Genentech Acquires Developer of Sustained-Release Implants
ForSight Vision4 supplies reservoir for Lucentis delivery.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Genentech (Roche Holding) clearly signaled that it believes in the future of sustained-release delivery of biologic drugs that treat retinal disease when it acquired ForSight Vision4 late last year. ForSight has been collaborating with Roche’s Genentech division since 2010 when it licensed the exclusive rights to its refillable rigid port delivery system (RPDS) to Genentech as an initial step toward offering Lucentis (ranibizumab) in a sustained-release format.
Currently, the ophthalmic drugs approved by the FDA for sustained-release delivery have been almost exclusively limited to steroids. These approved drugs include Ozurdex (Allergan) for uveitis and DME, Iluvien (Alimera Sciences) for DME, and Retisert (Bausch + Lomb) for uveitis.
The RPDS is a durable intravitreal implant that is placed through a scleral incision in a one-time surgical procedure. The timing for refills is currently being studied but it is estimated by the company at 4 to 6 months. Currently in a phase 2 clinical trial, it could potentially replace intravitreal injections of Lucentis now normally given every 4 to 6 weeks.
TECHNOLOGY FROM AN OPHTHALMIC INCUBATOR
Terms of the ForSight Vision4 acquisition included an upfront payment and additional payments for meeting certain clinical and commercial milestones. ForSight Vision4, which is focused on the development of sustained-release delivery for a range of therapeutic agents, is one of a number of new companies that have come out of the ForSight Labs ophthalmic incubator.
In recent years, Genentech has been moving sustained-release technology through early-stage clinical trials. Currently, the company is conducting the 220-patient phase 2 LADDER study that, if successful, would bring doctors and patients one step closer to a less burdensome treatment regimen requiring fewer office visits and injections.
Genentech researchers have long believed that ranibizumab could be successful in a sustained-release format, because the drug has the stability to remain effective for months when placed in an implant.1
In the small phase 1 study, the RPDS implant was well tolerated and showed an improvement in visual acuity comparable to monthly Lucentis injections, establishing proof of concept for the system. Genentech’s RPDS implant also has received fast-track designation from the FDA.
“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, in an announcement about the product.
- Helzner J. Anthony P. (Tony) Adamis, MD: a giant in the fight against retinal disease. Retinal Physician. 2015;12(1):25-26. http://www.retinalphysician.com/issues/2015/jan-feb/innovation-in-retina .
■ Study: Tissue factor involvement in wet AMD. Iconic Therapeutics presented new phase 2a trial data at the recent Angiogenesis 2017 meeting in Miami that pointed to the overexpression of tissue factor as a possible root cause of inflammation and angiogenesis in wet AMD. The company said its fusion protein ICON-1, injected intravitreally, showed “strong signals of biologic activity” in the 88-patient, 6-month EMERGE trial that provide a basis for further study. EMERGE was not powered for statistical significance.
■ Ropivacaine found superior as peribulbar block. Researchers in China found that 1% robivacaine, used alone, is a superior anesthetic for vitrectomy when used as a peribulbar block. The researchers said the superiority is due to its qualities of long action, relative nontoxicity, pain relief, and lower incidence of subconjunctival hemorrhage when compared to bupivacaine, lidocaine, and a bupivacaine/lidocaine combination.
The study, led by Ya-Li Zhou, MD, of the Ninth People’s Hospital in Shanghai, and reported in the British Journal of Ophthalmology, included 140 patients undergoing vitrectomy. Patients were measured for time of onset, efficacy, postoperative pain, and intraoperative and postoperative complications.
Should Every Patient Be Genetically Profiled?
A useful tool toward more personalized evaluation.
■ Studies have found that while macular degeneration patients clinically present similarly, 40% respond differently to the same drugs and dosages, says Pravin Dugel, MD, of Retinal Consultants of Arizona. In the future, personalized medicine may be the answer to containing costs while improving the quality of care.
“What we’re realizing is that we need to look at the genotype of the patient and personalize the diagnostics and therapeutics for that particular person,” he says.
In recent years, increasing attention has been paid to the role of genetics in retinal disease. A genetic profile can be predictive of an individual’s risk for retinal disease. It also has potential for being a useful diagnostic tool, pointing practitioners to specific therapies that may be effective for an individual patient. For the longer term, there is the promise of gene therapy, in which a defective gene is replaced by a healthy one, facilitating a cure.
Genetics is already influencing efforts to combat retinal disease. Commercial companies such as Arctic DX are teaming with ophthalmologists to offer relatively simple genetic tests (a cheek swab taken in the doctor’s office) designed to evaluate the risk profile of individuals who have either been recently diagnosed with AMD or who have a family history of AMD.
Genentech genetically profiled every patient in its phase 2 MAHALO clinical trial using the drug lampalizumab for dry AMD and found that specific genetic subsets of patients got more therapeutic benefit from the drug than other subsets. Genentech believes that this was the first ophthalmic clinical trial in which all patients were genetically profiled.
In 2014, Regeneron embarked on a collaboration with Geisinger Health System to genetically profile at least 100,000 individuals to develop a database for future drug development that encompasses genetic factors. During the initial 5-year collaboration term, Geisinger plans to collect samples from consented patient volunteers, while Regeneron, through its subsidiary, Regeneron Genetics Center LLC, will perform sequencing and genotyping to generate deidentified genomic data. The size and scope of the study are meant to facilitate precision in identifying and validating the associations between genes and human disease.
“Genetics has been at the core of our research efforts at Regeneron since its early days,” said George D. Yancopoulos, MD, PhD, chief scientific officer and president, Regeneron Laboratories, in a press release. “In fact, our first FDA-approved therapy treats a rare genetic disorder, and the target of one of our product candidates in late-stage development that acts to lower LDL cholesterol was identified using human genetics.”
Some in the retina community are advocating that patients considering taking eye health supplements to reduce the risk of macular degeneration should first be genetically profiled to determine if the supplements would be of any benefit. This position has sparked fierce debate in the retina community, with studies on the merits of supplements for specific patient cohorts being both cited and challenged.
While the initiatives and efforts outlined above are still at an early stage, Dr. Dugel’s view that retinal disease is highly individualized and must be treated as such is borne out by the widely varying effectiveness of specific therapies with selected patients. Thus, genetic profiling offers one potential avenue to achieving a more personalized and successful approach to combating retinal disease.
■ Use of turmeric for eye health not supported. Recent social media attention has been directed at reported use of the herbaceous plant turmeric as a supplement to promote eye health, primarily for diabetes-related retinal disease. Turmeric is mainly used for cooking and as a food coloring.
Emily Y. Chew, MD, of the National Institute of Health and the National Eye Institute and an expert in supplements used for eye health, says despite turmeric’s increased popularity as a health supplement, there are no studies that support its use to promote eye health.
“We have never considered turmeric in our supplementation studies. I know of only one basic scientist who thinks flavonoids, which may include curcumin (found in turmeric), might be important,” says Dr. Chew.
Aura Biosciences’ New Approach to Ocular Melanoma
Therapy targets only malignant cells.
Aura Biosciences is preparing to soon begin its first human clinical trial for its AU-O11 combination drug/laser therapy that is designed to selectively bind virus-like therapeutic particles (VLPs) to cancer cells and then eliminate only those malignant cells through laser activation of the particles. The FDA recently cleared Aura to begin a phase 1b, dose-ascending clinical study treating small to medium ocular melanoma at 5 sites in the United States.
In vivo results presented at the ARVO annual meeting demonstrated how synthetic VLPs modeled on the human papillomavirus (HPV) are able to bind uniquely to cancer cells while leaving healthy surrounding tissue unharmed. The authors determined that tumor cells differ from healthy cells in the over-expression and modifications of heparan sulfate proteoglycans on their membrane as well as on the extracellular matrix, which provides a unique binding site for HPV variations and for engineered VLPs.
Currently, ocular (or uveal) melanoma is usually treated with surgery and radiation, though the type of radiation used varies with a number of factors, including the size and location of the tumor. Best outcomes are achieved when the disease is caught at an early stage, though enucleation of the eye is often necessary. Once the disease metastasizes to the liver, it is nearly always fatal. Many studies have shown that the incidence of ocular melanoma is greatest among white males over the age of 60.
Aura said its selective targeting approach should be effective with a number of cancers but has chosen ocular melanoma for its initial human test. The company received $21 million in venture capital funding in 2015. In addition, AU-011 was granted orphan drug status by the FDA last year.
“There are currently no approved drug therapies for the treatment of uveal melanoma, which is a rare but life-threatening disease. We are thrilled to receive this Orphan Drug Designation that, together with the positive preclinical data, is enabling us to move this drug one step closer to the clinic,” says Elisabet de los Pinos, founder and CEO of Aura Biosciences, in a statement.
■ Genentech completes enrollment in pivotal GA trials. Genentech has completed enrollment in 2 large-scale, phase 3 clinical trials, CHROMA and SPECTRI, investigating the efficacy and safety of lampalizumab in reducing the progression of geographic atrophy (GA) lesions secondary to AMD. The move into pivotal trials comes after the successful phase 2 MAHALO study.
Lampalizumab is a monoclonal antibody fragment designed to inhibit complement factor D, a rate-limiting enzyme of the alternative complement pathway. This complement pathway is implicated in the development of age-related macular degeneration, including GA.
The 2 identical, double-masked, sham-controlled studies have enrolled 1,881 patients at nearly 300 study locations in more than 20 countries. The primary endpoint of both studies is the mean change in GA lesion area at 1 year, comparing treatment to sham, with a planned overall treatment duration of 2 years. Secondary endpoints assess visual function changes. Importantly, GA patients often report visual dysfunction that is not always reflected in standard BCVA measurements until late in the course of their disease. To provide a more comprehensive measurement of visual function outcomes, CHROMA and SPECTRI use assessments such as low-luminance visual acuity, microperimtery, reading speed, and patient-reported outcomes in addition to BCVA.
■ ThromboGenics begins enrolling DME trial. ThromboGenics NV has begun enrolling patients in a phase 2 clinical study evaluating safety and efficacy of 2 dose levels of THR-317 for the treatment of DME. THR-317 is a recombinant human monoclonal antibody directed against the receptor-binding site of human placental growth factor, commonly referred to as PIGF. The study will evaluate the safety of 3 intravitreal injections of 4 mg and 8 mg THR-317. It will also assess the effectiveness of THR-317 to improve BCVA and to reduce central retinal thickness. The study will enroll 50 patients over the next year. Initial data from the study are expected early next year.
The company says preclinical results indicate that THR-317 has potential as both a standalone therapy and as a complement to existing anti-VEGF agents.
Fellows’ Forum Introduces “Real World” Retina
Dr. Gary Abrams gives guest lecture.
■ The 17th annual Retina Fellows’ Forum took place on January 27 and 28 in Chicago, Illinois. Seventy North American vitreoretinal fellows from 60 programs participated in an educational and social program that has become an anticipated fixture of the final year of vitreoretinal training.
As in past years, the fellows spent considerable time in the lecture hall with a panel of faculty led by course director Dr. David Chow and co-directors Drs. Carl Awh and Tarek Hassan. Drs. Dean Eliott, Mike Jumper, Peter Kaiser, Tamer Mahmoud, Jon Prenner, and Amy Schefler completed the faculty.
The opening session focused on controversies and current research in AMD. The faculty debated anti-VEGF treatment strategies and drug selection, with the fellows voting for “winners” using an audience response system. Lectures and discussion about the role of genetic testing in the management of AMD and of current and future clinical trials rounded out the AMD session. A surgical video rounds session featured a series of challenging cases and panel discussion that emphasized the many “correct” ways to attack a surgical problem.
Saturday offered a full day of panel-driven discussions and one-on-one faculty debates on retinal detachment, retinal vein occlusion, diabetic retinopathy, trauma, macular surgery, dislocated IOLs, and surgical instrumentation. A highlight of the meeting was the distinguished guest lecture, this year delivered by Dr. Gary Abrams on “Pivotal Moments in Vitreoretinal Surgery,” an inspiring reflection on his life and career. The afternoon concluded with a “Real World” panel discussion devoted to career decisions, practice-building, and balancing work and personal demands.
The prestigious and competitive Retina Fellows’ Forum research award went to Dr. Bozho Todorich of Associated Retina Consultants for his paper, “Structural Analysis and Long-Term Surgical Outcomes of the Sutureless Intrascleral Fixation of Secondary Intraocular Lenses in Human Eyes.” Dr. Todorich will present his paper at the 2017 annual American Society of Retina Specialists meeting as a specially recognized lecture.
■ New studies under way for retinal diseases. Three new clinical trials aimed at combating retinal disease have begun.
A 50-patient phase 2 study (DAWN), sponsored by Wills Eye, employs the commonly used glaucoma drop dorzolamide-timolol as a potential adjunct therapy to reduce swelling in wet AMD. In the phase 2 STAIRWAY trial, Roche/Genentech is employing its RG7716 bispecific ANG2 inhibitor/anti-VEGF in a 75-patient extended-dosing study for wet AMD. RG7716, which has attracted great interest in the retina community, is already being studied in the phase 2 BOULEVARD and AVENUE trials for DME and wet AMD, respectively. And in a 20-patient phase 1 study, the National Eye Institute is using the FDA-approved oral antibiotic minocycline as a potential treatment for branch retinal vein occlusion.
■ New initiative aimed at diabetic eye disease. Nikon, Optos, and Verily (formerly Google Life Sciences), announced a global collaboration aimed at leveraging the companies’ advanced capabilities to improve the quality of ophthalmic diagnostics for earlier detection and treatment of DR and DME.
The 3 companies will create technology and solutions for enhanced screening of DR and DME by diabetes-treating physicians to improve efficient referral of patients to eye care specialists, and provide these specialists with assisted reading programs for easier diagnosis of disease. Ultimately, the aim is to improve the standard of care across the patient journey to help prevent disease progression and blindness.
VisionCare Seeks to Expand IMT Indications
New trial for post-cataract patients.
■ VisionCare, Inc., a developer of advanced visual prosthetic devices for the treatment of end-stage AMD, said the FDA has approved the company’s investigational device exemption for a new US clinical study of the Implantable Miniature Telescope (IMT). The study will for the first time evaluate the safety and effectiveness of the telescope implant in patients who were previously implanted with an IOL. In the study, the IOL will be exchanged for the IMT in a team procedure that always includes a retina specialist.
Called the Telescope Exchange Study (TES), the trial will encompass 75 patients age 65 and older with best-corrected distance visual acuity of 20/160 to 20/800. Principal investigators will be Stephen S. Lane, MD, of Associated Eye Care, Stillwater, Minnesota, and Derek Kunimoto, MD, JD, of Retinal Consultants of Arizona in Phoenix. Patients will be followed for at least 3 years post implantation.
Under current indications, the telescope implant is proven to improve visual acuity and quality of life for patients with end-stage macular degeneration whose sight is permanently obstructed by a blind spot in their central vision (in both eyes), making it difficult or impossible to see faces, read, and perform everyday activities such as watching TV, preparing meals, and self-care. It is the only FDA-approved surgical device for end-stage macular degeneration and is Medicare eligible.
According to current labeling, the telescope implant is contraindicated in patients with previous intraocular or corneal surgery of any kind in the operative eye, including any type of surgery for either refractive or therapeutic purposes.
■ Ohr pauses enrollment in phase 3 AMD study. Ohr Pharmaceutical has announced a pause in enrollment in its pivotal phase 3 study of topical squalamine in combination with Lucentis for wet AMD with 200+ of a planned 650 patients already enrolled.
Citing strategic reasons for the pause, Ohr CEO Jason Slakter, MD, said in a conference call that recent disappointments in wet AMD combination studies (Regeneron and Ophthotech) had created a negative landscape but that squalamine has major differences in activity, method of administration, patient selection, and previous trial results than the drugs in the disappointing studies.
Dr. Slakter said that by continuing the trial with just the 200+ patients already enrolled, efficacy data can be made available by late 2017, a year earlier than previously planned. He emphasized that no safety issues were involved in this decision and that Ohr continues to hold discussions with potential partners.
■ FDA OKs Lucentis for myopic CNV. The FDA has approved Lucentis (ranibizumab 0.5 mg) for the treatment of patients with myopic choroidal neovascularization (mCNV), a complication of severe nearsightedness that can lead to blindness. Lucentis is the first FDA-approved anti-VEGF therapy to treat mCNV in the United States. This is the fifth FDA-approved indication for Lucentis since it was launched in 2006.
This approval is based on the results of the 276-patient, phase 3 RADIANCE study, which demonstrated that treatment with Lucentis provided superior visual acuity gains in people with mCNV compared to verteporfin photodynamic therapy (vPDT). At 3 months, average visual acuity gains for patients treated with Lucentis were more than 12 letters, compared to 1.4 letters for those treated with vPDT.
In related news, the Lucentis pre-filled 0.5-mg syringe, approved by the FDA in October, is now available for order.
■ GenSight RP therapy receives orphan status. GenSight Biologics said the FDA has granted orphan drug status to its product candidate GS030 for the treatment of retinitis pigmentosa. The product employs GenSight’s optogenetics technology platform that involves gene therapy, the restoration of light-sensitive cells, and a wearable device. It is expected to enter a phase 1/2 clinical trial later this year.