SUBSPECIALTY NEWS
iSonep Fails in Phase 2 Wet AMD Study
It was tried in combination and as monotherapy.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Lpath, Inc. (San Diego), a developer of bioactive lipid-targeted therapeutics, said its multicenter, phase 2 Nexus clinical trial evaluating iSonep in patients with wet AMD did not meet its primary or key secondary endpoints. Wet AMD patients who had not responded adequately to existing anti-VEGF therapies did not show any statistically significant improvement in visual acuity when treated with iSonep as an adjunctive or monotherapy.
Nexus is a prospective, randomized, double-masked, positive-control, phase 2 clinical trial conducted in the United States that enrolled 158 patients with wet AMD. All enrolled patients had been subresponsive to treatment with anti-VEGF drugs and had received at least three previous injections of an anti-VEGF drug. Nexus study patients each received four intravitreal injections over the 90-day dosing period. There were approximately 39 patients in each of the four treatment arms.
The prespecified primary endpoint of the study was mean change in BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) from day 0 to day 120. At day 120, patients who received intravitreal injections of 4.0 mg iSonep alone lost a mean of 3.17 letters on the ETDRS, a combination of 0.5 mg iSonep and anti-VEGF therapy gained a mean of 4.22 letters, a combination of 4.0 mg iSonep and anti-VEGF therapy gained a mean of 3.63 letters, and anti-VEGF therapy alone gained a mean of 4.34 letters.
BCVA and anatomical endpoints were collected throughout the nine-month period. The data collected suggests that in this study iSonep was safe and well tolerated across all dose levels when administered alone or in combination with anti-VEGF therapy. Of the 158 patients randomized in the study, 11 patients continue to be evaluated, with completion of follow-up at month nine for all patients expected in September 2015.
“This trial was designed to evaluate the activity of iSonep in wet AMD patients who had previously received at least three prior injections of an anti-VEGF agent and had not responded well. While the primary endpoint of the trial was not met, we will be conducting a complete analysis of the data, including additional anatomical endpoints, to better understand the results from each arm of the trial,” stated Dario Paggiarino, MD, Lpath’s senior vice president and chief development officer.
Full study results will be presented during the Retina Subspecialty Days in conjunction with the American Academy of Ophthalmology in Las Vegas in November 2015.
Lpath said it will restructure its workforce and conduct a strategic evaluation of its research and development programs in order to conserve working capital and focus its resources on those programs deemed most likely to create value in the near term.
IN BRIEF
■ Avalanche gene therapy: mixed results in wet AMD. Twelve-month data from a phase 2a, 32-patient clinical trial using a combination of Avalanche AVA-101 gene therapy and ranibizumab to treat wet AMD showed mixed results, according to results released by Avalanche Biotechnologies (Menlo Park, CA).
The major positives from the data were an excellent safety profile and a reduction in the need for ranibizumab rescue injections among the 21 patients treated with the combination. Those patients on average required two fewer ranibizumab retreatments (2) than the 11 patients in the control group (4).
Less impressive were the data on retinal thickness, which showed no improvement in the combination group, and in vision improvement, which was +2.2 letters in the combination group.
Avalanche said it will use the phase 2a data to help design the upcoming phase 2b study of AVA-101.
■ Acucela dry AMD therapy has positive response. Data from a 72-patient, phase 2a, 90-day study of the oral therapy emixustat hydrochloride (Acucela, Seattle) showed a dose-dependent pharmacological response in line with the drug’s proposed mechanism of action. The results were reported in the online edition of the journal Retina.
Emixustat targets the visual cycle and is in development for the potential treatment of geographic atrophy associated with dry AMD. A phase 2b/3 study of emixustat is ongoing.
EyeGate Gets Path to Initial Approval
Instilling drugs through electrical stimulation.
■ EyeGate Pharmaceuticals, Inc. (Waltham, MA), a specialty pharmaceutical company focusing on developing therapeutics and novel drug delivery systems for treating diseases of the eye, said the FDA has provided a path to approval for the company’s investigational treatment for anterior uveitis.
EyeGate specializes in the delivery of drugs to both the anterior and posterior segments of the eye through the noninvasive process of iontopheresis, a form of electrical stimulation that enables medications to be administered through the skin. The company has also identified dry eye and macular edema as targets for its iontophoretic technology.
The FDA provided guidance that if the planned phase 3 trial of EGP-437 in anterior uveitis meets noninferiority criteria, data from this trial along with data from a previously completed phase 3 trial in anterior uveitis will be sufficient to support a New Drug Application (NDA) filing. The FDA also communicated that the design of the planned phase 3 study is acceptable and that the nonclinical work completed to date is sufficient to support a NDA filing.
The planned trial will be a prospective, multicenter, randomized, double-masked, parallel-arm, positive control noninferiority study evaluating iontophoretic dexamethasone phosphate ophthalmic solution compared to the standard of care, prednisolone acetate ophthalmic suspension (1%) in patients with noninfectious anterior segment uveitis. The trial is expected to enroll up to 250 subjects at approximately 60 US clinical sites. Noninferiority will be evaluated based on the proportion of subjects with total anterior chamber cell clearing at Day 14 of EGP-437 treatment vs standard of care.
“The FDA comments are an important milestone in our clinical development plan for EGP-437, and we are pleased that they have determined that the proposed phase 3 trial design is acceptable. The guidance that data from this planned study, along with our previous phase 3 study of EGP-437 should be sufficient to support a NDA filing gives us a clear clinical and regulatory path for our lead product candidate,” said Stephen From, president and CEO of EyeGate. “We believe that EGP-437 represents a potential breakthrough in the treatment of ocular diseases and that this trial, if successful, would provide a significant validation of the use of iontophoresis for delivery of drug to the eye. We expect that iontophoretic delivery could be applied to a variety of ocular drugs that have traditionally been administered topically or via injection, and could provide a viable therapeutic alternative to patients in need.”
IN BRIEF
■ Doheny names retina specialist as new leader. After an extensive search for a new president and chief scientific officer, the Doheny Eye Institute turned selected retina specialist SriniVas (Vas) Sadda, MD, to head the prestigious institution. Dr. Sadda has been affiliated with Doheny since 2002.
Dr. Sadda completed his medical degree and residency at the Johns Hopkins University School of Medicine in 1994. After his residency, he completed fellowships in neuro-ophthalmology and medical retina at Johns Hopkins’ Wilmer Eye Institute. He is a cofounder of the Pacific Retina Club, the largest retina organization on the West Coast. He also serves on the editorial boards of the prestigious publications Ophthalmology, Retina, and OSLI Retina and has served on multiple NIH study sections. He has served on the executive committee of the Macula Society and on various committees for the Retina Society and the American Society of Retina Specialists. He is also the Section Head for Retina for the American Academy of Ophthalmology O.N.E. Network.
■ Minimal inflammation after anti-VEGF injections. Following up on reports of inflammation after anti-VEGF injections for wet AMD, researchers at the Robert Wood Johnson Medical School (New Brunswick, NJ) conducted a 106-eye study to determine a rate of incidence.
Subjects in the study had received a mean of 18 injections of either ranibizumab or aflibercept. Some treatment-naïve subjects were also included in the study.
No significant clinical inflammatory reactions were identified in any of the 106 eyes up to three days following intravitreal injection. The researchers said they intend to bring additional subjects into this study.
Anti-VEGF and GA: Is There a Link?
Some factors point to an association
■ One of the issues currently being studied by the retinal community is whether anti-VEGF treatment over a period of time in itself increases the incidence of geographic atrophy (GA). So far, the verdict has been relatively inconclusive.
In an effort to determine the effect, if any, of anti-VEGF therapy on the development of GA, researchers from the University of Rochester School of Medicine and the NEI followed a mixed group of 69 previously treated and treatment-naïve subjects over a four-year period from 2009 to 2012. The average age of the subjects at baseline was 78.1 years and the average follow-up time was 40 months.
Of the 64 patients who had baseline quality images, 23 had GA at baseline (which on average continued to progress during the study period), and 41 had no GA at baseline. By the end of year two of the study, eight subjects (19.5%) who had no previous GA developed it. The researchers found that those who developed GA during the study tended to have had prior anti-VEGF treatment, be older, and have GA in the fellow eye. Those who did not develop GA during the study tended to be treatment-naïve and have fewer injections during the first year (6.9 vs 10.4). They also had a lower average age and less fellow-eye GA.
All of the subjects who developed GA during the study showed abnormal RPE at baseline.
The researchers concluded that the factors cited above could be contributory to the development of GA for patients receiving anti-VEGF therapy. They also suggested the fundus autofluorescence imaging could be helpful in identifying eyes susceptible to the development of GA.
This research was presented at the recent ARVO meeting in Denver, CO, under the following title: “Evolution of geographic atrophy in patients treated with ranibizumab for neovascular age-related macular degeneration.”
IN BRIEF
■ AGTC makes key appointments. AGTC (Alachua, FL) has appointed Mark S. Shearman, PhD, as Chief Scientific Officer and Rabia Ozden, MD, as Vice President of Clinical Research and Development. These individuals will be instrumental to the company as it moves forward in the development of its gene therapy product candidates for treating rare inherited eye diseases, including its lead product candidates, which focus on X-linked retinoschisis (XLRS) and achromatopsia (ACHM).
Prior to joining AGTC, both professionals held leadership positions in drug discovery and development at two of the world’s research-based global pharmaceutical companies. Dr. Shearman was at EMD Serono, Inc., the US and Canadian subsidiary of Merck KGaA, since 2009 in the capacity of Senior Vice-President of Research and Early Development. Dr. Ozden was employed most recently by GlaxoSmithKline, where she served as Vice President and Head of Clinical Ophthalmology since May 2014.
■ Intravitreal injections and blood spatter. Researchers from Loyola University (Chicago) and the University of Michigan conducted a study to determine whether blood splatter was an issue during intravitreal injections.
A single vitreoretinal specialist performed 100 consecutive intravitreal injections. After patients’ eyes received anesthetic via pledgets soaked in 4% lidocaine and cleaned with betadine swabs, the specialist wore a plastic eyeshield.
Once the injection was performed, the eyeshield was removed and a new eyeshield was used for each injection. The shields were subsequently dried and stored.
Each shield was sprayed with luminol a bioluminescence blood detection system. A questionnaire was provided after each injection for the vitreoretinal specialist asking if there was any intraprocedural blood splatter.
Of the 100 shields, seven were found to have blood splatter. On the post-procedure questionnaire, the vitreoretinal specialist reported no indication of blood splatter for these seven injections.
The researchers concluded by cautioning that blood splatter during intravitreal injections risks transconjunctival transmission of human immunodeficiency virus and viral hepatitis. This study is the first of its kind to document a 7% risk of blood splatter during intravitreal injections.
pSivida: Good Safety Profile for Medidur Implant
An interim assessment of phase 3 study.
■ pSivida Corp. (Watertown, MA), a developer of sustained-release drug delivery methods for treating eye diseases, announced positive safety data from its ongoing assessment of its first phase 3 clinical trial of its Medidur long-term implant for posterior uveitis.
At three months, only 4% more study eyes (2/3 of which received Medidur) experienced elevated IOP than the fellow non-study eyes (none of which received Medidur). The company said the minimal difference observed in elevated IOP in the assessment suggests favorable results for a key safety measure of the trial, the number of eyes that develop clinically significant increases in IOP within 12 months of receiving Medidur relative to control eyes.
“These data are very encouraging for the safety profile of Medidur,” said Paul Ashton, PhD, president and CEO of pSivida. “A significant treatment challenge with posterior uveitis patients is managing the serious side effects of prolonged steroid use, the current first-line treatment. A therapy that can provide the benefits of steroids on a sustained basis for three years with a single injection with a lower incidence of side effects would be a very significant advance in treatment of this disease.”
The assessment of masked data compared the elevation of IOP over 21 mm Hg at three months for study eyes and fellow eyes for the 105 out of 129 enrolled subjects with at least three-month follow-up data.
“We are very optimistic for the final IOP safety results in this trial,” said Dr. Ashton. “We expect topline results from this first phase 3 trial of Medidur to be available in Q2 2016, and with favorable results from this and our second trial, which has just been initiated, we intend to file for US approval in the first half of 2017.”
IN BRIEF
■ Loss of reading speed seen as assessment tool. An interesting sidelight to the MAHALO clinical trial for the treatment of geographic atrophy with lampalizumab was that the trial included both a reading speed test and a functional reading independence questionnaire. Researchers, led by Rohit Varma, MD, of the USC Eye Institute, initiated the test on the premise that a decline in reading ability might occur in advance of a loss in measurable BCVA and serve as a valuable tool for assessing patients.
One hundred MAHALO subjects participated in the test, with average baseline reading speed of 105 words per minute. At 18 months, the average speed had dropped to 82 words per minute, with the greatest decline occurring between 12 and 18 months. Those patients whose reading speed dropped below 80 words per minute reported the greatest problems with reading independently.
The researchers concluded that tests of reading speed and functional reading independence could be useful additions to future clinical trials in geographic atrophy.
■ FAME extension study confirms Iluvien efficacy. Researcher Baruch Kuppermann, MD, PhD, invited patients with DME who had participated in the phase 3 FAME trial of Iluvien to take part in an extension Study. Iluvien is a long-term sustained-release implant that provides continuous therapy for 36 months. The extension study was conducted to test a new Iluvien microinjector.
Sixty-four subjects from the FAME study agreed to participate and received a single 0.2 μg/d FAc (fluocinolone acetonide) implant in the same eye treated during FAME.
Patients were on average 68 years old (mean DME duration = 7.32 years). Mean time elapsed between exiting FAME and receiving a treatment in the new study was 585 days. The mean BCVA for these 64 patients entering the FAME Extension Study was 62.7 ETDRS letters. After 12 months, BCVA showed a modest gain of approximately two letters and improved retinal anatomy from a baseline of 316.6 μm to 261.0 μm. In general, 0.2 μg/d FAc was well-tolerated. Adverse events were consistent with the class: mean IOP increased by approximately 2.5 mm Hg; four patients developed ocular hypertension, and cataract and IOP-lowering surgeries were performed on one patient each.
Dr. Kuppermann concluded that in the FAME Extension Study, on average, BCVA was maintained and retinal anatomy improved. The safety profile was consistent with the class and supports the use of 0.2 μg/d FAc implants for the treatment of DME.
Dr. Hariprasad Honored With Named Professorship
University of Chicago gives endowed chair to retina specialist.
■ Seenu M. Hariprasad, MD, professor in the Department of Ophthalmology and Visual Science at the University of Chicago, has been named the department’s first Shui-Chin Lee Professor in Ophthalmology and Visual Science.
Dr. Hariprasad is an internationally recognized expert in the diseases and surgery of the retina, vitreous, and macula. He is an active leader in the Department of Ophthalmology and Visual Science, serving as chief of the vitreoretinal service, director of clinical research, and Director of the Fellowship in Vitreoretinal Diseases and Surgery.
Since joining the University of Chicago in 2005, Dr. Hariprasad has gained a reputation as a leading specialist in various vitreoretinal disorders, including AMD, diabetic eye disease, intraocular infection, and RVO. He has been recognized for bringing more effective and efficient sutureless microincisional vitrectomy techniques to the University of Chicago.
The university notes that Dr. Hariprasad’s clinical research has contributed to the understanding and use of new medications to combat a wide variety of vitreoretinal disorders. He has served as principal or subinvestigator in more than 40 national and international clinical trials evaluating various medications, sustained drug-delivery devices, and surgical innovations to treat a variety of diseases such as AMD, diabetic retinopathy, and RVO.
His work has led to nearly 200 peer-reviewed publications, meeting abstracts, and textbook chapters. He has presented more than 150 individual lectures in cities around the world. Dr. Hariprasad’s recently published textbook, Management of Retinal Vein Occlusion: Current Concepts, is one of only a small number of textbooks dedicated to this disease.
He has also been awarded numerous honors, including an AAO Achievement Award, and an ASRS Honor Achievement Award. He has been named a top doctor in publications such as US News & World Report and Chicago Magazine. RP
IN BRIEF
■ Wilmer and Bayer in drug development pact. Bayer HealthCare and Johns Hopkins University have entered into a five-year partnership agreement to jointly develop new ophthalmic therapies targeting retinal diseases. The partners will jointly work on the discovery and development of innovative drugs for the treatment of serious back-of-the-eye diseases that affect many people worldwide, including AMD, DME, and RVO.
“Bayer is strongly committed to further expanding its research efforts in the area of retinal diseases,” said professor Andreas Busch, head of Global Drug Discovery and member of the executive committee of Bayer HealthCare. “The Wilmer Eye Institute’s deep understanding of eye disease biology and patient care and Bayer’s expertise in drug discovery and development in ophthalmology complement each other perfectly.”
The goal of the strategic research alliance is to accelerate the translation of innovative approaches from the laboratory to the clinic, ultimately offering patients new treatment options for several retinal diseases.
“There is a critical need for new therapies that treat a variety of serious diseases of the eye,” said Peter J. McDonnell, director of the Wilmer Eye Institute. Additional research will allow us the opportunity to make significant advances in this area.”
Under the agreement, Bayer and JHU will jointly conduct research activities evaluating new targets and disease mechanisms, drug delivery technologies, and biomarkers for diseases with high unmet medical need. Both parties will contribute personnel and infrastructure to address important scientific questions. Bayer will have an option for the exclusive use of the collaboration results.
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