Neurotech Changes Strategic Focus
Drops AMD program after trial fails.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Neurotech (Cumberland, RI), has terminated its research effort in wet and dry AMD after a 150-patient, phase 2 trial, using the company’s NT-503 encapsulated cell therapy (ECT) to treat wet AMD, required early rescue of a significant percentage of patients. The company will now focus on its NT-501 ECT research program in macular telangiectasia (MacTel) and glaucoma.
The failed wet AMD trial had a preponderance of difficult-to-treat patients and the sustained production of the company’s proprietary anti-VEGF agent from the ECT platform was inadequate for many of these patients, explained Charles Johnson, MD, Neurotech’s chief medical officer. “It was a dosing issue,” he said. “In this group of elderly patients, we were not able to get enough drug into the eye. Their age may have been a factor in that.”
The company already has a 66-patient, phase 2 trial under way in MacTel, using the sustained-release ECT platform to deliver ciliary neurotrophic factor (CNTF) as a neuroprotective designed to protect and stimulate photoreceptor cells, Muller cells, and retinal ganglion cells. Two-year data is expected in the second quarter of 2017. In addition, Neurotech said an investigator-sponsored study in glaucoma has shown promising results, suggesting that CNTF may promote the survival of retinal ganglion cells. The company is currently supporting a signal-seeking trial for the glaucoma indication.
The termination of the NT-503 program in wet and dry AMD came as something of a surprise to the retina community. Knowledge leaders had often cited Neurotech’s AMD research as among the most promising in terms of delivering an effective and durable next-generation therapy via a sustained-release implant.
“While we are disappointed that NT-503 did not perform as expected in this trial, the outcome does not change our commitment to the ECT platform,” said Dr. Johnson. “We believe that ECT could potentially fill an unmet need of delivering long-term treatment in several chronic ocular diseases.”
■ Regeneron’s Eylea/anti-PDGF combo disappoints. Regeneron (Tarrytown, NY) said its Eylea/anti-PDGF combination for the treatment of wet AMD performed no better than Eylea (aflibercept) alone at 12 weeks in the 52-week phase 2, 505-patient CAPELLA study. The drugs, which are coformulated in a single injection, have been designed to be complementary. The role of the proprietary anti-PDGF is to break down a protective barrier of pericytes surrounding the VEGF, allowing the anti-VEGF Eylea to be more effective.
Given the disappointing early results, Regeneron has re-randomized the study, adding two new higher-dose groups to the initial three.
The Regeneron setback came after a 12-patient, eight-week phase 1 trial for this combination was deemed successful enough to move on to phase 2. Regeneron also has an Eylea/anti-Ang2 antibody combination in clinical trials, for which the data is more supportive than the Eylea/anti-PDGF study.
■ Allergan drug durable in DME study. Results from Allergan’s 151-patient, phase 2 PALM study, presented at the recent AAO meeting by Tarek Hassan, MD, of Royal Oak, MI, showed that abicipar pegol, injected every 8 or 12 weeks, offered comparable functional and anatomical effects as Lucentis (ranibizumab) injected monthly. Patients receiving 2 mg abicipar pegol required fewer injections than patients receiving ranibizumab over a 28-week period, according to a news release from Molecular Partners, a Swiss company that is partnering with Allergan in the development of abicipar pegol.
Allergan is currently enrolling patients for a planned phase 3 trial of an updated version of abicipar pegol, with topline data expected in 2018.
Abicipar pegol belongs to a new class of genetically engineered antibody mimetic proteins called DARPins and exhibiting highly specific and high-affinity target protein binding. Molecular Partners is pioneering this new class of drugs.
J&J Begins Major Cell Therapy Trial
New surgical techniques used to combat GA..
■ Though Johnson & Johnson has long had a presence in eye care through its Acuvue contact lens business, most people view the company’s recent agreement to acquire Abbott Medical Optics (AMO) from Abbott Labs as the company’s first move into the realm of ophthalmology. However, they would be wrong. For the last several years, the Janssen drug development division of J&J has been pursuing an intriguing initiative using cell therapy to attempt to reverse the vision loss associated with geographic atrophy (GA).
Now, after a promising but preliminary and uncontrolled small phase 1/2 clinical trial, Janssen has moved its proprietary cell therapy CNTO 2476 into the major 255-patient phase 2b PRELUDE study. Because there was a 15% incidence of retinal detachment in the earlier trial in which the human-derived umbilical cells were inserted by microcatheter, a new subretinal delivery kit and some changes in the surgical procedure have been implemented for the PRELUDE trial, says Allen Ho, MD, of Wills Eye Hospital, the lead investigator for both studies.
In the earlier 35-patient trial, the mean BCVA gain at one year was more than four letters, while 25% of the patients gained three lines of vision or more. The average vision loss at one year for untreated fellow eyes was two letters.
Asked whether he expected these results to be replicated in the larger trial, Dr. Ho said: “Let’s hope so. We shall see.”
Patients in the PRELUDE study will get a single injection of either, 60,000 cells, 300,000 cells, or sham. Cell therapy can have either a regenerative or trophic approach, says Dr. Ho. In the regenerative approach, the transplanted cells are meant to take the form of the dead or damaged native photoreceptor cells. With the trophic approach, the new cells are intended to support, repair, and rescue the native photoreceptor cells but remain differentiated from the native cells. The PRELUDE study uses a trophic approach.
Janssen selected human-derived umbilical cells for these studies because they were judged as having the best chance of being effective of the four cell types tested.
■ Brimonidine seen as promising for GA. In a presentation at AAO Retina Subspecialty Day, William R. Freeman, MD, of San Diego, termed Allergan’s 113-patient, phase 2 clinical trial of six months delivery of sustained-release brimonidine as promising as a treatment for geographic atrophy (GA). In the study, the lower dose and the higher dose resulted in, respectively, 18.8% and 27.5% reductions in the rate of lesion progression at 12 months. Brimonidine, which has shown neuroprotective qualities, is used topically as Allergan’s glaucoma drug Alphagan.
Allergan is continuing to study brimonidine for GA in the larger BEACON study, which is fully enrolled. There is currently no FDA-approved therapy for the treatment of GA.
■ Lucentis gets priority review for myopic CNV indication. Genentech said the FDA has accepted a supplemental Biologics License Application (sBLA) and granted Priority Review for Lucentis (ranibizumab) for the treatment of myopic choroidal neovascularization (mCNV), a complication of severe nearsightedness that can lead to blindness. The sBLA is based on results from the phase 3 RADIANCE study that demonstrated treatment with Lucentis provided superior visual acuity gains in people with mCNV compared to verteporfin photodynamic therapy, the only treatment currently approved by the FDA for mCNV.
“With the current FDA-approved therapy, people with myopic choroidal neovascularization achieve only temporary stabilization of vision, while mCNV patients treated with Lucentis in the RADIANCE study experienced significant improvement of their vision,” said Sandra Horning, MD, Genentech chief medical officer and head of Global Product Development.
In mCNV, new, abnormal blood vessels grow directly into the retina. These vessels may break and leak blood or fluid into the retina, possibly causing irreversible central vision loss. Myopic CNV is believed to affect approximately 41,000 people in the United States.
In related news, the FDA has approved a ready-to-use, pre-filled syringe to deliver 0.5 mg of Lucentis for patients being treated for wet AMD and macular edema associated with RVO.
Allegro Drug Shows Durability in DME
Equivalence to anti-VEGF with half the injections.
■ Allegro Ophthalmics, LLC (San Juan Capistrano, CA), said its unique integrin peptide therapy Luminate for retinal disease demonstrated a more durable response than existing anti-VEGF drugs in a 136-patient phase 2b clinical trial for DME and expects to enter a phase 3 trial within a year.
Initially developed in collaboration with scientists at CalTech, Allegro says what makes Luminate unique is that it attacks the “machinery” that creates neovascularization directly, as well as the signaling of VEGF itself. By disrupting the process that creates the unwanted blood vessels, it becomes difficult for this process to regenerate and restart.
DEL MAR STUDY HIGHLIGHTS
The DEL MAR study — designed to highlight Luminate’s durability and monotherapy treatment potential — met its primary and secondary endpoints, demonstrating encouraging visual acuity gains and reduction in central macular thickness (CMT) that were deemed equivalent to bevacizumab (Avastin) monotherapy. The company said the trial included a range of disease severity, including difficult-to-treat patients.
The gains were achieved with only half the number of Luminate injections (compared to bevacizumab) and were recorded at 12 weeks following the final Luminate injection, the company said, showing promise of a major potential reduction in treatment burden. However, other retina drugs showing a durable response are already into phase 3 trials, including Ophthotech’s Fovista/anti-VEGF combination and Alcon’s brolucizumab, both for wet AMD. In addition, Allergan’s abicipar pegol (DARPin) has demonstrated a durable response of up to 12 weeks in the phase 2 PALM trial for DME.
The primary endpoint of the DEL MAR study was non-inferiority to bevacizumab (defined as ≤3-letter difference) in mean change in BCVA at 20 weeks. The Luminate results were achieved after three injections and 12 weeks off of treatment, compared to 6 injections given every 4 weeks with bevacizumab. The data showed the mean gain in BCVA was 5.2 letters for patients in the 1.0 mg Luminate arm at 12 weeks off after initial Luminate loading, compared to 7.0 letters for patients in the 1.25 mg bevacizumab arm dosed every 4 weeks. The secondary endpoint was non-inferiority to bevacizumab (defined as ≤30 µm difference) in mean change in CMT as measured by OCT. At week 20, patients in the 1.0 mg Luminate arm showed a mean reduction of 77 µm 12 weeks off Luminate loading versus 104 µm in the 1.25 mg bevacizumab arm dosed every 4 weeks.
The controlled, double-masked, multi-center, dose-ranging study, which included three Luminate arms (1.0 mg, 2.0 mg, and 3.0 mg) treated with three monthly Luminate loading injections followed by 12 weeks off treatment, and a 1.25 mg bevacizumab arm of six monthly injections, also found that Luminate was well-tolerated with no drug toxicity or intraocular inflammation noted.
“These positive results continue to affirm the safety and efficacy of Luminate, and confirm its 12-week monotherapy durability,” said Vicken Karageozian, MD, president and chief medical officer, Allegro Ophthalmics.
“The DEL MAR phase 2 results appear to be very promising,” said Peter K. Kaiser, MD, professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine, and member of Allegro’s Scientific Advisory Board. “With half the number of injections and a unique mechanism of action, Luminate has demonstrated non-inferiority to anti-VEGF injections and appears to be extremely well-tolerated. Luminate may potentially provide physicians and DME patients with a completely new option that improves visual and anatomic outcomes while reducing the burden of intravitreal injections.”
Luminate has also shown promise in a phase 2 study for the treatment of vitreomacular traction (VMT) and vitreomacular adhesion (VMA), which met its primary endpoint with 50% of eyes achieving VMT/VMA release by 90 days. RP
■ Genentech GCA drug gets breakthrough status. Genentech (South San Francisco, CA) announced the FDA granted Breakthrough Therapy Designation status to Actemra (tocilizumab) for the treatment of giant cell arteritis (GCA), a chronic, potentially life-threatening, autoimmune condition that can lead to blindness. Actemra is a non-steroidal biologic, made from a humanized monoclonal antibody and already approved for rheumatoid arthritis and juvenile idiopathic arthritis. There have been no therapies approved for GCA in more than 50 years. Due to the variety of symptoms, complexity of the disease and its complications, people with GCA are often seen by several physicians including rheumatologists, neurologists and ophthalmologists.
■ FDA clears new Nidek microperimeter NIDEK (Fremont, CA) said the FDA has issued 510 K Clearance for the MP-3 Microperimeter, which is now available in the United States. The MP-3 measures local retinal sensitivity for functional assessment of the retina. The results can be displayed over a color fundus image, correlating retinal anatomy to retinal function.
For enhanced clinical assessment, the MP-3 now includes a wider range of stimulus intensity, from 0 to 34 dB, compared to the MP-1. The MP-3 measures perimetric threshold values, even for normal eyes. A maximum stimulus luminance of 10,000 asb allows evaluation of low-sensitivity.
Retinal morphology can be evaluated with the 12-megapixel fundus camera included in the MP-3 unit. The camera acquires high-resolution images of retinal pathology and allows easy image acquisition.
■ Jim Taylor to direct key Topcon initiatives Topcon Medical Systems and its subsidiary company, ifa systems AG, said industry veteran Jim Taylor will drive planning and implementation of key eyecare strategies, including big data management in healthcare, eg, the recently announced IBM “Watson Health” initiative.
Mr. Taylor brings more than 30 years of management, technical experience, and leadership in the medical device industry. He previously served as president and CEO of Oraya Therapeutics and president and CEO at sector-leading companies including Carl Zeiss Meditec, Coherent Medical, and Ohmeda Medical Systems. At Coherent and subsequently at Carl Zeiss, he led the introduction of several landmark technologies in eyecare, including OCT imaging systems for AMD treatment and diagnosis, as well as an array of other technologies for glaucoma, refractive, and cataract applications.