Bispecific Faricimab Now in Phase 3 for BRVO, CRVO
Drug will be compared to aflibercept.
■ Genentech has begun 2 phase 3 clinical trials in branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) for faricimab. Faricimab is the first investigational bispecific antibody designed for the eye. It targets 2 distinct pathways — angiopoietin-2 and VEGF-A — that drive a number of retinal conditions.
COMINO is a randomized, multicenter, double-masked, active comparator-controlled, parallel-group global study, which will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared to aflibercept (Eylea; Regeneron) in 750 people living with macular edema secondary to central retinal or hemiretinal vein occlusion. BALATON is a randomized, multicenter, double-masked, active comparator-controlled, parallel-group global trial, which will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared to aflibercept in 570 people living with macular edema secondary to BRVO.
Both studies have 2 treatment arms: faricimab 6.0 mg administered at fixed 4-week intervals from day 1 through week 20 (part 1), followed by a personalized treatment interval (PTI) dosing regimen from week 24 to week 72 (part 2); aflibercept 2.0 mg administered at fixed 4-week intervals from day 1 through week 20 (part 1), followed by faricimab 6.0 mg administered at a PTI dosing regimen from week 24 through week 72 (part 2). To maintain masking in part 2 of the studies, all patients will receive a sham procedure at study visits when they are not receiving treatment with faricimab.
The primary endpoint for these studies is the average change in BCVA score from baseline through week 24. Faricimab is also currently in phase 3 studies for wet AMD and diabetic macular edema.
Patient Develops Hypotony in Adverum DME Trial
Study will be unmasked to analyze event.
■ Adverum Biotechnologies announced a Suspected Unexpected Serious Adverse Reaction of hypotony in its INFINITY clinical trial evaluating ADVM-022 gene therapy for the treatment of DME. This event occurred 30 weeks after randomization in 1 patient treated with a single intravitreal injection of the high dose (6x10^11 vg/eye) of ADVM-022 who has developed hypotony, with panuveitis and loss of vision in the treated eye.
The event represents a major setback for Adverum, whose goal is to develop and commercialize a “one-and-done” single-injection gene-derived version of the anti-VEGF aflibercept for a range of retinal diseases. Until now, the most serious side effect associated with ADVM-022 has been inflammation.
In the interest of patient safety, Adverum will unmask the phase 2 study to better understand this event and to help identify and manage any similar potential risk to other patients in this study, which completed patient dosing in December 2020. Additionally, the company is conducting a thorough review of data from the ADVM-022 program and plans to report its findings.
“We are fully committed to thoroughly assessing this case and ongoing monitoring of this patient and all patients treated with ADVM-022,” said Laurent Fischer, MD, CEO of Adverum, in a news release.
The INFINITY study is evaluating 2 doses of a single intravitreal injection of ADVM-022 gene therapy, either a high-dose 6x10^11 vg/eye or low-dose 2x10^11 vg/eye. As of December 2020, the INFINITY study was fully enrolled, and all patients completed dosing of the single IVT injection of ADVM-022. All patients continue to be evaluated regularly during the monitoring phase of this study. Adverum is working closely with the data monitoring committee and the study sites to proactively develop additional recommendations for patient monitoring and management. All clinical trial sites, as well as the FDA, have been advised of this case.
Dr. Fischer also offered a positive update for Adverum’s OPTIC-1 trial of ADVM-022 in wet AMD. “In OPTIC, ADVM-022 with wet AMD has demonstrated durability out to 2 years with the ease of a single, in-office intravitreal injection. We believe that we are well within the therapeutic window with the [low] dose with 60% of patients supplemental injection free beyond 1 year. Additionally, the aflibercept protein levels at the [low] dose were within the modeled therapeutic range and sustained out to at least 1 year, consistent with levels observed 4 weeks to 6 weeks after an aflibercept injection.”
Study Examines Drops vs Ointment After Vitrectomy
Shorter-course ointments may be preferable.
■ Michelle Abou-Jaoude, MD, of Retina Associates of Kentucky, led an effort to determine the most effective postoperative regimen following vitrectomy. Traditional drop regimens after vitreoretinal surgery can be burdensome, and whether abbreviated ointment-based regimens are equally effective has not been addressed in the literature.
The research group performed a retrospective consecutive case series from a single surgeon before and after a regimen switch to assess rates of cystoid macular edema (CME) and endophthalmitis among patients who received an extended drop regimen vs short-term ointment therapy for routine vitreoretinal cases.
A retrospective chart review of 245 eyes that underwent routine vitreoretinal surgery at multiple sites was conducted with IRB approval. Data collected included patient age, diagnosis, lens status, type of surgery, use of subconjunctival medications, use of sub-Tenon Kenalog (Bristol-Myers Squibb) (STK), final ocular fill, and postoperative regimen (4 weeks of drops vs 1 week of ointment).
Of 245 eyes, 111 received antibiotic/steroid ointment for 1 week and 131 received an extended steroid drop taper with 1 week of antibiotic drops. One of 111 in the ointment group developed endophthalmitis, compared to no patients in the drop group. In addition, 35 of 111 eyes in the ointment group vs 48 of 131 eyes in the drops group developed CME requiring treatment. Statistically significant risk factors for CME across groups included type of surgery, use of STK, and age.
The researchers, who reported their findings at the virtual Association for Research in Vision and Ophthalmology meeting, found no difference in the development of CME between the 2 postoperative regimen cohorts. Only 1 case of endophthalmitis was found, so statistical analysis was not possible for this endpoint. Further validation is required, but shorter ointment regimens may be a more feasible and equally efficacious alternative to extended drop regimens for routine vitrectomy.
Ocuphire to Study Oral Therapy for DR
The company’s goal is a more patient-friendly treatment.
■ Ocuphire Pharma has screened the first patient in ZETA-1, a 100-patient, 24-week phase 2 US trial to evaluate oral APX3330 in nonproliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (mild PDR). Effects on DME will be explored as a secondary outcome.
Current approved treatments for DR and DME involve administering anti-VEGF injections to decrease inflammation into eyes with advanced retinal disease. The ZETA-1 trial is investigating the potential of APX3330 to offer an innovative and conveniently administered oral treatment for diabetic retinopathy that addresses both abnormal blood vessel proliferation and inflammation. Until now, no oral or topical therapies have been approved by the FDA for combating retinal disease.
Peter K. Kaiser, MD, professor of ophthalmology at the Cole Eye Institute of the Cleveland Clinic Foundation, said in a news release, “There remains a strong need to develop a noninjectable alternative treatment option for patients with DR as these injectables, although approved for this indication, are not widely used. If successfully developed, APX3330 could lead to the first oral option for DR as well as an adjunct therapy that may improve dosing convenience and compliance by alleviating some of the burden of chronic anti-VEGF injection treatments for DME and other retinal diseases.”
APX3330 is a small-molecule oral drug candidate and a first-in-class inhibitor of the transcription factor regulator Ref-1 (reduction-oxidation effector factor-1). The drug blocks the downstream pathways regulated by Ref-1, including those involving angiogenesis and inflammation, to decrease abnormal activation of both angiogenesis and inflammatory pathways that are implicated across several ocular diseases, including DR, DME, and AMD.
The primary endpoint of the study will evaluate the percentage of subjects with a ≥2-step improvement on the Diabetic Retinopathy Severity Scale score. Secondary endpoints include evaluation of central subfield thickness to assess effects on diabetic macular edema, BCVA, safety and tolerability.
IN BRIEF
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Elamipretide Most Effective in Early-stage Geographic Atrophy
■ Stealth Biotherapeutics, a clinical-stage biotechnology company focused on novel therapies for diseases involving mitochondrial dysfunction, presented new positive data at the virtual meeting of the Association for Research in Vision and Ophthalmology from a post hoc analysis of the phase 1 ReCLAIM study evaluating elamipretide in patients with noncentral geographic atrophy (GA) and high-risk drusen associated with dry AMD. Findings indicated that patients with early-stage disease had the best chance of benefiting from elamipretide therapy.
The data indicated that for patients with GA treated with elamipretide for 24-weeks, improvements from baseline in low light visual acuity (LLVA), the primary efficacy endpoint in Stealth’s fully enrolled phase 2 ReCLAIM-2 trial, were significantly correlated to baseline assessments of mitochondrial health in the ellipsoid zone (EZ). The EZ is a mitochondria-rich area of the retina that supports photoreceptor function and is attenuated in dry AMD.
Ellipsoid zone imaging assessments were conducted using OCT and included panmacular EZ-retinal pigment endothelium cell (RPE) volume and macular percentage of EZ-RPE attenuation. Improvements in LLVA were significantly correlated to both baseline EZ-RPE volume and EZ-RPE attenuation, with eyes gaining 2 or more lines showing significantly less EZ-RPE attenuation and percentage area of macular GA at baseline.
“It is exciting to confirm the relationship between elamipretide-mediated improvements in visual function and mitochondrial health in patients suffering from progressive vision loss due to GA,” said CEO Reenie McCarthy in a news release. “These data support our confidence in our ReCLAIM-2 trial design, which focuses on the earlier stages of GA before irreversible mitochondrial and RPE damage is thought to have occurred. We are encouraged to learn that intervening at this stage of the disease may not only slow disease progression, but also restore visual function and visual quality of life to patients suffering from this life-limiting disease.”
Whites Overrepresented in RVO Clinical Trials
■ Researchers led by Aleksandra Rachitskaya, MD, of the Cole Eye Institute at Cleveland Clinic, set out to determine if the ethnic makeup of 8 retinal vein occlusion (RVO) clinical trials reflected the US population as a whole, based on the 2019 census. The researchers conducted a cross-sectional study of the racial demographics of 8 randomized, controlled trials (RCTs) for RVO and compared them to the 2019 United States census data. The number and percentage of White, Black, Hispanic, Asian, American Indian/Alaska Native, Native Hawaiian/Pacific Islander participants was recorded. Overrepresentation or underrepresentation of each race in every RCT was denoted.
Of the 8 RVO RCTs, the White patient cohort was overrepresented in 5. The difference was not statistically significant in 3. Of note, 1 study described the study participants only as White and non-White. The Black patient cohort was underrepresented in 5, and not statistically different in 2. The Hispanic patient cohort was underrepresented in 6 and not statistically different in 1. The Asian patient cohort was overrepresented in 2 RCT, underrepresented in 1, and not statistically different in 4. The American Indian/Alaska Native and Hawaiian/Pacific Islander patient cohort was underrepresented in 6 RCT and not statistically different in 1.
The researchers, who presented their findings at Virtual ARVO, concluded that more efforts should be made to recruit underrepresented minorities to improve trial external validity and better serve these subpopulations.
Study Evaluates Risk for Retinal Detachment
■ Researchers led by Ahmed Abdelhady, MD, of Lehigh Valley Health Network in Allentown, Pennsylvania, set out to describe the demographics, comorbidities, and socioeconomic factors associated with retinal detachment (RD), which has a modest incidence with a lifetime risk of 3% by age 85 and is considered a true ophthalmic emergency. Left untreated, RD frequently leads to blindness in the affected eye. This is unfortunate and sometimes inevitable, as patients often present to their general practitioner after their central vision has been compromised. Studies have demonstrated that RD is associated with events such as myopia, cataract surgery, and trauma.
The researchers used the Healthcare Cost and Utilization Project, National Inpatient Sample database, to identify patients with a discharge diagnosis of RD between 2012 and 2016. The Elixhauser Comorbidity Index was used to identify comorbid conditions and comorbidity burden. Demographic, geographic, and socioeconomic factors as well as incidence of blindness were evaluated.
A total of 6,985 patients with RD were identified. The mean age was 59, 56% were male, and 60% were of White race. Most patients (73%) were discharged from urban teaching hospitals and 33% were from the southern United States. Thirty percent of RD patients had an annual income lower than $42,000, and 52% had Medicare insurance. The most frequent comorbidities were hypertension (59%), diabetes mellitus (36%), anemia (24%), and renal disease (23%). Blindness was present in 6.5% of RD patients.
The researchers, who presented their findings at the virtual 2021 Association for Research in Vision and Ophthalmology meeting, found that RD patients present most often to urban teaching hospitals with common chronic health conditions. Clinicians should understand the influence that these comorbid conditions and demographic and socioeconomic factors have in the emergent treatment of RD to avoid adverse outcomes.
Combination Therapy for DME Effective
■ A study conducted by Ashkan Abbey, MD, of Texas Retina Associates set out to determine the potential safety, efficacy, and durability advantages of Ozurdex (Allergan) in conjunction with intravitreal aflibercept (Eylea; Regeneron) compared with aflibercept monotherapy for treatment of DME. Dr. Abbey’s premise was that the combination could result in reduced time to resolution of DME on OCT and fewer total injections.
In a prospective, randomized, open-label, multicenter collaborative study, patients were randomized 1:1 to Ozurdex and aflibercept (study group) or aflibercept monotherapy (control group), and assessed over 48 weeks. Treatment-naive eyes with DME (or eyes previously treated with anti-VEGF after a 3-month washout period) with best-corrected visual acuity of 25 to 73 letters and central subfield retinal thickness (CST) of more than 300 μm were included.
Patients that completed 24 weeks of the trial were included in this preliminary analysis. The study group (n=13) received Ozurdex and aflibercept at baseline. They then received monthly injections of AF, and treatment with Ozurdex every 3 months PRN. Patients in the control group (n=10) received aflibercept at baseline. These patients subsequently received monthly injections of aflibercept or PRN. At each visit, fluid measurements and changes in best-corrected visual acuity were assessed to determine whether to treat.
At week 24, the difference in mean best-corrected visual acuity (study group vs control group) was not statistically significant. However, the difference in mean CST was -37.88±73.87. Eyes in the study group received fewer treatments (mean 4.23 vs 5.4).
Dr. Abbey, who presented his findings at the virtual 2021 Association for Research in Vision and Ophthalmology meeting, concluded that Ozurdex administered in conjunction with intravitreal aflibercept for treatment of DME was safe and provides similar visual benefit at 24 weeks’ follow-up compared with aflibercept monotherapy and shows anatomic benefit with potential to reduce treatment burden.
Postmarketing Study of Beovu Has Mixed Results
■ A postmarketing study of brolucizumab (Beovu; Novartis) that included 544 individuals with wet AMD and conducted by Scott Walter, MD, MSc, demonstrated that Beovu is a potent drying agent but does not improve BCVA when switched from another anti-VEGF. In this study, the researchers evaluated the efficacy and safety of brolucizumab in their own practice during the initial 7.5 months following its commercial release. A consecutive case series of 544 patients with wet AMD were treated with intravitreal injections of brolucizumab. The study population included both treatment-naive patients and others switched from an alternate anti-VEGF therapy.
Visual acuity (VA) was compared before initiation of brolucizumab therapy and at the end of the study period. Anatomic outcomes were assessed with spectral-domain optical coherence tomography and included central subfield thickness (CST), macular volume (MV), presence of intraretinal fluid (IRF), presence of subretinal fluid (SRF), and presence of serous pigment epithelial detachment (sPED) on foveal line scans. The cumulative incidence of drug-related adverse effects during the study period was also reported.
The 544 patients received a total of 1,438 brolucizumab intravitreal injections during the study period. A statistically significant improvement in VA was observed in treatment-naïve eyes (+3.7 letters) but not in eyes switched from another anti-VEGF agent (-0.5 letters). For both groups of patients, there were significant reductions in CST (-47.8 µm), MV (-0.40 mm3), presence of IRF (-18.5%), presence of SRF (-28.6%), and presence of sPED (-7.3%; all P<.001). Drug-related adverse events occurred in 26 patients (4.8%), including intraocular inflammation (25), retinal vasculitis (3), retinal artery occlusion (1), and urticarial rash (1) after an average of 2.0 intravitreal injections.
The researchers, who presented their findings at the virtual 2021 Association for Research in Vision and Ophthalmology meeting, found brolucizumab to be a potent drying agent in both treatment-naive and previously anti-VEGF treated eyes. However, no VA improvement was observed when eyes were switched to brolucizumab from an alternate anti-VEGF agent. The incidence of brolucizumab-related inflammatory events observed in this postmarketing surveillance study corroborates a recent reanalysis of clinical trial data by an independent safety review committee.
Clearside Resubmits Xipere New Drug Application
■ Clearside Biomedical announced the resubmission of its New Drug Application to the US Food and Drug Administration (FDA) for Xipere (triamcinolone acetonide suprachoroidal injectable suspension) for the treatment of macular edema associated with uveitis. Clearside’s resubmission is a full and complete response to all of the items identified in the Complete Response Letter received from the FDA on October 18, 2019. Clearside believes this application will be considered a Class 2 resubmission, with a targeted 6-month review timeline under the Prescription Drug User Fee Act.
Suprachoroidal injection enables the rapid dispersion of medicine to the back of the eye, offering the potential for the medicine to act longer and minimize harm to the surrounding healthy parts of the eye. Bausch + Lomb is the exclusive licensee for Xipere in the United States and Canada. RP
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