Lineage Reports Positive OpRegen Data in GA
Nine of 12 patients in one cohort gained vision.
■ Lineage Cell Therapeutics reported new positive interim results from its ongoing, 24-patient phase 1/2a clinical study of its lead product candidate, OpRegen. OpRegen is an investigational cell therapy consisting of allogeneic retinal pigment epithelium (RPE) cells administered to the subretinal space for the treatment of dry AMD with geographic atrophy (GA). Additional interim data were collected on all 24 patients enrolled in the study, including the 12 patients treated in cohort 4, whose characteristics included less advanced disease, better baseline visual acuity, and smaller areas of GA.
Overall, 9 of 12 (75%) of the cohort 4 patients’ treated eyes were at or above baseline visual acuity at their last assessment, based on per-protocol scheduled visits ranging from 3 months to >2 years after transplant. Improvements in BCVA reached up to +19 letters on an EDTRS chart. In contrast, 9 of 12 (75%) of the patients’ untreated eyes were below baseline entry values at the same time points. Among the newly reported data, 3 (50%) of the more recently treated cohort 4 patients exhibited marked improvements in BCVA, ranging from +7 to +16 letters at their last scheduled assessments of at least 4.5 months. Two additional cohort 4 patients remained within 2 letters of their baseline values (one each above and below). One patient measured 7 letters below baseline.
Previously reported structural improvements in the retina and decreases in drusen density have continued with evidence of durable engraftment of OpRegen cells in some treated patients now extending to more than 5 years in the earliest treated patients. A trend toward slower GA progression in treated compared to fellow eyes also continued, although significant changes in GA growth over a 3-month period following treatment are not expected. Overall, OpRegen has been well tolerated with no unexpected adverse events or serious adverse events.
“Improvements in BCVA have become apparent within a few months after dosing, consistent with the predicted activity of an RPE cell transplant,” stated Brian M. Culley, Lineage CEO. “If these early indications of a treatment effect are maintained or improve further, it will be another positive indicator for the potential of OpRegen to improve outcomes in this condition. We continue to monitor all patients on study, and in the coming months we will be looking in particular for indications of retinal restoration, reductions in the size and growth of the areas of GA, and functional improvement in visual acuity. Further, the multiyear stability of OpRegen transplants, some in excess of 5 years without signs of rejection, is notable for the durability of our allogeneic cell therapy approach, especially as patients did not require long-term immunosuppression.”
Annexon Begins GA Trial for Complement Inhibitor
Phase 2 study will evaluate efficacy and safety.
■ Annexon has begun dosing in its phase 2 ARCHER study of its anti-C1q therapy, ANX007, to treat geographic atrophy (GA). Currently, there are no approved treatment options to prevent onset or progression of GA.
The randomized, multicenter, double-masked trial is designed to evaluate the efficacy and safety of ANX007 in reducing the area of GA as evaluated by fundus autofluorescence (FAF) in patients with GA. Monthly and every-other-month dosing schedules will be evaluated.
ANX007 is an investigational monoclonal antibody antigen-binding fragment for the treatment of patients with complement-mediated neurodegenerative ophthalmic diseases. Formulated for intravitreal administration, ANX007 is designed to potently bind to C1q and inhibit activation of all downstream components of the classical complement cascade, including C3 and C5, but not to interfere with the normal function of C3 and C5 as part of other complement pathways. In phase 1 studies, intravitreal ANX007 demonstrated full C1q inhibition at 29 days and was well tolerated by patients.
Graybug Wet AMD Trial Shows Durable Response
Gains in vision were noted but were inferior to aflibercept.
■ Graybug Vision provided a mixed bag of preliminary top-line data from the 12-month treatment phase of its phase 2b ALTISSIMO trial of GB-102 for the treatment of wet AMD, Graybug’s proprietary microparticle depot formulation of sunitinib malate injected intravitreally. The ALTISSIMO trial is a masked and controlled dose-ranging study of 2 doses of GB-102 with a single control arm of patients on aflibercept, conducted across 33 study sites in the United States. The primary endpoint is median time to first supportive therapy with a VEGF inhibitor, and secondary endpoints are measures of mean change BCVA from baseline and mean change of central subfield thickness (CST) of the retina from baseline.
Analysis of the ALTISSIMO 1-mg arm shows the primary endpoint of median time to first supportive therapy was 5 months. Moreover, 48% of patients did not require supportive therapy for at least 6 months, and 62% of patients for at least 4 months or more, at least once during the trial. The 1-mg dose performed better than the 2-mg dose.
Overall, GB-102 1 mg was well tolerated. There were no drug-related serious adverse events, and the majority of drug-related adverse events were mild to moderate. Medication was detected in the anterior chamber in less than 10% of GB-102 1-mg injections, and no adverse event required surgical intervention. There was no vision-threatening inflammation observed, and there was no increase in IOP reported.
Central subfield thickness and BCVA were measured as secondary endpoints. Central subfield thickness in the GB-102 1-mg arm was consistent with the study control arm. The mean change from baseline for BCVA for all 20 completers was approximately 9 letters lower across all time points, on average, than that observed in the study controls.
The trial was originally designed to evaluate 2 separate doses of GB-102, 1 mg and 2 mg, injected every 6 months, compared with aflibercept injected every 2 months. Based on the results of an interim safety analysis, the 2-mg dose was discontinued after the initial dose, and all patients in that arm were switched to 1 mg for their second dose.
ProQR to Advance Usher Drug to Pivotal Trials
Multiple benefits spurred the decision.
■ ProQR Therapeutics released positive results from an analysis of its phase 1/2 Stellar trial of QR-421a in adults with Usher syndrome and nonsyndromic retinitis pigmentosa (nsRP) due to USH2A exon 13 mutations. In the trial, QR-421a demonstrated benefit on multiple measures of vision that moved in concordance, including visual acuity, visual fields, and OCT imaging, after a single dose. QR-421a was observed to be well tolerated with no serious adverse events reported. Based on these findings, the company plans to advance QR-421a to 2 parallel pivotal phase 2/3 trials by the end of 2021 — one in early-moderate patients, and one in advanced patients.
In the Stellar trial, across all treated patients (n=14), a mean benefit of 6.0 letters was observed at week 48 in the treated eyes compared to the untreated (contralateral) eyes after a single injection. Among advanced-disease patients (n=6), a mean benefit of 9.3 letters was observed at week 48 in the treated eyes as compared to the untreated eyes and the benefit was maintained for >12 months. All 6 patients with advanced disease had a benefit in the treatment eye, whereas none of the patients in the sham group had a benefit in the treatment eye. QR-421a was observed to be well tolerated at all doses. There were no serious adverse events reported and no inflammation was observed.
In another ProQR development, University of Pennsylvania researchers report that the ProQR investigational therapy sepofarsen enabled a patient with Leber congenital amaurosis (LCA10) to gain vision, which lasted more than a year, after receiving a single injection of this experimental RNA therapy into the eye. The clinical trial was conducted by researchers at the Scheie Eye Institute in the Perelman School of Medicine. Results of the case, detailed in a paper published in Nature Medicine, show that the treatment led to marked changes at the fovea, the most important locus of human central vision.
IN BRIEF
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Home Monitoring of AMD Conversion Scores Well
■ A real-world data analysis of 3.2 million tests performed by the ForeseeHome AMD Monitoring Program was recently published in the Journal of Clinical Medicine. The large-scale study showed that the use of ForeseeHome provided a significant benefit to patients by helping to detect their wet AMD earlier with better visual acuity, a factor previously shown to improve long-term visual outcomes of anti-VEGF treatment. The retrospective analysis identified 306 eyes that converted to wet AMD between October 2009 and September 2018. Functional vision (20/40 or better) at conversion was maintained in 81% of patients in the real-world ForeseeHome cohort compared to only 34% in the IRIS Registry real-world data using standard of care, which is defined by routine office visits and use of an Amsler grid.
Second Sight Receives Approval for Retinal Prosthesis
■ Second Sight Medical Product said the FDA has approved the Argus 2s Retinal Prosthesis System, a redesigned set of external hardware (glasses and video processing unit) initially for use in combination with previously implanted Argus II systems for the treatment of retinitis pigmentosa (RP). The company expects that the Argus 2s will be adapted to be the external system for the next generation Orion Visual Cortical Prosthesis System currently under development. In addition to ergonomic improvements, the Argus 2s system offers significantly more processing power, potentially allowing for improved video processing.
“We are very pleased to have received this approval, as it presents an opportunity to offer external hardware that we believe enhance comfort and aesthetics compared with the legacy Argus II system,” said Matthew Pfeffer, acting CEO of Second Sight.
Urgent/Emergent Procedures Plunged During COVID Lockdown
■ Seventeen major US eyecare institutions participated in a survey to determine whether the number of urgent/emergent vitreoretinal procedures was affected on a year-over-year basis during the height of the COVID lockdown from March 30, 2020, to May 2 2020. The frequency of 11 billed vitreoretinal CPT codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region, practice setting, and date of respective statewide stay-at-home orders.
A total of 526,536 CPT codes were ascertained: 483,313 injections, 19,257 lasers or cryotherapy, 14,949 RD repairs, and 9,017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30, 2020, to May 2, 2020, with a maximal 38.6% decrease from April 6, 2020, to April 12, 2020. A weekly decrease was also identified that spanned a longer interval (March 16 to May 31), for lasers and cryotherapy, with a maximal 79.6% decrease from April 6, 2020, to April 12, 2020. For RD repairs, a maximal 59.4% decrease occurred from April 13, 2020, to April 19, 2020, and for other vitrectomies, a maximal 84.3% decrease from April 6, 2020, to April 12, 2020. No differences were identified by region, setting, or state-level stay-at-home order adjustment. The researchers reported their findings in JAMA Ophthalmology. They found that although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic’s initial exponential growth phase.
Oxular Receives Funding to Advance DME Drug
■ INTERNATIONAL NEWS – UK-based Oxular has completed a $37 million (£27 million) financing to fund continued clinical development of its lead asset, OXU-001, for the treatment of DME, as well as accelerating development of its early product pipeline. The investment will fund phase 2 human clinical studies, beginning in late 2021, to evaluate OXU-001 for DME. A key challenge facing patients with DME is the need for frequent clinic visits for repeated treatment injections. To address this, OXU-001, an innovative, sustained-release formulation of dexamethasone, provides up to 12 months of treatment effects following a single administration.
Clearside Doses Initial Cohort in Axitinib Trial
■ Clearside Biomedical has completed dosing the first cohort of OASIS, its 15-patient, phase 1/2a trial of CLS-AX (axitinib injectable suspension) in patients with wet AMD. OASIS is a US-based, multicenter, open-label dose-escalation trial in wet AMD patients to assess the safety and tolerability of a single dose of CLS-AX administered by suprachoroidal injection. The first cohort of patients have received aflibercept at their first visit and a single dose of CLS-AX at their second visit 1 month later. The primary endpoint for the trial will assess the safety and tolerability of CLS-AX for 3 months following the administration of CLS-AX.
Axitinib is a tyrosine kinase inhibitor currently approved to treat renal-cell cancer that achieves pan-VEGF blockade, directly inhibiting VEGF receptors 1, 2, and 3 with high potency and specificity. Clearside believes this broad VEGF blockade may have efficacy advantages over existing retinal therapies by acting at a different level of the angiogenesis cascade, and that it may benefit patients who suboptimally respond to current, more narrowly focused anti-VEGF therapies.
AREDS2 Data Made Available to Researchers
■ The NEI Data Commons now enables researchers to access data from patients with macular degeneration who participated in AREDS2. The database complements newly available stem cell lines created by the New York Stem Cell Foundation Research Institute (NYSCF) from blood cells of AREDS2 study participants. Together, these resources will accelerate the discovery of therapies for AMD and other blinding conditions, according to an NEI news release.
“With the addition of AREDS2 data, the NEI Data Commons now includes data on thousands of participants with AMD. The new portal enables researchers to make the greatest use of this fantastic trove of information,” said Steven Becker, PhD, director of the NEI Office of Regenerative Medicine.
AREDS2 included participants with a variety of genetic profiles, including genes that increase or decrease AMD risk. An NEI collaboration with NYSCF has generated induced pluripotent stem cell lines from a spectrum of AREDS2 participants. With these cells, researchers will be able to create human disease-relevant models with a variety of genetic backgrounds to better understand how genes contribute to AMD.
Conversion From Dry to Wet AMD in Fellow Eye
■ INTERNATIONAL NEWS – According to researchers at the Singapore National Health Center who studied 229 eyes with baseline wet AMD for a minimum of 1 year, patients with high levels of lipids and triglycerides in their blood (hyperlipidemia) were the most likely to develop dry AMD in their fellow eye and also more likely to have the fellow eye more quickly convert to wet AMD. Thirty-eight percent of the 21 fellow eyes that presented with dry AMD at baseline converted to wet AMD with a mean time to exudation of 377 days, suggesting that close monitoring of the fellow eye is necessary. The findings were published in Ophthalmology Retina.
Fewer Serious Vision Problems in Older Americans
■ American adults 65 years old and older have better vision than that age group did nearly a decade ago, according to a recent study published in the journal Ophthalmic Epidemiology. In 2008, 8.3% of those aged 65 and older in the United States reported serious vision impairment. In 2017, that number decreased to 6.6% for the 65-plus cohort. Put another way, if vision impairment rates had remained at 2008 levels, an additional 848,000 older Americans would have suffered serious vision impairment in 2017.
“Serious vision impairment can increase the risk of falls and fractures and undermine quality of life. Moreover, the cost of vision impairment to the US economy is in the tens of billions of dollars,” says the study’s first author, University of Toronto pharmacy student, ZhiDi Deng.
Black and Hispanic Americans older than age 65 showed greater reductions in vision impairment across the decade compared to Non-Hispanic White Americans, with a 27% decline in serious vision impairment among Black respondents and a 24% decline among Hispanic Americans. Non-Hispanic White Americans showed the smallest decline in serious vision impairment at 13%.
“The narrowing of racial/ethnic disparities in vision related problems during this period may be attributable, in part, to the implementation of the Affordable Care Act which led to a large increase in the percentage of insured Hispanics and Black Americans,” says Deng.
The study was based on 10 consecutive waves of the American Community Survey (2008-2017), which engaged a nationally representative sample of approximately half a million American respondents aged 65 and older annually, including those who lived in institutions such as long-term care homes, and those who were living in the community.
Characteristics of First Appointment “No Shows”
■ Researchers at the Penn State Eye Center in Hershey, Pennsylvania, found that 16.4% of people who made initial appointments with the ophthalmology department in 2019 failed to keep them. A multiple logistic regression model was used to assess the association between characteristics and no-show status.
The researchers, who reported their findings in the American Journal of Ophthalmology, determined that certain patient and appointment characteristics were associated with no-show status. These characteristics included younger age, certain minorities, lower median income (by ZIP code), Medicaid or no insurance, longer wait for appointments, longer commute distance, morning and winter appointments, and seeing a glaucoma or retina specialist. These findings may assist in the development of targeted interventions at the patient, practice, and health system levels to improve appointment attendance.
Lineage Treats AVMD Patient With OpRegen After Compassionate Use Approval
■ INTERNATIONAL NEWS – Lineage Cell Technologies said a patient suffering from adult-onset vitelliform macular dystrophy (AVMD) had recently been treated with its lead product candidate, OpRegen, at Hadassah-Hebrew University Medical Center in Jerusalem, using a compassionate use approval granted by the Israeli Ministry of Health. OpRegen is an investigational cell therapy consisting of allogeneic retinal pigment epithelium (RPE) cells administered to the subretinal space and is currently being investigated in a 24-patient phase 1/2a clinical trial for the treatment of dry AMD with geographic atrophy (GA). Because AVMD is a disease of impaired RPE function leading to atrophy and shares similar characteristics to dry AMD, the team at Hadassah approached Lineage about the potential to treat this patient on a compassionate use basis.
“When the team at Hadassah approached us about treating their existing AVMD patient with OpRegen on a compassionate use basis, we were supportive of the request and saw it as an opportunity to investigate a new application for our OpRegen product candidate,” said Brian Culley, Lineage CEO.
This patient presented to the department of ophthalmology at Hadassah-Hebrew University Medical Center in late December 2020 with sudden and severe visual acuity decreases in 1 eye. Best-corrected visual acuity in the worse-vision eye was measured at 20/200, compared to 20/40 in the patient’s contralateral eye. After an onset of blurred vision in 2018, evaluation and imaging diagnosed the patient as suffering from AVMD.
Off-label AREDS2 Supplementation in MacTel
■ In 2 single-center studies led by the University of Cincinnati Department of Ophthalmology (1 retrospective and 1 comparative), researchers found that off-label AREDS2 supplements given to patients with nonproliferative idiopathic macular telangiectasia type 2 could be helpful in maintaining stability and preventing anatomical and visual deterioration in a subset of eyes. Eyes were evaluated at baseline, 12 months, and 24 months, and central macular thickness remained stable for both cohorts throughout the studies. Findings were published in the journal Clinical Ophthalmology.
Aura Biosciences Gets $80 Million in New Financing
■ Aura Biosciences, a clinical-stage oncology company developing a novel class of virus-like drug conjugate (VDC) therapies for multiple oncology indications, announced the closing of an oversubscribed $80 million financing. Aura intends to use the proceeds to advance the clinical development of its VDC technology platform, including the pivotal phase 3 program for AU-011, the company’s lead candidate in development for the first-line treatment of choroidal melanoma, and ongoing research for additional programs in ocular oncology, as well as expanding the VDC technology into bladder cancer, the first nonophthalmic solid tumor indication. In addition to Aura, both Gemini Therapeutics and ProQR have announced new public stock offerings to fund continued drug development. RP
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