Apellis Reports Mixed Results for Geographic Atrophy Drug
Despite mixed results, the company plans to submit NDA to FDA in 2022.
■ Apellis Pharmaceuticals reported mixed results from the phase 3 DERBY and OAKS studies, which are evaluating intravitreal injections of pegcetacoplan, in 1,258 adults with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). For both multicenter, randomized, double-masked, sham-controlled studies, investigators gauged efficacy by measuring change in the total area of GA lesions from baseline. OAKS met the primary endpoint for both monthly and every-other-month injections, demonstrating a significant reduction in GA lesion growth of 22% and 16%, respectively, compared to pooled sham at 12 months. Conversely, DERBY did not meet its 12-month primary endpoint, showing lesion growth reduction of just 12% and 11% with monthly and every-other-month injections, respectively, compared to pooled sham.
Jeffrey S. Heier, MD, principal investigator of the DERBY study and director of retina service/retinal research at Ophthalmic Consultants of Boston, said in a news release, “Pegcetacoplan demonstrated a clinically meaningful slowing of disease progression with an even stronger effect in GA patients with extrafoveal lesions.” Based on results from both studies, the company plans to submit a New Drug Application (NDA) for pegcetacoplan for GA to the FDA in the first half of 2022. In a press release, Apellis’ Chief Medical Officer, Federico Grossi, MD, PhD, said “Pegcetacoplan is the first investigational therapy to significantly slow the progression of GA in a large phase 3 study. We look forward to working with regulatory authorities to bring this medicine to patients in need as quickly as possible.”
Pegcetacoplan was well tolerated in both phase 3 studies. The pooled rate of new-onset exudations was 6.0% of patients in the monthly pegcetacoplan groups, 4.1% in the every-other-month pegcetacoplan groups, and 2.4% in the sham groups. No events of retinal vasculitis or retinal vein occlusion were observed. According to the company, patients in DERBY and OAKS will continue on masked treatment for 24 months.
OpRegen May Provide Structural and Functional Benefits for AMD Patients
Lineage Cell Therapeutics releases updated interim clinical trial results.
■ Lineage Cell Therapeutics, Inc., released updated interim results from its phase 1/2a clinical study of OpRegen, at the 54th Annual Scientific Meeting of the Retina Society. OpRegen is an investigational retinal pigment epithelium cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD). Co-principal investigator, Christopher D. Riemann, MD, described the newly released data as both “statistically significant and clinically important” in a news release.
All 24 patients had bilateral, advanced, atrophic AMD. OpRegen was transplanted into the subretinal space, near or across the area of GA of their worse-seeing eyes, and patients were routinely followed. The newly presented data showed that as patients continued to progress into postoperative follow-up, eyes receiving OpRegen trended toward improvement in visual acuity (VA), a secondary objective under the study, whereas untreated eyes typically lost VA. As additional patients have reached longer periods post-treatment, differences in VA between treated and untreated eyes across cohort 4 patients became statistically significant beginning at month 9 and continuing to month 15. Cohort 4 comprised 12 patients with less advanced disease, better baseline VA, and smaller areas of GA. These results, when combined with previous reports showing evidence of retinal restoration in areas previously considered to be atrophic, suggest that both a structural and functional benefit is possible with OpRegen therapy.
“A significant number of better vision cohort 4 patients are now 9, 12, and even 15 months post-treatment with OpRegen,” said Dr. Riemann in a news release. “As a result, we were able to analyze the available results to ascertain if a detectable efficacy signal could be observed in a relatively small number of patients.
FDA Approves First Biosimilar to Treat Macular Degeneration
Approval was based on data comparing the biosimilar to the reference.
■ Samsung Bioepis and Biogen announced that the FDA has approved Byooviz (ranibizumab-nuna; SB11), a biosimilar referencing ranibizumab (Lucentis; Genentech), for the treatment of wet age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV). Byooviz is the first ophthalmology biosimilar approved in the United States. “The approval of the first ranibizumab biosimilar in the US is a monumental milestone for people living with retinal vascular disorders in the US,” said Kyung-Ah Kim, senior vice president and development division leader at Samsung Bioepis, in a news release.
The FDA approval of Byooviz was based on analytical findings, nonclinical data, and clinical data. In a randomized, double-masked, parallel group, multicenter phase 3 study of SB11, the efficacy, safety, pharmacokinetics, and immunogenicity of the drug were compared to ranibizumab in patients with wet AMD. In the study, 705 patients were randomized (1:1) to receive SB11 or ranibizumab in monthly injections (0.5 mg), and 634 patients continued to receive treatment up to week 48. The mean change in best-corrected visual acuity (BCVA) from baseline at week 52 was 9.79 letters for SB11, compared with 10.41 letters for ranibizumab. The mean change in central subfield thickness (CST) was -139.55 μm for SB11 vs -124.46 μm for ranibizumab, with a difference of -15.09 μm. Pharmacokinetic parameters and safety including incidence of treatment-emergent adverse events, and the immunogenicity profile of SB11 and ranibizumab were comparable at all time points up to week 52.
“This approval represents a great step toward the advancement of a new therapeutic option addressing debilitating disease progression of patients with retinal vascular disorders in the US,” said Ian Henshaw, senior vice president and global head of biosimilars at Biogen, in a news release. “Biosimilars could help broaden patient access to more affordable treatments and generate health-care savings to offset rising costs of these complex diseases while ensuring sustainability of health-care systems.”
KALAHARI Trial IDs Safe and Effective Dose of THR-149 for DME Treatment
Oxurion announces positive results from the first part of a 2-part study.
■ Oxurion announced positive data from part A of KALAHARI, a 2-part study of THR-149, a plasma kallikrein inhibitor, for the treatment of diabetic macular edema (DME). The aim of the first part of this randomized, prospective, multicenter study was to assess multiple intravitreal (IVT) injections of THR-149 in DME patients who have previously shown a suboptimal response to anti-VEGF therapy. Three dosages of THR-149 (0.005 mg, 0.022 mg, and 0.13 mg), administered in 3 monthly intravitreal injections, were evaluated to select the best dose for part B.
The highest dose, 0.13 mg, delivered the most promising results in terms of BCVA, and also delivered a stable CST. At month 3, this dose achieved a mean 6.1 letter improvement, with a range of -0.4 to 12.6 letters, and a stable CST with a mean change of 13 µm, and a range of -37.1 to 63.6 µm. No patients in the high-dose group (n=8) required rescue medication. All dosages had a favorable safety profile, with no serious adverse events and no resulting inflammation.
Arshad M. Khanani, MD, director of clinical research at Sierra Eye Associates in Reno, Nevada, said in a news release, “I am excited to see the results from part A of the KALAHARI study. These patients currently have limited treatment options, and the mean BCVA gains of + 6.1 letters at 3 months with stable CST in patients treated with the highest dose of THR-149 is encouraging. I am looking forward to recruiting patients into part B of this trial. I am hopeful that the KALAHARI study will demonstrate that THR-149 could benefit the 40% to 50% of DME patients who respond suboptimally to anti-VEGFs.”
IN BRIEF
Research and industry news in retina.
BY ROCHELLE NATALONI, CONTRIBUTING WRITER
Investigational Gene Therapy Shows Promise for X-linked Retinitis Pigmentosa
■ Gene therapy company MeiraGTx Holdings presented new data at EURETINA 2021 demonstrating a reversal of X-linked retinitis pigmentosa (XLRP) progression following treatment with its investigational gene drug, adeno-associated virus (AAV) vector AAV5-RPGR. The data are from MGT009, a phase 1/2, first-in-human, open-label, multicenter study of AAV5-RPGR for adults and children with XLRP caused by mutations in the RPGR gene.
The study includes 10 adults in a dose-escalation phase, 3 children in a pediatric dose-confirmation phase, and a randomized expansion phase that includes adults randomized 1:1:1 to receive immediate treatment at 1 of 2 doses or deferred treatment 6 months after randomization. Changes in mean retinal sensitivity and the volumetric analysis of the central 30 degrees of the retinal field were examined up to 48 months prior to the start of intervention with AAV5-RPGR and 12 months after intervention with AAV5-RPGR. For the intermediate dose escalation cohort (n=4), intervention with AAV5-RPGR therapy in the poorer-seeing eye altered the course of natural disease progression. At 12 months after intervention, mean retinal sensitivity and volumetric analysis of the central 30 degrees of the retinal field in the treated eye were similar to levels observed 24 months before intervention, while the untreated eye showed a continued downward trajectory.
AAV5-RPGR, which is designed to deliver functional copies of the RPGR gene to the subretinal space to improve and preserve vision, has been granted fast track and orphan drug designations by the FDA. There are currently no approved treatments for XLRP. In November 2020, 12-month MGT009 data demonstrated that statistically significant vision improvement was sustained 1 year after treatment in the dose-escalation phase of the trial.
Graybug Vision Reports ALTISSIMO Phase 2b Extension Study Outcomes
■ Graybug Vision, Inc., reported full analysis from the phase 2b ALTISSIMO trial of GB-102, a formulation of sunitinib malate intravitreally injected twice yearly, for the treatment of wet AMD. The ALTISSIMO trial was a multicenter, masked, controlled phase 2b dose-ranging study of 2 doses of GB-102, 1 mg and 2 mg, with a single control arm of patients on 2 mg aflibercept (Eylea; Regeneron). The primary endpoint was median time to first supportive therapy with a vascular endothelial growth factor (VEGF) inhibitor, and secondary endpoints were safety and pharmacodynamics, measured as mean change in BCVA and mean change in CST of the retina.
ALTISSIMO comprised 2 phases, the first was a 12-month treatment phase, or core study, in which GB-102 patients were dosed at day 1 and month 6, while a control arm received aflibercept every other month. The second phase of ALTISSIMO was a 6-month extension study in which patients were monitored without additional treatment to determine the duration of effect measured from their last treatment during the core study.
The extension study provided up to an additional 6 months for patients to demonstrate longer duration, and resulted in 55% of GB-102 1 mg patients experiencing a treatment duration of 12 months or longer, while maintaining VA and central retinal thickness. This is the longest duration ever achieved with an intravitreal injection in a randomized, masked, and controlled clinical trial in wet AMD. In addition, the injection burden was reduced by 73% on an annualized basis for those GB-102 1 mg patients who participated in the 6-month extension study.
As in the core study, GB-102 1 mg continued to be well tolerated and maintained a favorable safety profile during the extension study. No drug-related adverse events or vision-threatening inflammation were reported.
“We are encouraged by the extension study data that indicate a class-leading durability of GB-102 (1 mg) of 12 months, or longer,” said Fred Guerard, PharmD, chief executive officer of Graybug Vision, in a news release.
Brolucizumab May Improve VA in DME Patients with Fewer Injections
■ One-year results from the ongoing KESTREL and KITE studies evaluating anti-VEGF brolucizumab (Beovu; Novartis) vs aflibercept for the treatment of visual impairment in patients with DME, show that all cohorts achieved similar mean improvements in BCVA and CST, but more brolucizumab-treated eyes achieved a CST of less than 280 µm than aflibercept-treated eyes, and fewer brolucizumab-treated eyes had intraretinal or subretinal fluid than aflibercept-treated eyes.
Ramin Tadayoni, MD, PhD, professor of ophthalmology at the University of Paris, France, presented the phase 3 study outcomes at the virtual EURETINA 2021 meeting. In an abstract provided prior to the meeting, Dr. Tadayoni reported that brolucizumab 6 mg achieved robust vision gains and improved anatomical outcomes with more than 50% of DME patients maintained on a 12-week treatment interval schedule (after an initial period of 5 loading doses every 6 weeks) through week 52.
KESTREL and KITE are 2-year ongoing, double-masked, randomized, active-controlled, multicenter studies. In KESTREL, patients were randomized 1:1:1 to brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2mg; in KITE, patients were randomized 1:1 to brolucizumab 6 mg or aflibercept 2 mg. The primary endpoint was the change from baseline in BCVA at week 52; secondary endpoints included the proportion of brolucizumab patients maintained at a 12-week dosing interval up to week 52 and the change from baseline in CST. In both studies, the primary objective was met with brolucizumab 6 mg achieving noninferiority (margin of 4 letters) to aflibercept in change of BCVA from baseline at week 52. The brolucizumab groups received 5 loading doses every 6 weeks followed by 12-week dosing interval in the first year, with an option to adjust to 8-week dosing intervals if disease activity is identified at those prespecified visits. The aflibercept group received 5 loading doses monthly followed by a fixed 8-week dosing.
Dr. Tadayoni reported that brolucizumab demonstrated an overall well-tolerated safety profile, with fewer brolucizumab 6 mg patients having subretinal fluid and/or intraretinal fluid vs aflibercept at week 52: in KESTREL, 60.3% of patients receiving had fluid and 73.3% of patients receiving aflibercept did. In KITE, 54.2% of patients receiving brolucizumab had fluid, and 72.9% of patients receiving aflibercept did. As Retinal Physician previously reported, Novartis has submitted its application for Beovu in DME to the FDA.
LIGHTSIGHT II Study Shows PBM Improves Vision in Eyes With Dry AMD
■ Photobiomodulation (PBM; LumiThera, Inc.) therapy resulted in statistically significant improvements in BCVA 9 months after treatment in patients with dry AMD, and at 4 month intervals it provided consistent improvements in visual function and in morphologic signs of dry AMD, according to lead investigator Professor Benjamin Burton, MD, of James Paget University Hospital in Norfolk, England, who presented the LIGHTSIGHT II trial findings at EURETINA 2021.
The objective of LIGHTSIGHT II was to treat dry AMD subjects over the course of 3 rounds of PBM sessions every 4 months with a duration of 10 months. The study was converted to a smaller pilot because some of the enrolled subjects missed planned treatments due to COVID-19. Forty-four subjects were enrolled in a 2:1 ratio of PBM with the Valeda Light Delivery System delivering 590 nm, 660 nm, and 850 nm wavelengths of light or to sham with the Valeda Light Delivery System emitting noneffective treatment wavelengths.
The mean age of the subjects was 74.1 years and mean dry AMD duration was 3.7 years after diagnosis. The analysis included 32 eyes in the PBM group and 19 eyes in the sham group in the modified intent-to-treat group with at least 1 post-treatment visit and disease consistent with intermediate dry AMD. The subjects had 20/32 to 20/100 vision impairment and no central (1 mm) GA involvement.
Dry AMD patients treated with PBM demonstrated both functional and anatomic improvements. The anatomic benefits will require larger clinical trials to confirm benefits. “The data strongly suggests that the Valeda Light Delivery System can provide a safe, noninvasive treatment opportunity for dry AMD patients with limited options,” Professor Burton said in a news release.
Common Eye Conditions Linked to Higher Risk of Dementia
■ Age-related macular degeneration, cataract, and diabetes-related eye disease (DRED) are linked to an increased risk of dementia, according to research published online in the British Journal of Ophthalmology. The authors, led by Xianwen Shang, MPH, PhD, of Guangdong Eye Institute in China, analyzed data on 112,364 adults aged 55 to 73 years who were enrolled in the UK Biobank study, to determine whether ophthalmic conditions alone — in the absence of other high-risk systemic conditions — are indicators of a higher incidence of dementia.
Participants were assessed between 2006 and 2010 at baseline and were followed until early 2021. During this time, they recorded 2,304 cases of all-cause dementia along with 945 cases of Alzheimer disease and 513 cases of vascular dementia. Compared with people who did not have ophthalmic conditions at the start of the study, the risk of dementia was 26% higher in those with AMD, 11% higher in those with cataract, and 61% higher in those with DRED.
The scientists asked these participants whether a doctor had told them during the study period that they had certain conditions including heart disease, stroke, high blood pressure, depression, and diabetes. The researchers found that ARMD, cataract, and DRED, but not glaucoma, were independently associated with increased risk of dementia from any cause. The data analysis suggests that glaucoma can increase the risk for vascular dementia, but not Alzheimer disease.
The researchers concluded that individuals with both ophthalmic and systemic conditions are at higher risk of dementia than are those with an ophthalmic or systemic condition only. The findings suggest that the age at diagnosis of ophthalmic conditions and certain systemic conditions may be useful for detection or prediction of dementia. RP
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