Thanks to anti-vascular endothelial growth factor (VEGF) agents, the visual prognosis for patients with neovascular AMD — the leading cause of blindness in adults older than 65 years in the United States1 — has been revolutionized. Even so, current treatments require frequent and long-term administration, placing a considerable burden on patients and their caregivers; further, not all patients fully respond despite aggressive treatment, and initial visual gains appear to regress over time.2-4 Much interest therefore lies in novel treatments, with the goals of greater efficacy and durability.
In this article, we review the emerging therapies for neovascular AMD, with a focus on agents in Phase 2 and 3 clinical trials.
Brolucizumab (Novartis) is a humanized, single-chain antibody fragment with high affinity to all VEGF-A isoforms. Its small molecular weight of 26 kDa (compared with 48 kDa for ranibizumab [Lucentis, Genentech] or 115 kDa for aflibercept [Eylea, Regeneron]) makes it possible to prepare higher molar concentrations and administer up to 6 mg of the drug in a single 0.05-mL intravitreal injection, which theoretically may result in longer duration of effect, faster systemic clearance and improved ocular tissue penetration.5 The HAWK and HARRIER trials were Phase 3 randomized, double-masked multicenter studies of brolucizumab injections every 12 weeks vs. aflibercept every eight weeks for neovascular AMD. In the HAWK trial, patients were randomized to brolucizumab 3 mg or 6 mg, or aflibercept 2 mg. In HARRIER, patients received either brolucizumab 6 mg or aflibercept 2 mg.6 All groups received three monthly loading doses initially. The brolucizumab patients were adjusted to every eight weeks if disease activity persisted.
In both studies, the mean change in BCVA from baseline to week 48 was noninferior for brolucizumab compared with aflibercept. At week 48, brolucizumab patients in the HAWK study experienced a mean BCVA gain of 6.1 letters for the 3 mg group and 6.6 letters for the 6 mg group, compared with 6.8 letters for the aflibercept group. In HARRIER, brolucizumab patients gained 6.9 letters compared with 7.6 letters for aflibercept.6 Of note, approximately half of the patients treated with brolucizumab stayed at 12-week treatment intervals at the end of the 48 weeks, and there was greater central subfield thickness reduction on optical coherence tomography (OCT).
Brolucizumab is under expedited review by the FDA at press time. It provides a promising possibility for fixed 12-week dosing as well as an alternative treatment for poor responders to other anti-VEGF agents.
Designed ankyrin repeat proteins (DARPins) are a novel class of small therapeutic proteins genetically engineered from natural ankyrin repeat proteins, which are common binding proteins observed in the human genome. DARPins have small molecular weight, high stability and strong binding affinity that may overcome limitations from conventional immunoglobulins, in addition to possibilities for using them as a platform to target multiple ligands.
Abicipar pegol (Allergan) is a DARPin-based antagonist of VEGF-A. The longer half-life of DARPins may allow prolonged VEGF suppression and thus less frequent injections. The SEQUOIA and CEDAR trials were Phase 3 clinical trials demonstrating that both the eight-week and 12-week fixed-interval treatment regimens met the primary endpoint of non-inferiority to monthly ranibizumab.7 In both studies, abicipar demonstrated similar efficacy after six or eight injections compared to 13 ranibizumab injections in the first year.
However, the rates of intraocular inflammation events were higher in the abicipar groups in both trials. In SEQUOIA, 15.7% and 15.3% of patients in the abicipar eight- and 12-week arms reported inflammation vs. 0.6% in the ranibizumab arm. In CEDAR, those rates were 15.1% and 15.4% in the abicipar eight- and 12-week arms and 0% in the ranibizumab arm.
The recent MAPLE study used a modified manufacturing process and demonstrated decreased inflammation rates to 8.9%.8 Additional data from the MAPLE study will be presented at scientific meetings later in 2019.
Abicipar biologics license application submission to the FDA is underway.
Conbercept (Lumitin, Chengdu Kanghong Biotech Co.) is a recombinant fusion protein that blocks VEGF-A, VEGF-B and placental growth factor, similar to aflibercept. It is composed of the second immunoglobin (Ig) domain of VEGFR1 and the third and fourth Ig domains of VEGFR2 to the constant region (Fc) of human IgG1. The fourth binding domain of VEGFR2 is the unique addition compared to aflibercept, which is thought to potentially further stabilize the receptor-ligand complex and extend the half-life. Conbercept was approved for use in China for the treatment of neovascular AMD in 2013.
In a prospective, double-masked, multicenter Phase 3 trial in China, the PHOENIX study randomized patients with neovascular AMD to conbercept or sham in a 2:1 ratio.9 In the treatment arm, patients received monthly injections of conbercept 0.5 mg for three months, followed by quarterly injections. In the control “sham” arm, patients received sham injections for three months then switched to quarterly conbercept. At the three-month primary end point, the treatment arm experienced a +9.2-letter gain compared to +2.0 letters in the sham arm. At month 12, both groups achieved visual improvement, with the treatment arm achieving a 10.0-letter improvement and the delayed treatment group achieving an 8.8-letter improvement. No ocular serious adverse events were noted.9
The PANDA study is a Phase 3 clinical trial currently recruiting patients internationally, including in the United States. The study randomizes participants 1:1:1 to conbercept 0.5 mg every eight weeks, conbercept 1.0 mg every 12 weeks and aflibercept 2.0 mg every eight weeks.10 Conbercept may represent an opportunity for increased durability, but a focus would also be on a lower price point if it entered the U.S. market.
PORT DELIVERY SYSTEM (PDS) WITH RANIBIZUMAB
The ranibizumab PDS (Genentech) is a refillable nanoparticle reservoir. The preloaded implant is surgically implanted beneath the conjunctiva into the pars plana through a 3.2-mm scleral incision. The reservoir can be refilled in the office to provide continuous release of ranibizumab into the vitreous.
The LADDER study investigated the efficacy and safety of the PDS for the sustained delivery of ranibizumab in participants with neovascular AMD who have previously responded to treatment with anti-VEGF therapies.11 Three different concentrations of ranibizumab (10 mg/mL, 40 mg/mL and 100 mg/mL) were tested in the multicenter, Phase 2, randomized controlled trial, with a control group receiving monthly ranibizumab 0.5-mg injections.
In the 100 mg/mL treatment arm, 80% of patients maintained the full effect of the drug for six months or more. BCVA and anatomic outcomes were comparable to those of monthly ranibizumab. PDS implant insertion was generally well tolerated, with a postoperative vitreous hemorrhage rate of 4.5%. The vitreous hemorrhage rate was initially higher, but a modification in the surgical procedure — in which the choroid in the area of the sclerotomy is laser photocoagulated — substantially decreased this complication.
Based on these results, the Phase 3 ARCHWAY trial was initiated. ARCHWAY will evaluate the efficacy and safety of the ranibizumab PDS 100 mg/mL in patients with neovascular AMD with a fixed refill interval of 24 weeks, compared to an active comparator arm of monthly ranibizumab intravitreal injections.12
RGX-314 GENE THERAPY
We are accustomed to conceptualizing gene therapy as gene replacement therapy to treat allelic alterations. However, gene therapy can also be employed as a technique to introduce vectors that express new therapeutic proteins, such as anti-VEGF agents for long-term continuous VEGF suppression, potentially with a single administration.
More emerging therapies
Two more treatments that are still in early clinical trials:
DE-122 (Santen) is a formulation of carotuximab designed for intravitreal injection. Carotuximab is an antibody that targets the endothelial protein endoglin, which plays a crucial role in angiogenesis, and its expression appears to be increased by anti-VEGF therapy.29 While anti-endoglin therapy is being investigated in many oncology clinical trials, the aim of this drug in the ophthalmic space is to address anti-VEGF resistant neovascular AMD.
The results of the DE-122 Phase 1/2 study were reported at the 2018 Angiogenesis, Exudation and Degeneration meeting in Miami. This clinical trial included four dosing levels of a single injection of DE-122 in 12 subjects with treatment resistant neovascular AMD.30 No serious adverse events were found, and a decrease in CST indicated positive bioactivity. The Phase 2 AVANTE trial is currently comparing two doses of DE-122 combined with ranibizumab vs. ranibizumab monotherapy.31
PAN-90806 for topical treatment
PAN-90806 (Panoptica) is another anti-VEGF agent that targets VEGF-R2. PAN-90806 is administered in a topical drop formulation to avoid the associated risks of intravitreal injection and may improve treatment adherence. The initial drug solution caused a reversible keratopathy at high concentrations, but this problem has not been found in a new reformulated suspension.32
The agent is currently being studied in a Phase 1/2 trial of subjects with active neovascular AMD. Subjects are randomized to one of three dosing levels and receive the drug daily for three months.33 This study comes on the heels of another topical anti-VEGF therapy, squalamine (Ohr Pharmaceutical), which failed to meet its primary endpoint in a recent Phase 3 study.34
RGX-314 (Regenxbio) is an adeno-associated virus serotype 8 (AAV8) vector containing a gene encoding a monoclonal antibody fragment that binds to and neutralizes VEGF activity (essentially ranibizumab). It is at the forefront of current gene therapies for neovascular AMD.
Previous gene therapies for neovascular AMD examined the delivery of AAV2 vectors expressing sFLT-1, a soluble isoform of VEGF receptor 1, either subretinally (AVA-101, Adverum [formerly Avalanche])13 or intravitreally (AAV2-sFLT01, Sanofi Genzyme),14,15 but neither were deemed suitable to pursue in larger scale studies. In the meantime, the FDA approved a retinal AAV gene therapy for Leber’s congenital amaurosis, which has paved the road for future gene therapies.
A Phase 1/2a dose-escalation trial is currently evaluating five doses of RGX-314: 3 x 10^9 GC/eye (cohort 1), 1 x 10^10 GC/eye (cohort 2), 6 x 10^10 GC/eye (cohort 3), 1.6 x 10^11 GC/eye (cohort 4) and the newly added 2.5 x 10^11 GC/eye (cohort 5). The vector is delivered surgically into the subretinal space via vitrectomy for patients with previously treated neovascular AMD who are confirmed anti-VEGF responders. Interim data showed that at one year after administration of RGX-314, participants in cohort 3 continued to demonstrate evidence of sustained RGX-314 intraocular protein expression levels, with three of the six patients not requiring any rescue treatments.16
On May 30, Regenexbio announced completion of dosing for the Phase 1/2a trial. Topline results will include data from the higher dosed cohorts.17 Adverum has similarly refocused its neovascular AMD gene therapy pipeline to expression of established anti-VEGF proteins (ADVM-022 [AAV.7m8-aflibercept], ADVM-032 [AAV.7m8-ranibizumab]).18
Combination therapies to target multiple ligands has been an obvious strategy to pursue, but the optimism from early clinical trials have so far not translated into Phase 3 successes. Targeting platelet-derived growth factor (PDGF) was a highly anticipated approach, as PDGF is responsible for pericyte recruitment and survival, which is thought to encase and protect neovascular complexes and cause anti-VEGF resistance.19
However, both E10030/pegpleranib (Fovista, Ophthotech [now Iveric Bio]) and rinucumab (Regeneron) failed to show a benefit over anti-VEGF monotherapy in Phase 3 and 2 studies, respectively.20
The focus has now turned to the tyrosine kinase receptor (Tie2) pathway. Tie2 is activated by angiopoietin-1 (Ang-1), which plays a key role in retinal vascular stability and maintenance of the blood-retinal barrier. Ang-2, on the other hand, is an antagonist and negative regulator of Tie2 activation. Concurrent VEGF and Ang-2 inhibition is therefore a potential dual-mechanism approach for neovascular diseases. Faricimab (Genentech) is a single bispecific antibody developed to bind and neutralize VEGF-A and Ang-2 simultaneously.
The preliminary safety and efficacy data for faricimab was first presented in the Phase 2 AVENUE study, which found similar BCVA gains in both q4 and q8 week injection schedules to those seen with monthly ranibizumab. In October 2018, results of the Phase 2 STAIRWAY study were announced at the AAO annual meeting.21 STAIRWAY aimed to examine the efficacy of less frequent injection schedules of faricimab via subject randomization to one of three treatment groups: q12 week dosing of faricimab (after four monthly loading doses), q16 week dosing of faricimab (after four monthly loading doses) and monthly ranibizumab. Across the three groups, there was no significant difference in the proportion of subjects with improved/maintained visual acuity, reduction of central subfield thickness on OCT and change in CNV lesion size. No unique safety concerns regarding faricimab have surfaced from these studies. Fixed q16 week dosing may indeed become a possibility.
TENAYA and LUCERNE, two international Phase 3 clinical trials investigating 16-week dosing schedules, were initiated in early 2019. Phase 3 clinical trials YOSEMITE and RHINE comparing faricimab to aflibercept for diabetic macular edema are also underway. These studies come on the heels of Regeneron’s failed Phase 2 study ONYX, in which adding Ang-2 inhibitor nesvacumab (Regeneron) to aflibercept did not improve outcomes compared to aflibercept monotherapy.22
However, of note, the FDA requirement for combination therapies (aflibercept and nesvacumab) is demonstration of superiority compared to bi-specific monotherapies (faricimab), which require demonstration of non-inferiority, setting a lower bar for approval of the latter.
SUNITINIB/GB-102 MICROPARTICLE DEPOT
Sunitinib is a small molecule multiple receptor tyrosine kinase inhibitor, which selectively inhibits VEGF receptors (VEGFR-1, -2, -3), PDGR receptors (PDGFR-α, -β), stem cell growth factor receptor (KIT), colony stimulating factor receptor (CSFR-1) and Fms-related tyrosine kinase receptor (FLT3). These intracellular receptors have been associated with angiogenesis and vascular permeability. GB-102 (Graybug Vision) is a depot formulation of sunitinib that is encapsulated within microparticles that initially aggregate and then gradually biodegrade in the vitreous cavity.23
Preclinical reports in a rabbit model suggested biologically active levels of sunitinib were detected four months after injection and may allow for dosing two to three times per year.24 In August 2017, the Phase 1/2a ADAGIO study began to evaluate the safety and systemic exposure to sunitinib in escalating doses (0.25 mg, 0.5 mg, 1 mg, 2 mg) of a single intravitreal injection. At six months, 68% of participants were without rescue treatment.
One concern that emerged was in relation to non-aggregation of the drug once in the vitreous cavity, resulting in particle dispersion. Nine of 32 subjects experienced related symptoms, including eye pain, photophobia and blurriness.25 The manufacturing process is being optimized to allow improved aggregation of the microparticles, according to the company. The Phase 2b study PRELUDE, comparing two dose levels of sunitinib to aflibercept in a randomized study, is anticipated. Also, development of GB-103, which aims for once-a-year dosing, is in the pipeline.
VEGF C/D TRAP THERAPY
OPT-302 (Opthea) is a VEGF receptor 3 molecule engineered for intravitreal injection that traps and inhibits VEGF-C and -D. This molecule can be combined with inhibitors of VEGF-A to achieve a more complete blockade of VEGF drive. Opthea’s six-month Phase 2b trial randomized 366 participants with treatment-naive neovascular AMD to monotherapy or in combination with ranibizumab.26 The final patient visit for the trial was completed in May 2019, after which the company reported that top-line results were expected within the coming months.27
A PIPELINE OF POSSIBILITIES
Although the current anti-VEGF therapies have resulted in drastically improved patient outcomes, they require frequent injections and monitoring visits, and a subset of patients do not fully respond. Improved efficacy and durability are much needed. Thankfully, the pipeline for new therapeutic possibilities is packed with exciting potential.
Numerous other promising agents are on the way. They include other mechanisms of action, such as HMR59 (Hemera Biosciences) gene therapy that expresses CD59,28 RNAi technologies and biosimilar molecules amongst many other exciting developments in the dynamic field of neovascular AMD therapeutics. OM
- Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-116.
- Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175-1183.
- Silva R, Axer-Siegel R, Eldem B, et al. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration. Ophthalmology. 2013;120(1):130-139.
- Comparison of Age-related Macular Degeneration Treatments Trials Research G, Maguire MG, Martin DF, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-1761.
- Holz FG, Dugel PU, Weissgerber G, et al. Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration: A Randomized Controlled Study. Ophthalmology. 2016;123(5):1080-1089.
- Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2019.
- Allergan and Molecular Partners Announce Two Positive Phase 3 Clinical Trials for Abicipar pegol 8 and 12-week Regimens for the Treatment in Patients with Neovascular Age-Related Macular Degeneration [press release]. Available from: https://www.molecularpartners.com/allergan-and-molecular-partners-announce-two-positive-phase-3-clinical-trials-for-abicipar-pegol-8-and-12-week-regimens-for-the-treatment-in-patients-with-neovascular-age-related-macular-degeneration . Accessed June 1, 2019.
- Allergan and Molecular Partners Announce Topline Safety Results from MAPLE study of Abicipar pegol [press release]. Available from: https://www.molecularpartners.com/allergan-and-molecular-partners-announce-topline-safety-results-from-maple-study-of-abicipar-pegol . Accessed June 1, 2019.
- Liu K, Song Y, Xu G, et al. Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study. Am J Ophthalmol. 2019;197:156-167.
- ClinicalTrials.gov . Efficacy and Safety Trial of Conbercept Intravitreal Injection for Neovascular Age-related Macular Degeneration (PANDA-1). Available from: https://clinicaltrials.gov/ct2/show/NCT03577899 . NLM identifier: NCT03577899. Accessed June 1, 2019.
- Campochiaro PA, Marcus DM, Awh CC, et al. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology. 2019.
- ClinicalTrials.gov . A Phase III Study to Evaluate the Port Delivery System Implant With Ranibizumab Compared With Monthly Ranibizumab Injections in Participants With Wet Age-Related Macular Degeneration (Archway). Available from: https://clinicaltrials.gov/ct2/show/NCT03677934 . NLM identifier: NCT03677934. Accessed June 1, 2019.
- Avalanche Biotechnologies, Inc. Announces Positive Top-Line Phase 2a Results for AVA-101 in Wet Age-Related Macular Degeneration [press release]. Available from: http://investors.adverum.com/news-releases/news-release-details/avalanche-biotechnologies-inc-announces-positive-top-line-phase . Accessed June 1, 2019.
- Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet. 2017;390(10089):50-61.
- Moore NA, Bracha P, Hussain RM, Morral N, Ciulla TA. Gene therapy for age-related macular degeneration. Expert Opin Biol Ther. 2017;17:1235-1244.
- REGENXBIO REPORTS FIRST QUARTER 2019 FINANCIAL AND OPERATING RESULTS AND ADDITIONAL POSITIVE INTERIM PHASE I/IIA TRIAL UPDATE FOR RGX-314 FOR THE TREATMENT OF WET AMD [press release]. Available from: https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-reports-first-quarter-2019-financial-and-operating . Accessed June 1, 2019.
- REGENXBIO ANNOUNCES COMPLETION OF DOSING FOR PHASE I/IIA CLINICAL TRIAL OF RGX-314 IN WET AMD [press release]. Available from: https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-completion-dosing-phase-iiia-clinical-trial . Accessed June 1, 2019.
- Adverum Biotechnologies Provides Update on OPTIC Phase 1 Trial for ADVM-022 in Wet AMD [press release]. Available from: http://investors.adverum.com/news-releases/news-release-details/adverum-biotechnologies-provides-update-optic-phase-1-trial-advm . Accessed June 1, 2019.
- Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 2001;15(7):1239-1241.
- Regeneron Announces Phase 2 Study of Aflibercept Co-Formulated with Rinucumab (anti-PDGFR-beta) Shows No Benefit Over Aflibercept Alone in Neovascular Age-Related Macular Degeneration [press release]. Available from: https://www.prnewswire.com/news-releases/regeneron-announces-phase-2-study-of-aflibercept-co-formulated-with-rinucumab-anti-pdgfr-beta-shows-no-benefit-over-aflibercept-alone-in-neovascular-age-related-macular-degeneration-300337055.html . Accessed June 1, 2019.
- Khanani AM, et al. Simultaneous Inhibition of VEGF and Ang-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at: American Academy of Ophthalmology Annual Meeting; October 26, 2018; Chicago, IL.
- REGENERON PROVIDES UPDATE ON EYLEA® (AFLIBERCEPT) INJECTION AND NESVACUMAB (ANG2 ANTIBODY) COMBINATION PROGRAM [press release]. Available from: https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-eylear-aflibercept-injection-and . Accessed June 1, 2019.
- ClinicalTrials.gov . A Depot Formulation of Sunitinib Malate (GB-102) in Subjects With Neovascular (Wet) Age-related Macular Degeneration. Available from: https://clinicaltrials.gov/ct2/show/NCT03249740 . NLM identifier: NCT03249740. Accessed June 1, 2019.
- Yang M, Yu Y, Kays J, et al. GB-102 for Wet AMD: A Novel Injectable Formulation that Safely Delivers Active Levels of Sunitinib to the Retina and RPE/Choroid for Over Four Months. Invest Ophthalmol Vis Sci 2016;57(12):5037.
- Kaiser PK, Boyer D. Most exciting retinal drugs: 2019. Presented at: Retina 2019; Jan. 20-25, 2019; Waikoloa, HI.
- ClinicalTrials.gov . A Dose Ranging Study of OPT-302 With Ranibizumab in Neovascular (Wet) AMD. Available from: https://clinicaltrials.gov/ct2/show/NCT03345082 . NLM identifier: NCT03345082. Accessed June 1, 2019.
- Opthea Completes Final Patient Visit in Phase 2b Wet AMD Clinical Trial [press release]. Available from: https://wcsecure.weblink.com.au/pdf/OPT/02105614.pdf . Accessed June 1, 2019.
- Barnett JM, Suarez S, McCollum GW, Penn JS. Endoglin promotes angiogenesis in cell- and animal-based models of retinal neovascularization. Invest Ophthalmol Vis Sci. 2014;55(10):6490-6498.
- A Phase I/II Safety, Tolerability, Immunogenicity, and Bioactivity Study of DE-122 Injectable Solution for Refractory Exudative Age-related Macular Degeneration. Available from: https://clinicaltrials.gov/ct2/show/NCT02555306?term=DE-122&rank=1 . NLM identifier: NCT02555306. Accessed June 1, 2019.
- Study Assessing the Efficacy and Safety of Intravitreal Injections of DE-122 in Combination With Lucentis® Compared to Lucentis Monotherapy in Wet Age-related Macular Degeneration Subjects. Available from: https://clinicaltrials.gov/ct2/show/NCT03211234 . NLM identifier: NCT03211234. Accessed June 1, 2019, 2019.
- PanOptica Doses First Patient with New Formulation of PAN-90806, a Novel, Topical Anti-VEGF Eye Drop, in Phase 1/2 Clinical Trial [press release]. Available from: http://www.panopticapharma.com/wp-content/uploads/2018/05/PanOptica-New-Formulation-First-Patient-Dosed-News-Release-Final-May-17-2018.pdf . Accessed June 1, 2019.
- Study of PAN-90806 Eye Drops, Suspension for Neovascular AMD. Available from: https://clinicaltrials.gov/ct2/show/NCT03479372 . NLM identifier: NCT03479372. Accessed June 1, 2019.
- Ohr Pharmaceutical Announces Efficacy Results from the MAKO Study in Wet-AMD [press release]. Available from: https://ir.ohrpharmaceutical.com/press-releases/detail/492/ohr-pharmaceutical-announces-efficacy-results-from-the-mako-study-in-wet-amd . Accessed June 1, 2019.
- ClinicalTrials.gov . Treatment of Advanced Dry Age Related Macular Degeneration With AAVCAGsCD59. Available from: https://clinicaltrials.gov/ct2/show/NCT03144999?term=NCT03144999&rank=1 . NLM identifier: NCT03144999. Accessed June 1, 2019.