Gene Therapy: Solving the Reimbursement Riddle
Can million-dollar cures be cost effective?
■ The recent FDA approval of the Novartis gene-replacement therapy onasemnogene abeparvovec-xioi (Zolgensma) for nearly always fatal spinal muscular atrophy in babies brings into bold relief the key issue of how much a drug company should be reimbursed for a one-time, life-changing procedure that can replace years of costly and significantly less effective chronic disease treatments.
Novartis said it was putting a $2.1 million price tag on Zolgensma (spread over 5 years), making it the most expensive drug in history. Novartis said it based its pricing on 50% of the cost of 10-year chronic management of the disease with a comparator therapy, Spinraza (Biogen). Moreover, the Institute for Clinical and Economic Review, which assesses the cost-effectiveness of new drugs, quickly endorsed the $2.1 million price tag.
The Spark Therapeutics voretigene neparvovec-rzyl gene-replacement therapy for RPE65-mediated inherited retinal disease (Luxturna) was approved by the FDA in 2017, and the company has a good deal of recent experience in dealing with pricing issues. As opposed to Zolgensma, which has a comparator treatment, Luxturna was a totally groundbreaking therapy. Luxturna pricing was complicated by such issues as measuring quality-of-life improvements, indirect costs to society associated with progressive vision loss, and duration of effectiveness.
Spark demonstrated a willingness to be flexible in pricing Luxturna when it made its first insurer agreement with Harvard Pilgrim Health Care at $425,000 per eye. This agreement provides for a reduced net cost to Harvard Pilgrim for Luxturna by tying the level of payment to measured improvements in patients at a 30- to 90-day interval and then again at a 30-month mark. If the therapy fails to perform as agreed upon, Harvard Pilgrim would receive a rebate from Spark. The short- and long-term measures will be based on full-field light sensitivity threshold testing scores, with a baseline established for each eligible patient before administration of the drug.
With gene therapy “cures” now in the pipeline for diseases ranging from hemophilia to sickle-cell anemia to inherited retinal disease, the issue of pricing will always be a thorny one. The experience of Spark with Luxturna and Novartis with Zolgensma provide an indication that these issues can be resolved when drug developers and payers are open to innovative forms of reimbursement.
Anatomic Changes After 50 Anti-VEGF Injections
Analysis of 100 eyes of long-term patients.
■ Researchers from Moorfields Eye Hospital, London, England, using their in-house EMR system, conducted a retrospective review of their long-term wet AMD patients who had received 50 or more anti-VEGF injections of either ranibizumab or aflibercept from 2008 to 2017. Both the baseline and the 50th injection OCT were comprehensively analyzed.
One hundred eyes received 50 or more anti-VEGF injections. Of these, 33% had central intraretinal fluid and 75% had central subretinal fluid at baseline. At the 50th injection, central intraretinal fluid decreased to 27% and central subretinal fluid decreased to 42%. Drusen was present in 88% of eyes at both time points, while pigment epithelial detachment, found in 88% of eyes at baseline and 87% at 50th injection, remained consistent in the large majority of eyes. Presence of vitreomacular adhesion causing central deformation was similar at presentation and at 50th injections, while epiretinal membrane increased from 3% to 8% of eyes. Mean central retinal thickness decreased from 372.2±220.68 μm (standard deviation) at baseline to 283.96±154.6 μm at 50th injections.
The researchers, who presented their findings at the recent ARVO meeting, stated their belief that characterizing long-term morphological sequelae is crucial to understanding treatment efficacy and response. They found that repeated anti-VEGF injections for wet AMD induces significant reduction in subretinal fluid and overall central retinal thickness. Intraretinal fluid and pigment epithelial detachment were comparable at baseline and at the 50th injection.
Switching from Eylea to Lucentis in RVO
No improvement seen in 82-eye study.
■ Noting that many studies have evaluated therapeutic switches in the treatment of RVO, researchers at Wills Eye Hospital set out to conduct the first aflibercept-to-ranibizumab anti-VEGF switch. Their study, presented at the recent ARVO meeting, assessed the anatomic and functional outcomes of this exchange in RVO-related macular edema.
Only eyes that received at least 3 consecutive aflibercept injections for RVO and then switched to ranibizumab therapy were included. At the 3 visits before and after the switch and the switch date itself, BCVA, central foveal thickness (CFT) on spectral-domain OCT, and presence of intraretinal and subretinal fluid were assessed.
A total of 82 eyes from 81 patients were included. Eyes had received a mean of 14.9 intravitreal injections of aflibercept before the switch to ranibizumab. After the therapeutic conversion, visual acuity worsened significantly from the switch visit and CFT increased significantly for 2 visits after the switch visit.
The researchers observed short-term functional and anatomical worsening after the switch, mitigated by shortening the ranibizumab treatment interval. With additional ranibizumab treatment administered at a shorter interval between injections, CFT and VA approached levels similar to those at the switch visit. The researchers concluded that longer-term, prospective, controlled studies will be necessary to better characterize efficacy and durability differences between aflibercept and ranibizumab in RVO-related macular edema.
Second Sight to Focus Solely on Orion Development
Device could be effective with almost all forms of blindness.
■ Second Sight Medical said it will place virtually all of its resources behind the development of the Orion Visual Cortical Prosthesis System, which attaches directly to the brain and can provide a level of functional vision to individuals afflicted from almost any cause of blindness. The decision means that the FDA-approved Argus II retinal prosthesis, which is limited to those with end-stage retinitis pigmentosa, has been moved to the back burner in terms of company priorities, although the company will continue to support its users.
The company estimates that approximately 500,000 people in the United States could be candidates for the Orion, while only several thousand are suitable for the Argus II.
“Our decision to accelerate development of Orion is based on both the positive interim results of our early feasibility study and on the significant market opportunity we see for this potentially transformative product. We believe it is the right time to reallocate resources toward this more attractive platform, which holds the potential to treat virtually all forms of blindness and extend our leadership position in artificial vision,” said Will McGuire, president and CEO of Second Sight.
“We are also encouraged by our ongoing discussions with the FDA and CMS’s proposed new rule regarding reimbursement for Breakthrough Devices, such as Orion. We believe that Orion provides an opportunity to address a much larger patient population and a significant unmet need in the United States and globally,” continued McGuire.
As part of the Orion development effort, Second Sight will add 25 new hires. It will also seek to increase the electrode array of the Orion to provide a more defined visual display and study such enhancements as facial recognition, thermal sensors, and eye tracking. In early testing of the Orion, users have been able to sort laundry, identify parked cars in a driveway, and even walk around the block unaided. Second Sight is now well funded for the near term, having recently raised more than $34 million from a stock rights offering.
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Allegro Has Promising Trial for Dry AMD
■ Allegro Ophthalmics said its phase 2 study of risuteganib (Luminate) for the treatment of dry AMD met its primary endpoint, with 48% of patients in the risuteganib arm gaining 8 or more letters of vision at week 28 compared to baseline. Only 7% of patients in the sham group met the same standard.
At baseline, 40 patients were randomized to receive either intravitreal 1.0 mg risuteganib or sham injection. At week 16, patients in the risuteganib arm received a second dose of 1.0 mg risuteganib, and patients in the sham arm crossed over and received a single dose of 1.0 mg risuteganib. The primary endpoint was the percentage of the population with ≥8 letters BCVA gain from baseline to week 28 in the 1.0 mg risuteganib arm vs baseline to week 12 in the sham arm. The primary endpoint was prespecified as ≥8 letters to account for the variability in visual acuity measurements among patients with intermediate dry AMD.
The primary endpoint was met with 48% of patients in the risuteganib arm at week 28 and 7% of patients in the sham group at week 12 gaining ≥8 letters from baseline. Risuteganib was found to be safe, with no reported drug-related serious adverse events. Secondary outcomes, including microperimetry, color vision, and low-luminance visual acuity, are being evaluated.
MeiraGTx Addresses RPE65 Deficiency
■ MeiraGTx Holdings announced positive data from a phase 1/2 dose escalation trial of AAV-RPE65, the company’s investigational gene therapy for the treatment of RPE65 deficiency, a condition that causes blindness. AAV-RPE65 is a second-generation gene-therapy candidate optimized for transduction efficiency, potency, and stability. The trial achieved the primary endpoint of safety and tolerability. Additionally, AAV-RPE65 demonstrated statistically significant improvement across several secondary endpoints designed to assess clinical activity.
The open-label, multicenter, dose-finding trial evaluated AAV-RPE65 in patients with retinal dystrophy associated with disease-causing variants in the RPE65 gene and enrolled 15 patients, including 9 young adults across 3 dose escalation cohorts, and 6 children in a pediatric expansion cohort. Each patient was treated with subretinal delivery of AAV-RPE65 in the eye that was more affected at baseline. The patient’s other eye served as an untreated control. Significant improvement in vision was demonstrated at 6 months, as measured by assessments of vision-guided mobility, retinal sensitivity, visual acuity, and contrast sensitivity. Larger improvements from baseline in functional vision were observed between treated and control eyes at lower light levels. These outcomes address the core functional manifestation of RPE65 deficiency, which typically causes vision impairment beginning in early childhood that is most pronounced in low-light conditions.
Oxurion Begins Phase 2 Study of Anti-PIGF Drug
■ Oxurion has begun a fully enrolled, 70-patient phase 2 clinical trial for DME with its 8-mg THR-317 recombinant humanized monoclonal antibody directed against the receptor-binding site of human placental growth factor (PlGF). The trial combines THR-317 with the anti-VEGF ranibizumab (Lucentis; Genentech). The study is evaluating THR-317 in combination with conventional anti-VEGF therapy vs anti-VEGF therapy and sham for the treatment of DME. Topline data are expected in Q3 2019. A phase 1/2 trial of THR-317 as monotherapy showed that the drug was well tolerated and produced significant vision gains in 30% of treatment-naïve patients.
Iluvien Effective in Preventing Uveitis Relapse
■ Alimera Sciences reported positive 3-year follow-up data from the phase 3 clinical trial for Iluvien 190 micrograms intravitreal implant for the prevention of relapse in recurrent noninfectious posterior uveitis. The data will support the company’s planned launch of Iluvien for that indication in Europe during the second half of 2019. In the 129-patient prospective, randomized, masked clinical trial, patients received a single Iluvien implant or an active control sham injection, and recurrence was assessed based on the observation of specified symptoms or by active treatment by clinicians.
The median time to first recurrence of noninfectious posterior uveitis was significantly longer in the Iluvien arm of the trial (94 weeks), compared to the control sham arm (10 weeks). The number of recurrences of uveitis was significantly lower in the Iluvien arm (1.7) vs the sham arm (5.3) over the 36 months. There was a significantly greater improvement from baseline in BVCA in the Iluvien-treated arm (+9.1 letters) compared to sham (+2.5 letters). IOP was well-controlled in both arms, mainly by IOP-lowering medication.
ReNeuron Doses Another Cohort of RP Patients
■ ReNeuron Group announced an update to its ongoing phase 1/2 clinical trial in the United States of its human retinal progenitor cell therapy for retinitis pigmentosa. The company reported that dosing of the second cohort of 3 phase 2 subjects has now begun, following a positive review of the clinical data from the first phase 2 patient cohort in the study by the Data Safety Monitoring Board of the National Institutes of Health.
This dose cohort comprises patients who have a greater baseline level of visual acuity than those treated in the study thus far, providing a framework to better evaluate the safety of the treatment and to gain further clarity on the strong efficacy signal that was seen in the first phase 2 cohort.
In February, the company reported that all 3 of the first cohort of subjects in the phase 2 part of the study had reported a rapid and significant improvement in vision, on average equivalent to reading an additional 3 lines of 5 letters on the EDTRS eye chart.
Yutiq Implant Reduces Uveitis Recurrence at 3 Years
■ At the recent ARVO meeting, EyePoint Pharmaceuticals presented positive 36-month efficacy and safety data supporting the company’s Yutiq (fluocinolone acetonide intravitreal implant) 0.18 mg 3-year microinsert for the treatment of chronic posterior noninfectious uveitis.
“The 36-month follow-up data of the phase 3 clinical trial showed a uveitis recurrence rate of 56.3% for Yutiq, which was significantly lower than that of sham-treated eyes which was 92.9%,” said Glenn J. Jaffe, MD, professor of ophthalmology at the Duke University School of Medicine, in a news release. “It is critically important to decrease uveitic recurrences to prevent blindness associated with secondary effects of inflammation,” said Dr. Jaffe. “Safety results at 36 months were similar to the 24-month update with no unanticipated side effects. Of particular note, the procedure rate to treat glaucoma was no higher in the Yutiq group than in the sham group.”
Immunocore Launches Uveal Melanoma Website
■ Thinkuvealmelanoma.com , a new website created by Immunocore, offers physicians useful resources and information on the signs and symptoms, risk factors, and management of uveal melanoma. The site features an interactive tool that brings to life the common visual disturbances patients may experience and provides clinical perspectives through a video series featuring Bertil Damato, MD, PhD, senior clinical research fellow at the University of Oxford, United Kingdom. Important links to advocacy information that can be shared with patients are also provided.
“Approximately 1 in 5 patients with symptoms of uveal melanoma reports that their tumor was initially missed, and those patients are unfortunately more likely to have their eye removed,” said Dr. Damato. “Resources such as Think Uveal Melanoma are meant to aid physicians in detecting and managing the disease.”
Thinkuvealmelanoma.com will be updated throughout the year with educational tools and insights from ocular and oncology experts.
Zeiss Launches Dual-Speed Swept-Source OCT/OCTA
■ Zeiss Medical Technology has launched the first dual-speed swept-source OCT/OCTA that will now scan at 200 kHz, in addition to 100 kHz, providing doctors a deeper and more detailed view into the retina, enabling visualization options for various diseases. The PLEX Elite 2.0 enables faster, deeper, and higher resolution imaging of the eye. Varying speeds can be applied to different disease states in the eye and expand possibilities of research.
With the PLEX Elite 2.0’s deeper and more detailed view into the retina, doctors can fully image conditions such as posterior staphylomas, retinal detachments, high myopia, and choroidal tumors. This evolution provides faster scans to visualize from the retinal vitreous interface down to the choroid to better assess highly curved myopic eyes.
Omidria Reduces Incidence of Post-Cataract CME
■ Omeros Corporation said results of a real-world clinical study showing that its FDA-approved phenylephrine and ketorolac 1%/0.3% intraocular solution (Omidria) greatly decreases the incidence of cystoid macular edema (CME) following cataract surgery. The investigator-sponsored study was conducted by Keith A. Walter, MD, professor of ophthalmology at Wake Forest University School of Medicine. He conducted a retrospective analysis of 504 eyes (357 patients) on whom he had performed cataract surgery using Omidria plus only a topical nonsteroidal anti-inflammatory drug (NSAID), assessing the incidence of CME. The control group consisted of a collection of single and meta-analytic studies published in the peer-reviewed literature in which steroids, with and without topical NSAIDs, were used in cataract surgery in the absence of Omidria. Of the 504 eyes treated with Omidria, only 2 developed postoperative CME, an incidence of 0.39%, which is 3- to 12-fold lower than the CME rates (a range of 1.2% to 5%) in the published peer-reviewed studies using steroids both with and without NSAIDs in the absence of Omidria.
Aldeyra to Study Proliferative Vitreoretinopathy
■ Aldeyra Therapeutics said it now expects to begin a phase 3 adaptive clinical trial of the recently acquired drug ADX-2191 (intravitreal methotrexate) in proliferative vitreoretinopathy (PVR) in the second half of 2019. In January, Aledeyra acquired Helio Vision, a privately held biotechnology company. The acquisition added to Aldeyra’s pipeline the phase 3-ready product candidate ADX-2191 for the treatment of PVR, a sight-threatening inflammatory condition that causes retinal scarring and has no approved treatment. ADX-2191 has received orphan drug designation from the FDA.
Proliferative vitreoretinopathy affects up to 10% of patients undergoing surgery for retinal detachment and 50% or more of patients undergoing retinal surgery following open-globe injury. The drug was discovered by Dean Eliott, MD, director of the retina service at Mass. Eye and Ear. ADX-2191 was codeveloped by Dr. Eliott and retinal surgeon Tomasz Stryjewski, MD, also of Mass. Eye and Ear.
Following the completion of the initial part of the trial, expected in 2020, and assuming the results support advancement to further testing, Aldeyra expects to report the endpoints, dosing regimen, and sample size for the remainder of the trial. Aldeyra expects to report full clinical results following the completion of the trial.
Thermal Camera Improves Argus II Performance
■ In 2 separate small studies presented at the recent ARVO meeting, one conducted by researchers from Johns Hopkins University and one by researchers at the University of Minnesota, wearers of the Argus II retinal prosthesis performed significantly better at identifying heat-emitting objects (and people) when aided by a thermal-sensor camera (TSC) than they did with the standard Argus II camera.
In the Minnesota study, 5 subjects more accurately identified the number of heated household objects displayed, the location of the objects on the table, and the specific type of object presented with the TSC relative to the Argus II camera. In navigation tasks, subjects could more accurately localize people in a small room using the TSC in both the light condition and the dark condition. While walking down a hallway, subjects had less collisions with people standing and correctly identified more people standing with the TSC.
The Johns Hopkins study, with 4 Argus II wearers, encompassed somewhat similar tasks, with the outperformance of the thermal camera ranging from 19% to 41%.
Ophthotech Is Now Iveric
■ Ophthotech Corporation announced that, as part of its transition strategy to focus on discovering and developing novel gene-therapy solutions to treat orphan inherited retinal diseases with unmet medical needs, the company is changing its name to Iveric bio, Inc.
“We believe that gene therapy is the ideal solution to treat patients with orphan inherited retinal diseases for which there are no treatment options available,” said Kourous A. Rezaei, MD, chief medical officer of Iveric bio. “Our clinical therapeutic programs continue to remain on track, with clinical data expected by the end of 2019 and 2020 for these programs. If data are positive for these programs, we may seek partnership opportunities for future clinical development.”
Clearside Appoints Interim CEO
■ Clearside Biomedical has appointed veteran biopharmaceutical executive George Lasezkay, PharmD, JD, to the position of interim CEO to replace company founder and longtime CEO Daniel H. White, who resigned to pursue other opportunities. Dr. Lasezkay is a member of the Clearside board of directors. The board is initiating a search to identify a permanent CEO.
“We are excited about our suprachoroidal drug delivery platform and potential approval of our first agent (Xipere) for the treatment of macular edema associated with uveitis, which would be a significant milestone for Clearside,” said Dr. Lasezkay. “We also believe the platform has broad applicability in other eye diseases and continue to explore utilizing suprachoroidal administration with other small molecules and gene therapy.” RP