SUBSPECIALTY NEWS
Genzyme Gene Therapy Study Shows Promise
Four wet AMD patients respond to treatment.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ As gene therapy to combat a range of retinal diseases continues to attract increased interest and new funding, a recent presentation at the Retina Society meeting in Philadelphia has confirmed the potential value of this type of treatment. In a phase 1 study sponsored by Genzyme (Cambridge, MA), four wet AMD patients responded positively to gene therapy, with all four patients maintaining their gains as long as four years after gene implantation.
“This was a 19-patient study of individuals with very advanced macular degeneration and vision of 20/200 or less,” said Jeffrey Heier, MD, of Ophthalmic Consultants of Boston and principal investigator for the study. “Eight of the patients had too much scarring in the macula to respond to the treatment. Of the 11 patients we evaluated as potential responders, four had a positive response that has been maintained.” Dr. Heier said no common factors had yet been found that separated the responders from the non-responders.
Dr. Heier said the early-stage study was to determine safety and whether there was a biologic effect from the treatment. Patients were divided into four dose cohorts. He said the treatment was well tolerated, with no systemic safety signals and only one patient in the highest-dose cohort experiencing mild-to-moderate inflammation that was resolved by administration of topical steroids.
“I would call the data promising in that we see a few patients who have demonstrated a positive and durable response,” said Dr. Heier. “But this is a small, early-stage study, and I don’t want to overplay these results. In order for gene therapy via this approach to become a viable treatment alternative, we will need to see more consistent expression and treatment responses.”
The Genzyme study began in partnership with Applied Genetic Technologies Corporation (AGTC, Alachua, FL). AGTC gene-delivery technology, which uses a proprietary adeno-associated virus (AAV)-based platform, was employed in administering the treatment. This partnership has been ended and both Genzyme and AGTC are now pursuing their own gene therapy initiatives.
AGTC recently raised more than $80 million in two public stock offerings to continue its research.
IN BRIEF
■ Variability in compounded bevacizumab. A new study found that Avastin (bevacizumab) prepared by compounding pharmacies tended to have variable protein levels and less drug concentration than bevacizumab that came directly from the manufacturer Genentech (South San Francisco, CA). On the positive side, the researchers found that none of the 32 samples of compounded bevacizumab they evaluated contained microbial contaminants or endotoxins.
The researchers who conducted the study were all from Weill Cornell Medical College (New York). Their study was published in JAMA Ophthalmology online.
To determine if compounded bevacizumab matched drug that came directly from the manufacturer, the researchers purchase three samples of the drug from each of 11 compounding pharmacies. These were chemically analyzed and compared to the manufacturer’s product. Of the 33 samples that arrived, one was found to contain no drug.
The researchers expressed concern that the compounded drugs tended to have lower drug concentrations than the manufacturer’s bevacizumab. They noted that this deficiency could have both “clinical and ethical implications,” as patients deserve to receive medications that meet “a minimum quality control as set forth for other FDA-approved drugs.”
■ Eylea approved for both types of RVO. Regeneron Pharmaceuticals, Inc. (Tarrytown, NY) said the FDA has approved Eylea (aflibercept) for the treatment of macular edema following RVO, which now includes macular edema following BRVO in addition to the previously approved indication of macular edema following CRVO. The recommended dosage in patients with macular edema following RVO is 2 mg every month.
The expanded indication is based on the previously approved indication for CRVO and positive results from the phase 3 VIBRANT study of 181 patients with macular edema following BRVO. VIBRANT compared Eylea 2 mg once every four weeks with a laser photocoagulation control group. At 24 weeks, significantly more patients treated with Eylea gained at least 15 letters in vision.
Allegro Ophthalmics Begins Phase 2 DME Trial
Integrin peptide has shown a durable response.
■ Allegro Ophthalmics (San Juan Capistrano, CA), a developer of novel drug therapies for serious eye diseases, is now enrolling patients in a phase 2 trial that will evaluate the safety and efficacy of Luminate (formerly ALG-1001) in patients with DME.
This phase 2 study is a randomized, controlled, double-masked, multicenter, dose-ranging trial to evaluate the safety and efficacy of intravitreal injections of Luminate compared to the current standard of care for patients with DME. Patients will be randomized to one of five treatment groups that include three Luminate groups (1.0 mg, 2.0 mg, or 3.0 mg), an Avastin (bevacizumab, Genentech) group, and a focal laser photocoagulation group. All study subjects will return for examinations every four weeks for six months. Total planned enrollment for the trial is 150 patients.
“This phase 2 clinical study design follows the prospective analysis of the phase 1 DME study, which demonstrated strong safety and efficacy in monotherapy treatment with Luminate,” said Vicken Karageozian, MD, chief technical officer, Allegro Ophthalmics. “In the phase 1 study, eight of 15 end-stage DME patients treated with Luminate experienced a three-to-five line improvement in visual acuity with a corresponding improvement in macular anatomy as measured three months off treatment.”
Luminate, a first-in-class integrin peptide therapy, treats vitreoretinal diseases by targeting integrin receptors involved in cell signaling and regulation, and in the construction of new and aberrant blood vessels. By utilizing two mechanisms of action (anti-angiogenesis and vitreolysis), Allegro says Luminate has been shown to be effective at regressing and inhibiting new blood vessel formation, as well as reducing vascular leakage to maintain and restore vision.
IN BRIEF
■ Lucentis granted priority review for DR indication. Genentech (South San Francisco, CA) said the FDA has accepted the company’s supplemental Biologics License Application (sBLA) and granted accelerated Priority Review of Lucentis (ranibizumab) for the treatment of diabetic retinopathy. The FDA confirmed an action date of February 6, 2015.
The sBLA was submitted on August 7, 2014, to address the unmet need for approved ocular medications for the treatment of diabetic retinopathy. The submission was based on data from the phase 3 RISE and RIDE clinical trials. If approved by the FDA, Genentech said that Lucentis could be the first eye medicine available for diabetic retinopathy patients.
■ Nextech buys electronic records firm MDIntelleSys. Tampa-based Nextech Systems, a medical specialty information technology company, has acquired the electronic health records company MDIntelleSys (Clearwater, FL) that was founded in 2003 by retina specialist Daniel P. Montzka, MD. The MDIntelleSys system was initially created with many features that appealed to retina practices and the company has a significant percentage of retina practices among its clients. MDIntelleSys was also one of the first cloud-based electronic systems for ophthalmology.
The acquisition will expand Nextech’s electronic health records capabilities in ophthalmology and significantly increase its market share in the ophthalmology sector. The terms of the transaction were not disclosed.
■ Bioptigen awarded grant for intraoperative OCT. The National Eye Institute (NEI) has awarded $1.72 million in grants to Bioptigen Inc. (Research Triangle, NC) for the development of microscope-integrated intraoperative optical coherence tomography technology. Currently, perioperative OCT imaging is performed using a handheld probe, or by mounting such a probe to the surgical microscope. Under the new NEI grant, Bioptigen will advance the development of a novel intraoperative OCT system integrated directly into the optical train of the surgical microscope.
“The work advanced under these grants will bring surgeons one step closer to realizing the full value of intraoperative OCT,” said Eric Buckland, PhD, the CEO of Bioptigen. ”Ultimately, the ability to observe subsurface structures simultaneously with surgical manipulations will provide surgeons with a critical advance in microscopic visualization, with the goal of improving patient outcomes and reducing surgical risk.”
Eyedrop for Wet AMD to Enter Phase 3
Lucentis/squalamine combination has produced increased vision gains.
■ A combination of Lucentis (ranibizumab) injections and the self-administered squalamine aminosterol eyedrop (Ohr Pharmaceutical, New York) demonstrated better overall vision improvement than ranibizumab monotherapy in the recent phase 2 IMPACT trial conducted by Ohr. However, the combination did not meet its primary phase 2 endpoint of reducing the number of ranibizumab injections required by patients. So in planning its pivotal phase 3 trial with the FDA, Ohr has now made vision improvement its primary endpoint.
“Our recent meeting has provided us with valuable input to formulate a clear regulatory strategy for OHR-102 (squalamine),” said Dr. Irach Taraporewala, president and CEO of Ohr. “Importantly, the agency has agreed with our plan to use visual acuity, as defined by gains of ≥3 lines at nine months, as the primary endpoint in phase 3 trials. Visual acuity is the most clinically relevant endpoint for retinal disease.”
“Data from the IMPACT phase 2 study demonstrated improvements in best-corrected visual acuity and ≥3 line gains using the combination of OHR-102 and Lucentis as compared to the Lucentis monotherapy group at all timepoints from four to 38 weeks. We believe this robust and rapid response to OHR-102 is a result of its potent inhibition of multiple angiogenic targets,” said retina specialist Jason Slakter, MD, chief medical officer of Ohr. “Considering that the phase 3 primary endpoint will be at the same nine-month timepoint as the phase 2 study, we believe we have set a very realistic goal of achieving a similar outcome in the planned phase 3 trials.”
In the interim analysis of the ongoing phase 2,142-patient IMPACT study, more than twice the percentage of patients achieved ≥3 line gains in visual acuity at nine months with the combination of squalamine eyedrops and ranibizumab as compared to the ranibizumab monotherapy group (overall P=.025, classic lesions P=.007). At week 38, 48.3% of patients in the squalamine group had best corrected visual acuity gains of 15 letters or more, compared with 21.2% in the placebo group. Additionally, nearly 50% of squalamine-treated patients showed an improvement in visual function compared with 20% of the placebo group. Mean number of Lucentis injections was 6.2 in the squalamine group and 6.4 in the placebo group.
Two identical phase 3 studies will be conducted. The company plans to initiate the phase 3 trials in the first half of 2015 with the goal of submitting a New Drug Application following collection and analysis of the nine-month primary efficacy data.
During the first year of the study, patients will be randomized 1:1 to receive monthly ranibizumab plus squalamine eyedrops twice a day or Lucentis plus placebo. During the second year, they will receive Lucentis PRN plus squalamine or placebo twice a day.
IN BRIEF
■ Chinese company has effective wet AMD drug. Chengdu Kanghong Biotechnology Co., Ltd. (Chengdu, China) has completed two new promising studies for its anti-VEGF fusion protein conbercept, already approved in China in 2013 to treat wet AMD.
The AURORA study was a phase 2 trial in which researchers treated patients (n=111) with either 0.5 mg conbercept or 2.0 mg conbercept for three months before randomizing patients to one of four treatment groups: 0.5 mg conbercept PRN, 0.5 mg conbercept monthly, 2.0 mg conbercept PRN, and 2.0 mg conbercept monthly. At 52 weeks, the 0.5-mg PRN group gained 14.3 letters, the 0.5-mg monthly group gained 9.3 letters, the 2.0-mg PRN group gained 12.4 letters, and the 2.0-mg monthly group gained 15.4 letters. Mean central retinal thickness improved in all groups over the same time period.
In addition, in the phase 3 PHOENIX study, treatment-naïve patients (n=124) with wet AMD received 0.5 mg conbercept monthly for three months or sham monthly for three months. After three months, each group received 0.5 mg conbercept every three months. At 52 weeks, the continuous treatment group had a 9.9-letter gain in vision and the delayed treatment group had an 8.8-letter gain in vision; both gains were statistically significant from baseline. Each group also had significant reduction in central retinal thickness.
A potential advantage of conbercept is its durable response, say US retinal specialists who have studied the trial results. Most of the patients in the PRN cohorts required only two to three follow-on injections in the first year after receiving three loading doses of the drug.
More Initiatives Tackle Blinding Retinal Diseases
Approaches include devices and gene replacement.
■ While much attention is rightly being focused on advances in the treatment of such prevalent retinal diseases as wet AMD, DME, and RVO, more researchers are joining the battle against rarer, more serious, retinal diseases that lead to blindness. But while researchers are attacking wet AMD, DME, and RVO with drugs and newer drug combinations, approaches to the rarer conditions primarily involve highly sophisticated camera-like devices and gene-replacement therapy.
Following are descriptions of several of the major treatment initiatives for blinding retinal disease.
The Implantable Miniature Telescope (IMT, VisionCare Ophthalmic Technologies, Saratoga, CA) was approved by the FDA in 2010 for the treatment of end-stage AMD in patients age 75 and over. The approval was expanded in October to include patients 65 and over. The IMT is a tiny, camera-like device that is implanted in one eye to improve central vision.
Under VisonCare’s CentraSight program, patients are under the care of a multidisciplinary team that includes an anterior segment surgeon, retina specialists, and low-vision rehabilitation experts. Candidates are strictly evaluated for suitability before being accepted to receive the IMT.
The Argus II Retinal Prosthesis System (Second Sight Medical Products, Sylmar, CA) was approved by the FDA in 2013 after demonstrating that it can provide a level of functional vision to patients afflicted with retinitis pigmentosa. It also received the European CE mark in 2011. The implantable Argus II system encompasses a miniature video camera worn in the patient’s glasses, a patient-worn computer, an antenna, and an electrode array that emits small pulses of electricity, stimulating the patient’s remaining retina cells and transmitting information to the optic nerve and the brain.
Second Sight recently announced plans to raise $32 million in new funding by selling shares of the company to the public. The money will be used for additional research and expansion into new markets. One of the new initiatives will be a study that aims to determine whether blind patients with total central vision loss due to dry AMD can benefit from an artificial retina. Previously, the Argus II and other currently available retinal implants have been indicated only for use in patients with retinitis pigmentosa.
Internationally, both the German company Retinal Implant AG (Reutlingen) and the Australian consortium Bionic Vision (Melbourne) are moving ahead with human trials of sophisticated, miniaturized electronic devices designed to enable patients with retinitis pigmentosa to perceive light, discern shapes, and maneuver around obstacles. Both companies report some success in these areas. Retinal Implant recently reported on a 29-patient trial, and Bionic Vision provided results of a three-patient trial in October.
In the area of gene replacement, both Avalanche Biotechnologies (Menlo Park, CA) and Applied Genetic Technologies (Alachua, FL) are advancing the use of their adeno-associated virus (AAV) delivery systems to implant healthy genes to replace defective ones. While Avalanche has initiated a phase 2 clinical trial for the treatment of wet AMD, it is also focusing on rarer, more serious diseases, such as juvenile X-linked retinoschisis (XLRS). Avalanche recently entered into a major partnership with Regeneron (Tarrytown, NY) for the development of gene replacement therapies for retinal disease.
Applied Genetic Technologies Corporation has its own AAV-based platform and is targeting three blinding orphan retinal diseases, with human trials scheduled to begin in 2015.
Both Avalanche and Applied Genetic Technologies have recently completed successful public stock offerings, with Avalanche raising more than $100 million and AGTC adding more than $80 million in new funding. The success of these offerings indicates a high level of optimism for the potential success of gene replacement as a possible cure for blinding retinal diseases. RP
IN BRIEF
Corrections & Clarifications
■ In the September 2014 issue of Retinal Physician, the OCT image on the cover and on page 4 of the issue was misidentified as being provided by Justis Ehlers, MD. The image was provided by Gabor Scharioth, MD, PhD, and also appears as part of Figure 4 in Dr. Scharioth’s article in the same issue. We apologize for the error.
![]({"src":"/media/1kgltpk2/112014.jpg","focalPoint":null,"crops":[{"alias":"thumbnail","width":1110,"height":700,"coordinates":null}]})