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SUBSPECIALTY NEWS: Promising new data presented at the American Academy of Ophthalmology meeting.

Faricimab Data Confirm 16-Week Efficacy at 1 Year

A 6-mg dose shows no new safety concerns.

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■ New data presented at the recent AAO meeting confirms earlier projections that a 6-mg dose of Genentech’s bispecific anti-VEGF/anti-Ang2 faricimab (formerly RG7716) delivered every 16 weeks can on average provide as good or better vision gains than Lucentis (ranibizumab; Genentech) administered every 4 weeks. The 1-year data were from Genentech’s phase 2 STAIRWAY study made up of 76 treatment-naïve patients with wet AMD.

Given the new STAIRWAY data, faricimab becomes the first investigational treatment for wet AMD to achieve confirmed 16-week dosing for the majority of patients in a clinical trial. The potential of more durable every 16-week dosing is considered important because other investigational drugs for wet AMD have recently shown efficacy at 12-week retreatment intervals, while Eylea (aflibercept; Regeneron) and Lucentis have been approved for 12-week dosing based on physician assessment.

“The STAIRWAY data show the potential of faricimab to allow fewer injections while achieving and sustaining the same visual gains seen with a current standard of care. Based on these data, we will be initiating a global phase 3 program for faricimab in wet AMD,” said Sandra Horning, MD, chief medical officer and head of Global Product Development in a news release.

Patients in the STAIRWAY study were treated with either faricimab 6 mg every 12 weeks or every 16 weeks, or ranibizumab 0.5 mg every 4 weeks. After 52 weeks, the average visual acuity gains for each treatment group were +11.4 letters with faricimab 16-week dosing, +10.1 letters with faricimab 12-week dosing, and +9.6 letters with ranibizumab 4-week dosing.

Among the treatment groups, the proportion of patients gaining more than 15 letters, the proportion of patients avoiding a loss of more than 15 letters, and reductions in central retina thickness were comparable. The rates of ocular and systemic adverse events observed with faricimab were similar to the rates observed with ranibizumab. No new safety signals were observed. The overall safety profile of faricimab appears consistent with the safety profile reported in patients with wet AMD who receive intravitreal anti-VEGF therapies.

Arshad Khanani, MD, MA, of Sierra Eye Associates in Reno, Nevada, who presented the STAIRWAY data, said the drug’s unique bispecific nature is a key advantage of the drug.

“The Ang2 inhibition offered by faricimab contributes to vascular stabilization and decreases microvascular inflammation,” he said.

Ocular Melanoma Therapy Promising at 1 Year

Aura Biosciences cites stable disease in trial.

■ Aura Biosciences, a developer of novel targeted therapies in ocular oncology, has said updated clinical data from its phase 1b/2 clinical trial evaluating the safety and efficacy of light-activated AU-011, the company’s lead product candidate for the primary treatment of choroidal melanoma, demonstrated encouraging results at the 1-year mark. This open-label, multicenter trial is designed to investigate single and multiple ascending doses of light-activated AU-011 in approximately 36 adult subjects with clinically diagnosed primary choroidal melanoma.

The data show that multiple administrations of AU-011 are well tolerated with no related serious adverse events, severe adverse events, or dose-limiting toxicities observed. Drug-related adverse events were all expected and included anterior-chamber inflammation, posterior-chamber inflammation, and increase in IOP, but all were manageable with standard-of-care treatments and resolved without clinical sequelae.

Treatment with AU-011 achieved preservation of BCVA with a mean change of -1.06 letters at 6 months and a mean change of -0.75 letters at 12 months. BCVA was preserved even in high-risk patients with tumors close to the fovea or the optic disk, a factor that typically correlates with a higher risk of irreversible severe vision loss following radioactive treatments. All patients achieved stable disease at the prespecified preliminary efficacy endpoint at 3 months. Biological activity has been confirmed with long-term tumor control in those patients with documented growth before treatment, reduction in tumor thickness, and localized inflammation around the tumor. An expansion cohort of the study is currently under way. The company plans to initiate a pivotal phase 3 clinical program following the phase 1b/2 study.

Eylea NPDR Trial Has Positive Results at 1 Year

New data will support approval application.

■ Regeneron’s phase 3, 402-patient PANORAMA trial evaluating Eylea (aflibercept) in patients with moderately severe and severe nonproliferative diabetic retinopathy (NPDR) met its 52-week primary endpoint and key secondary endpoints, the company announced. The new data will be added to previously released 24-week findings and used to buttress Regeneron’s application for approval of Eylea for NPDR, currently under review by the FDA.

On the primary endpoint at 1 year, 80% and 65% of patients receiving Eylea on an every 8- and every 16-week interval (after an initial monthly dosing period), respectively, experienced a 2-step or greater improvement from baseline on the Diabetic Retinopathy Severity Scale, compared to 15% of patients receiving sham injection. The 2 key secondary endpoints, which were reported for the first time and indicate the need for early intervention, achieved statistical significance based on the prespecified hierarchical analysis. Treatment with Eylea reduced vision-threatening complications (VTCs) by 82% to 85% and the development of center-involved diabetic macular edema (CI-DME) by 68% to 74% compared with sham injection.

The development of VTCs (proliferative diabetic retinopathy and anterior segment neovascularization) was 3% for the Eylea every 8-week group, 4% for the Eylea every 16-week group, and 20% for the sham injection group. CI-DME occurred in 8% of the Eylea every 8-week group, 7% of the Eylea every 16-week group, and 26% of the sham injection group. These events collectively occurred in 11% and 10% of patients receiving Eylea every 8 weeks or every 16 weeks, respectively, compared to 41% of patients receiving sham injection.

“In this trial of patients with diabetic eye disease and normal vision, it is notable that without treatment more than one third of patients developed a vision-threatening complication or diabetic macular edema within 1 year,” said George D. Yancopoulos, MD, PhD, president and chief scientific Officer of Regeneron, in a news release. “Eylea was able to reduce these complications by 68% to 85% even with every 4-month dosing, and moreover was able to reverse the anatomic severity of the disease. These results point to the potential value of earlier intervention in diabetic retinopathy.”

The average number of injections in the first year was 8.6 (of 9 planned) for the Eylea every-8-week group and 5.5 (of 6 planned) for the Eylea every-16-week group. Adverse events were consistent with the known profile of Eylea.

Brolucizumab Shows Continued Efficacy at Year 2

Additional data announced from phase 3 trials.

■ Novartis announced additional brolucizumab phase 3 results from year 2 (96 weeks) that reaffirmed its positive year 1 (48 weeks) findings from the large-scale HAWK and HARRIER trials. Brolucizumab met its primary endpoint of noninferiority versus aflibercept (Eylea; Regeneron) in BCVA and exhibited superiority in key retinal outcomes at year 1 while maintaining robust visual gains in year 2 in patients with wet AMD. These new 96-week data, based on prespecified secondary endpoints, were presented at the AAO 2018 annual meeting as a follow-up to year 1 data.

Relative to aflibercept, fewer brolucizumab 6 mg patients with wet AMD had intraretinal fluid and/or subretinal fluid at week 96 (24% for brolucizumab 6 mg vs 37% for aflibercept in HAWK and 24% vs 39% in HARRIER). Of the patients on brolucizumab 6 mg who successfully completed year 1 on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year 2. No new, previously unreported types of safety events were identified at week 96, and brolucizumab continued to be comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies.

According to Novartis, brolucizumab (RTH258) is a humanized single-chain antibody fragment and the most clinically advanced, humanized single-chain antibody fragment to reach this stage of development. The company says single-chain antibody fragments have characteristics such as small size, enhanced tissue penetration, rapid clearance from systemic circulation, and drug delivery characteristics. The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms.

Chinese Anti-VEGF Shows Good Durability

Conbercept may be a candidate for US approval.

■ Recently published data from the 114-patient, phase 3 PHOENIX trial in wet AMD shows that the anti-VEGF conbercept (Chengdu Kanghong Biotech), a recombinant fusion protein, provided a mean gain of almost 10 letters at 12 months with 12-week dosing. The data were published in the American Journal of Ophthalmology.

The conbercept group received intravitreal injections of conbercept (0.5 mg) once monthly for the first 3 months, then once quarterly until month 12. A sham group received first 3 monthly sham injections and then 3 monthly injections of conbercept (0.5 mg) followed by quarterly administrations until month 12. The primary endpoint was mean change from baseline in BCVA at month 3, which was +9.20 letters for the conbercept cohort and +2.02 letters for the sham group. The conbercept group also achieved a mean 79.2 micron reduction in central retinal thickness at 3 months.

At 12 months, the mean changes from baseline in BCVA letter score were +9.98 letters in the conbercept group and +8.81 letters in the sham group. The most common ocular adverse events were associated with intravitreal injections, such as conjunctival hemorrhage and increased IOP.

There has been much speculation in the retina community as to whether Chendu Kanghong plans to eventually file for US approval of conbercept, already approved for wet AMD in China. That will largely depend upon the results of the ongoing, 1,140-patient phase 3 PANDA study for treatment-naïve patients, which is scheduled to be completed in 2020. The PANDA study has 2 conbercept arms (0.5 mg and 1.0 mg) plus an Eylea (aflibercept; Regeneron) 2.0 mg arm as a comparator. In 2020, conbercept may face a crowded field of other durable potential competitors.

Orion Cortical Prosthesis System Now in Home Testing

Some users can sort laundry and identify curbs.

■ Second Sight Medical recently reported that 4 of 5 patients in its feasibility study of the company’s next-generation Orion Cortical Prosthesis System are now using the device at home and achieving some level of functional vision. The Orion attaches directly to the brain’s visual cortex, thus making it suitable to address almost any cause of blindness. Some of the patients in the feasibility study have shown that they are able to identify curbs, locate signs, locate a person in front of them, and/or distinguish light from dark laundry.

Second Sight President and CEO Will McGuire said the company is in the process of gathering data for the FDA on the device’s ability to provide functional vision for various tasks and improve the user’s quality of life. The data will be used as the basis for designing a 30-patient (or more) pivotal trial of the Orion.

In related news, the Centers for Medicare & Medicaid Services has finalized its Medicare hospital outpatient payment rate of $152,500 for the company’s first-generation Argus II Retinal Prosthesis System and the associated surgical implantation procedure for calendar year 2019. This is a significant increase from the $122,500 CMS allotted for the Argus II in 2018.

“We are delighted to have received CMS’ final 2019 outpatient payment rate, which provides Medicare patients continued access to our life changing technology,” said McGuire. “We are also happy to see the change in methodology that considers multiple years of historic data when setting a rate for a low volume device such as Argus. We believe this change will temper future year-to-year fluctuations in the reimbursement rate.”

In recent months, Second Sight has been primarily funded by company chairman Gregg Williams, but McGuire said Second Sight is now evaluating possible long-term financing options.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Brimonidine Implant for GA to Advance to Phase 3

■ Allergan announced plans to conduct a phase 3 clinical trial for its brimonidine sustained-release biodegradable implant for the treatment of geographic atrophy after the therapy was deemed effective in reducing lesion progression at 24 months and 30 months. The 303-patient phase 2b BEACON study was terminated after 2 years because it demonstrated effectiveness, said Yehia Hashad, MD, vice president and Global Head Clinical Development Ophthalmology, Dermatology and Medical Aesthetics, Allergan.

At 24 months and 30 months, GA area growth was reduced by a statistically significant 10% and 12% in the treatment group, with greater reduction of progression in larger-size lesions. Brimonidine is known to have a neuroprotective effect. In the BEACON trial, 400 micrograms of brimonidine was injected every 3 months using a 25-gauge injector similar to the Ozurdex (Allergan) injector.

Dextenza Approved for Pain After Ocular Surgery

■ The FDA has approved Dextenza (dexamethasone ophthalmic insert) 0.4 mg for intracanalicular use for the treatment of ocular pain following ophthalmic surgery. Dextenza is the first FDA-approved intracanalicular insert delivering dexamethasone to treat postsurgical ocular pain for up to 30 days with a single administration, replacing a complex eye drop regimen. The approval was based on demonstrated efficacy in 2 randomized, vehicle-controlled, phase 3 studies in which a statistically significantly higher number of subjects was pain free at day 8 after cataract surgery compared to the vehicle control group, and safety in the 2 phase 3 studies as well as a third randomized, vehicle-controlled phase 2 study.

The company believes the delivery profile represents a differentiated and potentially transformational new product for patients and physicians.

Suprachoroidal Combo in RVO No Better Than Anti-VEGF Alone

■ Clearside Biomedical said the primary endpoint was not achieved in its 460-patient phase 3 SAPPHIRE trial investigating potential superiority of Xipere (formerly “suprachoroidal CLS-TA”) in combination with Eylea, compared to intravitreal Eylea monotherapy, for combating RVO in treatment-naïve patients. The primary endpoint was improvement in BCVA from baseline of at least 15 letters ETDRS scale at 8 weeks after initial treatment.

“Approximately 50% of patients in both arms showed at least a 15-letter improvement in vision; unfortunately, there was no additional benefit for patients receiving Xipere together with intravitreal Eylea,” said Daniel White, president and CEO of Clearside. “In light of these 8-week topline data, we plan to discontinue clinical development of combination therapy for RVO, which includes SAPPHIRE and its companion phase 3 clinical trial, TOPAZ.”

RegenxBio Plans Phase 2 for Gene-Derived Anti-VEGF

■ Following the report that all 6 patients in the higher-dose third cohort of its trial for RGX-314 gene-derived ranibizumab continued to have sustained expression of anti-VEGF at 6 months, RegenxBio said it would move the therapy into a phase 2 clinical trial for wet AMD. Three of the 6 patients needed no rescue injections of anti-VEGF at 6 months. The therapy’s goal is to employ a single subretinal injection of gene-derived anti-VEGF to create continuous therapy over the long term. If successful, the concept would greatly decrease the treatment burden of regular anti-VEGF injections.

12 Burning Questions in Medical Retina for 2019

  1. Having earned high marks for efficacy and durability in phase 3 trials, will brolucizumab (Novartis) be the next big anti-VEGF retinal drug?
  2. Will the bispecific anti-VEGF/anti-Ang2 faricimab (Genentech) continue to post stellar clinical data in phase 3 as it has in phase 2?
  3. Will the FDA require Allergan to conduct another clinical trial to attempt to resolve the concerning adverse event (inflammation) profile that was demonstrated in phase 3 trials?
  4. Will sustained-release implants prove to be an effective, patient-friendly delivery vehicle for anti-VEGF? What are the potential risks and in whom will retinal physicians use this method?
  5. Will the concept of gene-derived anti-VEGF produced directly in the eye (ie, therapies in development by RegenxBio and Adverum) prove to be a breakthrough?
  6. Considering that neuroprotectives and high-dose statins have shown early promise in treating dry AMD and geographic atrophy, will we see breakthroughs?
  7. Will artificial intelligence be found more capable of diagnosing retinal diseases than humans?
  8. Will investigator-sponsored clinical trials become more of a factor in answering “real-world” questions for retina specialists that company-sponsored trials do not always address?
  9. Will attempts continue to be initiated to repurpose drugs approved for other diseases as treatments for retinal disease? So far, only Avastin has been a success in this regard.
  10. Will new therapies that inhibit the plasma kallikrein enzyme prove effective in combating chronic DME not responsive to anti-VEGF?
  11. Will the Trump administration be successful in an initiative to slash reimbursement for costly anti-VEGF drugs?
  12. Will smaller companies such as Allegro, Aerpio, Clearside, and Opthea advance their promising retinal drugs through the approval process?

Xipere Resolves Haze in Uveitic Macular Edema

■ Clearside Biomedical has announced additional data from PEACHTREE, the company’s pivotal phase 3 trial of Xipere (formerly suprachoroidal CLS-TA) in patients with uveitic macular edema. In the PEACHTREE trial, at week 24, 40.9% of patients with baseline scores of 2+ vitreous haze, based on the Standardization of Uveitis Nomenclature (SUN) scale, experienced resolution in the Xipere arm, compared to 0% of patients in the control arm who underwent a sham procedure. Additionally, in the Xipere arm, 68% of patients with any baseline level of vitreous haze, 72% of patients with anterior chamber cell inflammation and 74% of patients with anterior chamber flare had their inflammation resolve, compared to 23%, 17%, and 20% for the sham arm. Resolution was defined as achieving a score of 0 on the applicable SUN scale, implying that no measurable inflammation was present.

Opthea Pan-VEGF Promising in Chronic DME

■ Opthea Limited has announced encouraging data from a 9-patient phase 1b “pan-VEGF” dose-escalation study for patients with chronic DME. The study evaluated 3 escalating dose levels of OPT-302 (0.3, 1.0, or 2.0 mg), a novel VEGF-C/D “trap” therapy, in combination with aflibercept (Eylea; Regeneron) administered once every 4 weeks for a total of 3 intravitreal injections in 9 patients with persistent central-involved DME despite suboptimal responses to standard of care anti-VEGF-A therapy.

Eyes with persistent DME sub-responsive to multiple prior anti-VEGF-A injections demonstrated visual and anatomic improvement at 12 weeks following conversion to OPT-302/Eylea combination treatment that inhibits VEGF A, C, and D. A dose-response relationship of increased gains in visual acuity was shown with ascending dose levels of OPT-302/Eylea combination treatment, which also produced reductions in retinal swelling.

The mean change at week 12 from baseline in BCVA across all OPT-302 combination therapy dose groups was a gain of 7.7 letters (baseline of 65 letters) with a corresponding mean reduction in central subfield thickness of 71 µm (baseline of 434 µm). A dose-response relationship of improved visual acuity at all time points from baseline to week 12 was demonstrated with ascending dose levels of combination treatment with BCVA gains of 3.0, 5.7, and 14.3 letters seen at 0.3 mg, 1.0 mg, and 2.0 mg of OPT-302, respectively. Opthea also announced that enrollment of its phase 2b trial of OPT-302 for wet AMD is complete.

Costly Drugs May Face Medicare Reimbursement Cuts

■ Costly anti-VEGF drugs for retinal disease are among the physician-administered medications being targeted for sharp price cuts under the Trump administration’s new plan to slash Medicare spending. The US government, through the Medicare Part B program, pays 80% more than several other countries pay for the same drugs, according to a US Health and Human Services (HHS) analysis. The federal agency wants to create an international price index for the drugs based on discounted amounts other countries pay for the same medications. Medicare would still pay a 26% premium over the average price paid internationally.

HHS Secretary Alex Azar said the administration would like to start a pilot program with a reduced-reimbursement formula in half the county. The Pharmaceutical Research and Manufacturers of America strongly opposes the federal government’s plan to change its Medicare Part B pricing policy, contending it would discourage innovation and curtail patient access to important drugs.

Switch to Lucentis PRN Maintains DR Improvements

■ Researchers led by Jennifer K. Sun, MD, MPH, of the Harvard Medical School analyzed the results of the 500-patient open-label extension of the RIDE/RISE clinical trials in diabetic retinopathy and found that the 279 patients who were switched from monthly Lucentis dosing to PRN at 36 months were largely able to maintain their improvements in DR severity at the 48-month mark. The research findings were published in a recent issue of Ophthalmology.

Adverum Begins Gene-Derived Anti-VEGF Trial

■ Adverum Biotechnologies said the first patient was dosed in the OPTIC phase 1 trial evaluating ADVM-022 for patients with wet AMD.

“We look forward to providing an interim update of this phase 1 by the first quarter of 2020,” said Leone Patterson, Adverum CEO.

Adverum’s gene therapy candidate, ADVM-022, utilizes a proprietary vector capsid (AAV.7m8) carrying an aflibercept coding sequence under the control of a proprietary expression cassette and is administered as a single intravitreal administration. The therapy is designed to provide potentially sustained therapeutic levels of aflibercept and to minimize the burden of frequent anti-VEGF injections.

Autoinjector for GCA Approved

■ The FDA has approved ACTPen, a single-dose prefilled autoinjector for Actemra (tocilizumab) as an additional formulation for adult patients with giant cell arteritis (GCA), a chronic and severe form of vasculitis that, if left untreated, can lead to blindness. Vision problems occur in approximately 30% of people with GCA, and about 15% experience permanent vision loss. RP