the nine physicians concerning their reasons for decreased use of bevacizumab, seven (78%) strongly agreed and one (11%) agreed that the burden of PSPs changed their choice of drug used for injection.
The researchers concluded that use of bevacizumab was reduced by 32.7% one year after the regulatory requirement for PSPs for compounded medications. This change seemed to have more association with the requirement for PSPs than with a known change in efficacy or safety concerns. Although this study was based on a single US practice, regulation of repackaged medication for safety concerns should also consider the evaluation of treatment burden, cost, and adherence. RP
IN BRIEF
■ FDA approves Leica EnFocus intrasurgical OCT. Leica Microsystems’ OCT division Bioptigen has received 510(k) clearance from the FDA to market its EnFocus intrasurgical OCT system. EnFocus is an upgrade solution for new and existing ophthalmic surgical microscopes, extending their capability. EnFocus allows visualization of ocular tissue microstructure during surgery in high resolution, providing surgeons with subsurface insight while operating.
“The EnFocus intrasurgical OCT system provides excellent optical imaging performance for the surgeon, employing a modular design which enables sharing between multiple microscopes in an operating theater,” said Markus Lusser, president of Leica Microsystems. “It cleverly adds an important capability to ophthalmic microscope platforms. The device is an innovative advancement in ophthalmic imaging that Leica customers called upon us to deliver.”
The EnFocus imaging systems, while mounted to surgical microscopes, are intended for use with patient populations from pediatric to adults. The systems acquire, process, and display depth-resolved images of ocular tissue using SD-OCT and are compatible with common retina fundus viewing systems.
■ Clearside begins phase 3 trial enrollment. Clearside Biomedical has enrolled the first patient in its phase 3 clinical trial of CLS-TA, the company’s proprietary form of triamcinolone acetonide, using suprachoroidal space (SCS) drug administration for the treatment of macular edema associated with noninfectious uveitis.
The new PEACHTREE study is a randomized, sham-controlled trial to assess the efficacy and safety of 4 mg of CLS-TA administered via SCS injection in subjects with macular edema associated with noninfectious uveitis. The clinical endpoint in the trial is the proportion of patients with a change in baseline of at least 15 letters in BCVA as measured at 24 weeks. Several secondary efficacy and safety endpoints will also be evaluated.
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